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MASSIMO FEDERICO

COLLABORATORE COORDINATO CONTINUATIVO
Dip. Medico, Chirurgico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico e di Medicina Rigenerativa - sede CdL Fisioterapia, Padiglione Spallanzani, Viale Umberto I n. 50, Reggio Emilia

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Pubblicazioni

2023 - The SALENTO prognostic model for limited-stage peripheral T-cell lymphoma from the International T-Cell Project Network [Articolo su rivista]
Hapgood, Greg; Civallero, Monica; Stepanishyna, Yana; Vose, Julie M; Cabrera, Maria Elena; Advani, Ranjana H; Pileri, Stefano A; Manni, Martina; Horwitz, Steven M; Foss, Francine M; Hitz, Felicitas; Radford, John; Dlouhy, Ivan; Chiattone, Carlos Sérgio; Kim, Won-Seog; Skrypets, Tetiana; Nagler, Arnon; Trotman, Judith; Luminari, Stefano; Federico, Massimo
abstract

: The natural history of limited-stage peripheral T-cell lymphomas (PTCLs) remains poorly defined. We investigated outcomes and prognostic variables in patients registered in the T-Cell Project (TCP)(NCT01142674) to develop a model to predict overall survival (OS) for the common nodal PTCL subtypes (PTCL-NOS, AITL, ALCL). The model was validated in an independent data set from Australian and Brazilian registries. 211 patients registered in the TCP between 2006-2018 were studied. The median age was 59 years (range 18-88) and median follow-up was 49 months. 127 patients (78%) received anthracycline-based regimens, 5 patients (3%) radiotherapy alone (RT), 24 patients (15%) chemotherapy+RT. 5-year OS and PFS were 47% and 37%, respectively. Age >60y, elevated LDH and low serum albumin were independent prognostic factors. The model identified three groups with low- (26%, score 0), intermediate- (41%, score 1), and high-risk (33%, score 2-3) with 5-yr OS of 78% [95% CI 29-127], 46% [95% CI 24-68], and 25% [95% CI 20-30], respectively (P<0·001) and 5-yr PFS of 66% [95% CI 33-99], 37% [95% CI 9-65], and 17% [95% CI 9-25], respectively (P<0·001). The model demonstrated greater discriminatory power than established prognostic indices and an analogous distribution and outcomes in the three groups in the validation cohort of 103 patients. The SALENTO Model (Limited Stage Peripheral T Cell Lymphoma Prognostic Model) is an objective, simple and robust prognostic tool. The high-risk group has poor outcomes, comparable to advanced stage disease, and should be considered for innovative first-line approaches.

2022 - End of induction positron emission tomography complete response (PET-CR) as a surrogate for progression-free survival in previously untreated follicular lymphoma [Articolo su rivista]
Dixon, J. G.; Dimier, N.; Nielsen, T.; Zheng, J.; Marcus, R.; Morschhauser, F.; Evens, A. M.; Federico, M.; Blum, K. A.; Shi, Q.
abstract

Progression-free survival (PFS) has been the regulatory primary end-point for recent phase III trials in first-line follicular lymphoma (FL), but requires prolonged follow-up. Complete response (CR) at 30 months after initiation of induction treatment was validated as surrogate end-point for PFS. Our objective was to further evaluate surrogacy of CR measured by [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at the end of induction (EoI). Individual patient data were analysed from 1505 patients from five randomized trials. Trial-level surrogacy examining the association between treatment effects on EoI-PET-CR and PFS was evaluated using linear regression ((Formula presented.)) and bivariate Copula ((Formula presented.)) models. Although EoI-PET-CR strongly predicted PFS at a prognostic level, the trial-level assessment did not show strong correlation ((Formula presented.), confidence interval [CI]: 0.20–0.88; (Formula presented.), CI: 0.0–0.82). The high uncertainty in estimation was possibly due to the small number of trials and the population of patients with available PET data. Maintenance therapy affecting PFS beyond induction treatment, but not EoI-PET-CR end-point, may have distorted the association between treatment effects. However, there will probably be a number of additional trials approaching completion with available PET response data. Refined evaluation of PET-CR based surrogate end-points is still warranted.

2022 - High-risk stage IIB Hodgkin lymphoma treated in the H10 and AHL2011 trials: TMTV is a useful risk factor to stratify patients at baseline [Articolo su rivista]
Rossi, Cédric; André, Marc; Dupuis, Jehan; Morschhauser, Franck; Joly, Bertrand; Lazarovici, Julien; Ghesquières, Hervé; Stamatoullas, Aspasia; Nicolas-Virelizier, Emmanuelle; Feugier, Pierre; Gac, Anne-Claire; Moatti, Hannah; Fornecker, Luc-Matthieu; Deau, Bénédicte; Joubert, Clémentine; Fortpied, Catherine; Raemaekers, John; Federico, Massimo; Kanoun, Salim; Meignan, Michel; Traverse-Glehen, Alexandra; Cottereau, Anne-Ségolène; Casasnovas, René-Olivier
abstract

: Stage IIB Hodgkin lymphoma (HL) patients, with a mediastinum-to-thorax (M/T) ratio of ≥0.33 or extranodal localization have a poor prognosis and are treated either as limited or advanced stage. We compared these two approaches in patients included in two randomized phase III trials enrolling previously untreated early (H10) or advanced stage HL (AHL2011). We included HL patients with Ann-Arbor stage IIB with M/T ≥0.33 or extranodal involvement enrolled in the H10 or AHL2011 trials with available PET at baseline and after two cycles of chemotherapy (PET2). Baseline total metabolic tumor volume (TMTV) was calculated using the 41% SUVmax method. PET2 response assessment used the Deauville score. 148 patients were eligible, including 83 enrolled in the AHL2011 trial and 65 in the H10 trial. The median TMTV value was 155.5 mL (8.3-782.9), 165.6 mL in AHL2011 and 147 mL in H10. PET2 positivity rates were 16.9% (n=14) and 9.2% (n=6) in AHL2011 and H10 patients, respectively. With a median follow-up of 4.1 years (95%CI 3.9-4.4), overall 4-year PFS was 88.0%, 87.0% in AHL2011 and 89.2% in H10. In univariate and mutivariate analyses, baseline TMTV and PET2 response influenced significantly PFS (HR=4.94, HR=3.49 respectively). Notably, among the 16 patients who relapsed, 13 (81%) had a baseline TMTV baseline ≥ 155 mL. Upfront ABVD plus radiation therapy or upfront escBEACOPP without radiotherapy provide similar patient's outcome in high-risk stage IIB HL. TMTV is useful to stratify these patients at baseline.

2022 - The EHA Research Roadmap: Malignant Lymphoid Diseases [Articolo su rivista]
Dreyling, Martin; André, Marc; Gökbuget, Nicola; Tilly, Hervé; Jerkeman, Mats; Gribben, John; Ferreri, Andrés; Morel, Pierre; Stilgenbauer, Stephan; Fox, Christopher; Maria Ribera, José; Zweegman, Sonja; Aurer, Igor; Bödör, Csaba; Burkhardt, Birgit; Buske, Christian; Dollores Caballero, Maria; Campo, Elias; Chapuy, Bjoern; Davies, Andrew; de Leval, Laurence; Doorduijn, Jeanette; Federico, Massimo; Gaulard, Philippe; Gay, Francesca; Ghia, Paolo; Grønbæk, Kirsten; Goldschmidt, Hartmut; Kersten, Marie-Jose; Kiesewetter, Barbara; Landman-Parker, Judith; Le Gouill, Steven; Lenz, Georg; Leppä, Sirpa; Lopez-Guillermo, Armando; Macintyre, Elizabeth; Mantega, Maria Victoria Mateos; Moreau, Philippe; Moreno, Carol; Nadel, Bertrand; Okosun, Jessica; Owen, Roger; Pospisilova, Sarka; Pott, Christiane; Robak, Tadeusz; Spina, Michelle; Stamatopoulos, Kostas; Stary, Jan; Tarte, Karin; Tedeschi, Allessandra; Thieblemont, Catherine; Trappe, Ralf Ulrich; Trümper, Lorenz H; Salles, Gilles
abstract

In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1 to 2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy.

2021 - ALK-negative anaplastic large cell lymphoma: Features and outcomes of 235 patients from the International T-Cell Project [Articolo su rivista]
Shustov, A.; Cabrera, M. E.; Civallero, M.; Bellei, M.; Ko, Y. H.; Manni, M.; Skrypets, T.; Horwitz, S. M.; de Souza, C. A.; Radford, J. A.; Bobillo, S.; Prates, M. V.; Ferreri, A. J. M.; Chiattone, C.; Spina, M.; Vose, J. M.; Chiappella, A.; Laszlo, D.; Marino, D.; Stelitano, C.; Federico, M.; Savage, K.; Connors, J.; Gascoyne, R.; Chhanabhai, M.; Wilson, W.; Jaffe, E. S.; Armitage, J. O.; Weisenburger, D. D.; Anderson, J.; Ullrich, F.; Bast, M.; Hochberg, E.; Harris, N.; Smogorzews ka, A.; Levine, A.; Nathwani, B. N.; Miller, T.; Rimsza, L.; Montserrat, E.; Lopez-Guillermo, A.; Campo, E.; Cuadros, M.; Ferreira, J. A.; Delgado, B. M.; Holte, H.; Delabie, J.; Rudiger, T.; Muller-Hermelink, K.; Reimer, P.; Adam, P.; Wilhelm, M.; Schmitz, N.; Nerl, C.; Lister, A.; Norton, A.; Maclennan, K. A.; Zinzani, P. L.; Pileri, S. A.; Bellai, M.; Luminari, S.; Coiffier, B.; Berger, F.; Tanin, I.; Wannakrairot, P.; Au, W. Y.; Liang, R.; Loong, F.; Rajan, S.; Sng, I.; Tobinai, K.; Matsuno, Y.; Morishima, Y.; Nakamura, S.; Seto, M.; Tanimoto, M.; Yoshino, T.; Suzumiya, J.; Ohshima, K.; Kim, W. -S.
abstract

Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK- ALCL) is an aggressive neoplasm of T-cell/null-cell lineage. The T-Cell Project is a global prospective cohort study that consecutively enrolled patients newly diagnosed with peripheral T-cell lymphoma, registered through a centralized computer database between September 2006 and February 2018. Of 1553 validated cases from 74 sites in 13 countries worldwide, 235 were reported as ALK- ALCL. The median age at diagnosis was 54 years (range, 18-89 years), with a male predominance (62%). Stage III to IV disease was identified in 71% of patients, bulky disease and bone marrow involvement were uncommon, and 66% of patients presented with a low (0-1) International Prognostic Index score. Of all treated patients, 85% received multiagent initial chemotherapy, and 8% were consolidated with autologous hematopoietic cell transplantation. The initial overall and complete response rates were 77% and 63%, respectively. After a median follow-up of 52 months (95% confidence interval [CI], 41-63), the median progression-free survival (PFS) and overall survival (OS) were 41 months (95% CI, 17-62) and 55 months (95% CI, 36-75), respectively. The 3- and 5-year PFS rates were 52% and 43%, and the 3- and 5-year OS rates were 60% and 49%. Treatments containing both anthracycline and etoposide were associated with superior OS (P 5.05) but not PFS (P 5.18). In this large prospective cohort study, outcomes comparable to those previously reported in the retrospective International Peripheral T-Cell Lymphoma Project were observed. The study underscores the need for introducing novel platforms for ALK- ALCL and establishes a benchmark for future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT01142674.

2021 - BRCA mutation rate and characteristics of prostate tumor in breast and ovarian cancer families: analysis of 6,591 Italian pedigrees [Articolo su rivista]
Cortesi, L.; Domati, F.; Guida, A.; Marchi, I.; Toss, A.; Barbieri, E.; Marcheselli, L.; Venturelli, M.; Piana, S.; Cirilli, C.; Federico, M.
abstract

Objective: As prostate cancer (PrC) shows a BRCA mutation rate as high as 30%, it becomes crucial to find the optimal selection criteria for genetic testing. The primary objective of this study was to evaluate the BRCA mutation rate in families with PrC associated with breast and/or ovarian cancers; secondary aims were to compare the characteristics of families and BRCA-related PrC outcome among BRCA1 and BRCA2 carriers. Methods: Following the Modena criteria for the BRCA test, we evaluated the mutation rate in families with breast and/or ovarian cancer with a Gleason score ≥7 PrCs, by testing breast or ovarian cases and inferring the mutation in the prostate cases. The characteristics of families and BRCA-related PrC outcomes were measured using the chi-square (χ2) test and Kaplan-Meier methods, respectively. Results: Among 6,591 families, 580 (8.8%) with a Gleason score ≥ 7 PrCs were identified, of which 332 (57.2%) met the Modena selection criteria for BRCA testing. Overall, 215 breast or ovarian cancer probands (64.8%) were tested, of which 41 resulted positive for BRCA and one for CHEK2 genes (19.5%). No statistically significant differences were found in BRCA-related PrC prognosis and in the characteristics of families among BRCA1, BRCA2 and non-tested patients. Ten of 23 (44%) mutations in the BRCA2 gene fell in the prostate cancer cluster region (PCCR) at the 3′ terminal of the 7914 codon. Conclusions: It appears the Modena criteria are very useful for BRCA testing selection in families with breast and/or ovarian cancer and PrC. A trend toward a worse prognosis has been found in BRCA2 carriers.

2021 - Diagnosis, prevention and treatment of central nervous system involvement in peripheral t-cell lymphomas [Articolo su rivista]
Zing, N.; Fischer, T.; Federico, M.; Chiattone, C.; Ferreri, A. J. M.
abstract

Non-Hodgkin lymphomas with T-cell immunophenotype encompass a heterogeneous group of infrequent neoplasms that follow variable clinical courses but prevalently include aggressive behavior and high mortality rates. The involvement of the central nervous system (CNS) is an uncommon event in T-cell lymphomas, with wide variability among the different disease entities. CNS can be affected either at initial diagnosis or at recurrence, and both forms are considered “secondary CNS T-cell lymphoma”. Given the low incidence of secondary CNS T-cell lymphoma, related literature is sparse, contradictory, and primarily constituted by small case series and single case reports. However, reported studies uniformly suggest high mortality rates related to this event. Therefore, to improve our ability to identify high-risk patients and offer them successful CNS prophylaxis or timely and effective treatment once the event has occurred may prevent CNS-related T-cell lymphomas deaths. For example, some entities like aggressive adult T-cell leukemia/lymphoma, extranodal natural killer/T-cell lymphoma, and other peripheral T-cell lymphomas with involvement of two or more extranodal organs are prone to CNS dissemination and should be considered for personalized CNS prophylaxis. The level of evidence suggesting an increased risk of CNS recurrence for other T-cell lymphomas and for other risk factors is lower. Published case series show that, following the example of aggressive B-cell lymphomas, patients with T-cell lymphomas and putative increased CNS risk receive different forms of prophylaxis, mostly methotrexate and cytarabine delivered by intrathecal and/or intravenous routes, with varied success. To date, achievements in the treatment of CNS involvement in patients with aggressive B-cell lymphoma were not replicated in secondary CNS T-cell lymphomas, and identification of effective therapies remains an urgent research target. This review is focused on clinical findings, diagnosis, treatment, and prognosis of patients with T-cell lymphoma experiencing CNS dissemination either at presentation or relapse. It aims to provide logical and, oftentimes, evidence-based answers to the most common questions on the most probable risk factors to CNS involvement in patients with T-cell lymphoma, the indications and strategies to prevent this life-threating event, and the management of patients with CNS disease.

2021 - EHA/ESMO Clinical Practice Guidelines for the Management of Malignant Lymphoma: Recommendations for the Second Phase of the COVID-19 Pandemic [Articolo su rivista]
Dreyling, M.; Aurer, I.; Federico, M.; Jerkeman, M.; Kersten, M. J.; Linton, K.; Mey, U.; Tilly, H.; Buske, C.
abstract

No abstract available

2021 - Long-term results of the MCL01 phase II trial of rituximab plus HyperCVAD alternating with high-dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma [Articolo su rivista]
Massaro, F.; Stepanishyna, Y.; Manni, M.; Luminari, S.; Galimberti, S.; Marcheselli, L.; Visco, C.; Tecchio, C.; Stelitano, C.; Angrilli, F.; Petrini, M.; Merli, F.; Federico, M.
abstract

Mantle cell lymphoma is a rare and incurable lymphoproliferative disorder. In the MCL01 trial, patients were treated with the R-HCVAD regimen [rituximab plus HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; R-CVAD) alternating with high-dose methotrexate and cytarabine (AM)] for four cycles followed by autologous stem cell transplantation (ASCT) for those who reached only a partial response. After a median follow-up of 10·5 years, we reported 10-year progression-free and overall survival rates of 35% and 61% respectively, with a 10-years cumulative incidence rate of second malignancies of 10·6%. Mature results of the MCL01 trial confirmed the efficacy of HyperCVAD-AM as a frontline regimen for younger patients (≤65 years).

2021 - Obesity in Postmenopausal Breast Cancer Patients: It Is Time to Improve Actions for a Healthier Lifestyle. The Results of a Comparison Between Two Italian Regions With Different “Presumed” Lifestyles [Articolo su rivista]
Cortesi, L.; Galli, G. R.; Domati, F.; Conte, L.; Manca, L.; Berio, M. A.; Toss, A.; Iannone, A.; Federico, M.
abstract

Background: Adult body fatness is a convincing risk factor for postmenopausal breast cancer. With the aim to compare the different breast cancer (BC) features in Northern and Southern Italy, we investigated the relationship between BMI and BC characteristic in two groups of patients referred in the Modena and Lecce breast units. Materials and Methods: A retrospective analysis of a continuous series of BC patients referred to the Città di Lecce Hospital and the Modena Cancer Center, from January 2019 to December 2020 was performed. We identified four groups of BMI at BC diagnosis: underweight, BMI <18.5 kg/m2; normal weight, BMI ≥ 18.5–24.9 kg/m2; overweight, BMI ≥ 25.0–29.9 kg/m2; obese, BMI ≥30.0 kg/m2. BC characteristics and clinical outcomes were analyzed by the Kolmogorov-Smirnov test and Mann-Whitney U test; categorical data were compared using Pearson’s chi-square test, and dicotomic data were compared by odds ratio. Results: Nine hundred seventy-seven BC patients were included in the analysis. Overall, 470 were from Modena and 507 from Lecce. No differences were observed in the mean age of BC patients of Modena (61,42) and Lecce (62,08). No statistical differences between the two populations were shown in terms of tumor characteristics and pathological stage. Conversely, a statistical difference of BMI between the BC patients coming from Modena and Lecce (25.87 and 27.81, respectively; p = 0.000001) was found. BC patients diagnosed in Lecce at age ≥70 years had higher median BMI compared with the ones from Modena (p = 0.000002). The increased BMI in this aged population was also associated to larger tumor size (p = 0.040). Conclusion: The rate of overweight and obesity was higher in BC women living in Southern Italy, despite the presumed nutrition according to the so-called Mediterranean type dietary pattern. Unexpectedly, an increased BMI rate and a relationship with larger tumor size were found in Southern BC patients aged ≥70 years. Our findings strongly support the need for promoting a healthier lifestyle model in Italy, with the aim of reducing the rate of the obesity and, consequently, the increased risk of BC.

2021 - Outcomes and prognostic factors in angioimmunoblastic T-cell lymphoma: final report from the international T-cell Project [Articolo su rivista]
Advani, R. H.; Skrypets, T.; Civallero, M.; Spinner, M. A.; Manni, M.; Kim, W. S.; Shustov, A. R.; Horwitz, S. M.; Hitz, F.; Cabrera, M. E.; Dlouhy, I.; Vassallo, J.; Pileri, S. A.; Inghirami, G.; Montoto, S.; Vitolo, U.; Radford, J.; Vose, J. M.; Federico, M.
abstract

Angioimmunoblastic T-cell lymphoma (AITL) is a unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features and poor prognosis. We performed a subset analysis of 282 patients with AITL enrolled between 2006 and 2018 in the international prospective T-cell Project (NCT01142674). The primary and secondary end points were 5-year overall survival (OS) and progression-free survival (PFS), respectively. We analyzed the prognostic impact of clinical covariates and progression of disease within 24 months (POD24) and developed a novel prognostic score. The median age was 64 years, and 90% of patients had advanced-stage disease. Eighty-one percent received anthracycline-based regimens, and 13% underwent consolidative autologous stem cell transplant (ASCT) in first complete remission (CR1). Five-year OS and PFS estimates were 44% and 32%, respectively, with improved outcomes for patients who underwent ASCT in CR1. In multivariate analysis, age ≥60 years, Eastern Cooperative Oncology Group performance status >2, elevated C-reactive protein, and elevated β2 microglobulin were associated with inferior outcomes. A novel prognostic score (AITL score) combining these factors defined low-, intermediate-, and high-risk subgroups with 5-year OS estimates of 63%, 54%, and 21%, respectively, with greater discriminant power than established prognostic indices. Finally, POD24 was a powerful prognostic factor with 5-year OS of 63% for patients without POD24 compared with only 6% for patients with POD24 (P < .0001). These data will require validation in a prospective cohort of homogeneously treated patients. Optimal treatment of AITL continues to be an unmet need, and novel therapeutic approaches are required.

2021 - Primary refractory follicular lymphoma: a poor outcome entity with high risk of transformation to aggressive B cell lymphoma [Articolo su rivista]
Alonso-Alvarez, S.; Manni, M.; Montoto, S.; Sarkozy, C.; Morschhauser, F.; Wondergem, M. J.; Guarini, A.; Magnano, L.; Alcoceba, M.; Chamuleau, M.; Galimberti, S.; Gomes da Silva, M.; Holte, H.; Zucca, E.; Lockmer, S.; Aurer, I.; Marcheselli, L.; Stepanishyna, Y.; Caballero Barrigon, M. D.; Salles, G.; Federico, M.
abstract

Background: Primary refractory (PREF) follicular lymphoma (FL) has a completely different clinical course from that of FL that responds to front-line treatments. In addition to having poor responses to salvage therapies, it seems that patients with PREF are at increased risk of histological transformation (HT). The Aristotle consortium presented the opportunity of investigating the risk of HT in a very large series of cases. Thus, we investigated the risk of HT in patients with PREF FL compared with that of responding patients or in stable disease and ultimately their outcome. Methods: Six thousand three hundred thirty-nine patients from the Aristotle database were included in the analysis. These patients had a histologically confirmed grade 1, 2 or 3a FL diagnosed between 1997 and 2013. The primary end-points were the cumulative incidence (CI) of HT at the first progression or relapse and the survival after transformation. Findings.: The 5-year CI of HT among patients with PREF was 34% (95% confidence interval (CI): 27–43), whilst it was 7.1% (95% CI: 6.0–8.5) in the group of patients with partial response (PR) or stable disease (SD) (PR + SD) and 3.5% (95% CI: 3.0–4.2) in the group of patients achieving complete response (CR). The 5-year survival after relapse (SAR) was 33% (95% CI: 28–39) for the PREF group, 57% (95% CI 54–61) in patients with PR, 51% (95% CI 43–58) in the SD group after first-line therapy and 63% (95% CI: 66–72) in patients with CR after initial treatment (p-value <0.001). The 5-year SAR for those patients with PREF who developed HT was 21% (95% CI: 12–31), clearly diminished when compared with those patients with PREF who did not experience HT (38% [95% CI: 31–44]) (p-value = 0.001). Interpretation.: Patients with PREF FL have a dismal outcome and an associated very high rate of HT that further worsens their poor prognosis.

2021 - Response-Adapted Postinduction Strategy in Patients With Advanced-Stage Follicular Lymphoma: The FOLL12 Study [Articolo su rivista]
Luminari, Stefano; Manni, Martina; Galimberti, Sara; Versari, Annibale; Tucci, Alessandra; Boccomini, Carola; Farina, Lucia; Olivieri, Jacopo; Marcheselli, Luigi; Guerra, Luca; Ferrero, Simone; Arcaini, Luca; Cavallo, Federica; Kovalchuk, Sofya; Skrypets, Tetiana; Del Giudice, Ilaria; Chauvie, Stephane; Patti, Caterina; Stelitano, Caterina; Ricci, Francesca; Pinto, Antonello; Margiotta Casaluci, Gloria; Zilioli, Vittorio R; Merli, Anna; Ladetto, Marco; Bolis, Silvia; Pavone, Vincenzo; Chiarenza, Annalisa; Arcari, Annalisa; Anastasia, Antonella; Dondi, Alessandra; Mannina, Donato; Federico, Massimo
abstract

Purpose: We compared 2 years of rituximab maintenance (RM) with a response-adapted postinduction approach in patients with follicular lymphoma who responded to induction immunochemotherapy. Methods: We randomly assigned treatment-naïve, advanced-stage, high-tumor burden follicular lymphoma patients to receive standard RM or a response-adapted postinduction approach on the basis of metabolic response and molecular assessment of minimal residual disease (MRD). The experimental arm used three types of postinduction therapies: for complete metabolic response (CMR) and MRD-negative patients, observation; for CMR and MRD-positive (end of induction or follow-up) patients, four doses of rituximab (one per week, maximum three courses) until MRD-negative; and for non-CMR patients, one dose of ibritumomab tiuxetan followed by standard RM. The study was designed as noninferiority trial with progression-free survival (PFS) as the primary end point. Results: Overall, 807 patients were randomly assigned. After a median follow-up of 53 months (range 1-92 months), patients in the standard arm had a significantly better PFS than those in the experimental arm (3-year PFS 86% v 72%; P < .001). The better PFS of the standard vs experimental arm was confirmed in all the study subgroups except non-CMR patients (n = 65; P = .274). The 3-year overall survival was 98% (95% CI, 96 to 99) and 97% (95% CI, 95 to 99) in the reference and experimental arms, respectively (P = .238). Conclusion: A metabolic and molecular response-adapted therapy as assessed in the FOLL12 study was associated with significantly inferior PFS compared with 2-year RM. The better efficacy of standard RM was confirmed in the subgroup analysis and particularly for patients achieving both CMR and MRD-negative.

2021 - Targeted locus amplification to detect molecular markers in mantle cell and follicular lymphoma [Articolo su rivista]
Genuardi, E.; Klous, P.; Mantoan, B.; Drandi, D.; Ferrante, M.; Cavallo, F.; Alessandria, B.; Dogliotti, I.; Grimaldi, D.; Ragaini, S.; Clerico, M.; Lo Schirico, M.; Saraci, E.; Yilmaz, M.; Zaccaria, G. M.; Cortelazzo, S.; Vitolo, U.; Luminari, S.; Federico, M.; Boccadoro, M.; van Min, M.; Splinter, E.; Ladetto, M.; Ferrero, S.
abstract

Minimal residual disease (MRD) monitoring by PCR methods is a strong and standardized predictor of clinical outcome in mantle cell lymphoma (MCL) and follicular lymphoma (FL). However, about 20% of MCL and 40% of FL patients lack a reliable molecular marker, being thus not eligible for MRD studies. Recently, targeted locus amplification (TLA), a next-generation sequencing (NGS) method based on the physical proximity of DNA sequences for target selection, identified novel gene rearrangements in leukemia. The aim of this study was to test TLA in MCL and FL diagnostic samples lacking a classical, PCR-detectable, t(11; 14) MTC (BCL1/IGH), or t(14; 18) major breakpoint region and minor cluster region (BCL2/IGH) rearrangements. Overall, TLA was performed on 20 MCL bone marrow (BM) or peripheral blood (PB) primary samples and on 20 FL BM, identifying a novel BCL1 or BCL2/IGH breakpoint in 16 MCL and 8 FL patients (80% and 40%, respectively). These new breakpoints (named BCL1-TLA and BCL2-TLA) were validated by ASO primers design and compared as MRD markers to classical IGH rearrangements in eight MCL: overall, MRD results by BCL1-TLA were superimposable (R Pearson = 0.76) to the standardized IGH-based approach. Moreover, MRD by BCL2-TLA reached good sensitivity levels also in FL and was predictive of a primary refractory case. In conclusion, this study offers the proof of principle that TLA is a promising and reliable NGS-based technology for the identification of novel molecular markers, suitable for further MRD analysis in previously not traceable MCL and FL patients.

2021 - The Value and relevance of T-cell lymphoma registries [Capitolo/Saggio]
Skrypets, Tetiana; Manni, Martina; Civallero, Monica; Kriachok, Iryna; Federico, Massimo
abstract

2020 - Advances in Treatment of Follicular Lymphoma [Articolo su rivista]
Luminari, S.; Trotman, J.; Federico, M.
abstract

Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early and advanced stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first-line therapy and the duration and quality of the response. At present, there is no consensus for treatment of patients with early or multiply-relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. While the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This chapter considers prognostic factors and the evolving treatment landscape of FL, including recent and emerging therapies, as well as remaining unmet needs.

2020 - Double Hit Lymphoma Diagnosis and Treatment in Europe-A Cross-Sectional Survey of Clinical Practice by the EHA Lymphoma Working Party (EHA LyG) [Articolo su rivista]
Aurer, Igor; Dreyling, Martin; Federico, Massimo; Tilly, Herve; Linton, Kim; Kimby, Eva; Chamuleau, Martine E D; Kersten, Marie Jose
abstract

No abstract available

2020 - Hodgkin Lymphoma: Comments on ESMO Clinical Practice Guidelines [Articolo su rivista]
Aurer, Igor; Zing, Natalia; Federico, Massimo
abstract

No abstract available

2020 - Improving the international prognostic index score using peripheral blood counts: Results of a large multicenter study involving 520 patients with diffuse large B cell lymphoma [Articolo su rivista]
Marcheselli, Raffaella; Bari, Alessia; Tadmor, Tamar; Marcheselli, Luigi; Cox, Maria Christina; Papotti, Robel; Ferrari, Angela; Baldini, Luca; Gobbi, Paolo; Levy, Ilana; Pugliese, Giuseppe; Federico, Massimo; Polliack, Aaron; Pozzi, Samantha; Sacchi, Stefano
abstract

The main purpose of this study was to assess whether it is possible to improve the prognostic impact of international prognostic index (IPI) score by combining it with peripheral blood counts. Thus, we evaluated the prognostic power of lymphocyte, neutrophil, and monocyte counts in 520 patients with diffuse large B cell lymphoma treated with R-CHOP, confirming that these parameters have a strong impact on overall survival (OS). Using revised IPI (R-IPI), 44% of patients were categorized as poor-risk and showed an OS at 5 years of 46%. As OS at 5 years of the 520 patients is 67%, it is clearly evident that R-IPI tends to overestimate the proportion of patients with poor prognosis. Accordingly, in an attempt to improve the discriminating power of R-IPI, we evaluated and compared three different scores by combining the neutrophil lymphocyte ratio (NLR) and absolute monocyte count (AMC) with the following values: (a) IPI score 3-5, (b) age > 60 years and performance status, (c) age >= 65 years and LDH > ULN. The three indexes studied, had a similar 5 years OS for the high-risk group (46%-52%), but the proportion of patients classified as poor-risk were 37%, 20%, and 32%, respectively, which are lower than 44% identified with R-IPI. Thus, while R-IPI overestimates the number of high-risk patients, after applying our models, it is possible to recognize patients who are truly at high-risk. Of the three scores, the most accurate appears to be that based on NLR, AMC, LDH > ULN and age >= 65 years, which identifies 32% of high-risk patients, correlating well with what is seen in clinical practice.

2020 - Incidence and outcomes of rare T cell lymphomas from the T Cell Project: hepatosplenic, enteropathy associated and peripheral gamma delta T cell lymphomas [Articolo su rivista]
Foss, Francine M; Horwitz, Steven M; Civallero, Monica; Bellei, Monica; Marcheselli, Luigi; Kim, Won Seog; Cabrera, Maria E; Dlouhy, Ivan; Nagler, Arnon; Advani, Ranjana H; Pesce, Emanuela A; Ko, Young-Hyeh; Montoto, Silvia; Chiattone, Carlos; Moskowitz, Alison; Spina, Michele; Cesaretti, Marina; Biasoli, Irene; Federico, Massimo
abstract

The T Cell Project was the largest prospective trial to explore the incidence, treatment patterns, and outcomes for T cell lymphomas. The rare subtypes of T cell lymphomas, including hepatosplenic T cell lymphoma (HSTCL), enteropathy associated T cell lymphoma (EATL), and peripheral gamma delta T cell lymphomas (PGDTCLs) are poorly represented in most studies and there is little data regarding treatment patterns. We report results from 115 patients with hepatosplenic (n = 31), enteropathy associated (n = 65), and PGDTCLs (n = 19). While anthracycline regimens were most commonly used as first line therapy, response rates ranged from 20%-40% and were suboptimal for all groups. Autologous stem cell transplantation was performed as a consolidation in first remission in a small number of patients (33% of HSTCL, 7% of EATL, and 12% of PGDTCL), and four patients with HSTCL underwent allogeneic stem cell transplantation in first remission. The progression free survival at 3 years ranged from 28%-40% for these rare subtypes, and the overall survival at 3 years was most favorable for PGDTCL (70%). These data highlight the need for novel treatment approaches for rare subtypes of T cell lymphomas and for their inclusion in clinical trials.

2020 - Lifestyle intervention on body weight and physical activity in patients with breast cancer can reduce the risk of death in obese women: The EMILI study [Articolo su rivista]
Cortesi, L.; Sebastiani, F.; Iannone, A.; Marcheselli, L.; Venturelli, M.; Piombino, C.; Toss, A.; Federico, M.
abstract

Background obesity and sedentary lifestyle have been shown to negatively affect survival in breast cancer (BC). The purpose of this study was to test the efficacy of a lifestyle intervention on body mass index (BMI) and physical activity (PA) levels among BC survivors in Modena, Italy, in order to show an outcome improvement in obese and overweight patients. Methods: This study is a single-arm experimental design, conducted between November 2009 and May 2016 on 430 women affected by BC. Weight, BMI, and PA were assessed at baseline, at 12 months, and at the end of the study. Survival curves were estimated among normal, overweight, and obese patients. Results: Mean BMI decreased from baseline to the end of the study was equal to 2.9% (p = 0.065) in overweight patients and 3.3% in obese patients (p = 0.048). Mean PA increase from baseline to the end of the study was equal to 125% (p < 0.001) in normal patients, 200% (p < 0.001) in overweight patients and 100% (p < 0.001) in obese patients. After 70 months of follow-up, the 5-year overall survival (OS) rate was 96%, 96%, and 93%, respectively in normal, obese, and overweight patients. Overweight patients had significantly worse OS than normal ones (HR = 3.69, 95%CI = 1.82–4.53 p = 0.027) whereas no statistically significant differences were seen between obese and normal patients (HR 2.45, 95%CI = 0.68–8.78, p = 0.169). Conclusions: A lifestyle intervention can lead to clinically meaningful weight loss and increase PA in patients with BC. These results could contribute to improving the OS in obese patients compared to overweight ones.

2020 - Long-term overall survival and toxicities of ABVD vs BEACOPP in advanced Hodgkin lymphoma: A pooled analysis of four randomized trials [Articolo su rivista]
Andre, M. P. E.; Carde, P.; Viviani, S.; Bellei, M.; Fortpied, C.; Hutchings, M.; Gianni, A. M.; Brice, P.; Casasnovas, O.; Gobbi, P. G.; Zinzani, P. L.; Dupuis, J.; Iannitto, E.; Rambaldi, A.; Briere, J.; Clement-Filliatre, L.; Heczko, M.; Valagussa, P.; Douxfils, J.; Depaus, J.; Federico, M.; Mounier, N.
abstract

Purpose: We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) over doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in a pooled analysis of four randomized trials. Patients and methods: Primary objective was to evaluate the OS impact of BEACOPP using individual patient data. Secondary objectives were progression-free survival (PFS), secondary cancers, and use of autologous stem cell transplantation (ASCT). Results: About 1227 patients were included. The 7-year OS was 84.3% (95% CI 80.8-87.2) for ABVD vs 87.7% (95% CI 84.5-90.2) for BEACOPP. Two follow-up periods were identified based on survival curves and hazard ratio (HR) over time. For the first 18 months, there was no difference. For the second period of ≥18 months, ABVD patients had a higher death risk (HRABVD vs BEACOPP = 1.59; 95% CI 1.09-2.33). A Cox model stratified by trial and evaluating the effect of treatment and International Prognostic Index (IPI) score as fixed effects showed that both were statistically significant (treatment, P =.0185; IPI score, P =.0107). The 7-year PFS was 71.1% (95% CI 67.1-74.6) for ABVD vs 81.1% (95% CI 77.5-84.2) for BEACOPP (P <.001). After ABVD, 25 secondary cancers (4.0%) were reported with no myelodysplasia (MDS)/acute myeloid leukemia (AML) compared to 36 (6.5%) after BEACOPP, which included 13 patients with MDS/AML. Following ABVD, 86 patients (13.8%) received ASCT vs 39 (6.4%) for BEACOPP. Conclusions: This analysis showed a slight improvement in OS for BEACOPP and confirmed a PFS benefit. Frontline use of BEACOPP instead of ABVD increased secondary leukemia incidence but halved the requirement for ASCT.

2020 - Outcomes for Relapsed and Refractory Peripheral T-Cell Lymphoma Patients after Front-Line Therapy from the COMPLETE Registry [Articolo su rivista]
Lansigan, F.; Horwitz, S. M.; Pinter-Brown, L. C.; Rosen, S. T.; Pro, B.; Hsi, E. D.; Federico, M.; Gisselbrecht, C.; Schwartz, M.; Bellm, L. A.; Acosta, M.; Shustov, A. R.; Advani, R. H.; Feldman, T.; Lechowicz, M. J.; Smith, S. M.; Tulpule, A.; Craig, M. D.; Greer, J. P.; Kahl, B. S.; Leach, J. W.; Morganstein, N.; Casulo, C.; Park, S. I.; Foss, F. M.
abstract

Background: Outcomes for patients with peripheral T-cell lymphoma (PTCL) who fail to achieve complete response (CR) or relapse after front-line therapy are poor with lack of prospective outcomes data. Objectives: COMPLETE is a prospective registry of 499 patients enrolled at academic and community sites in the United States detailing patient demographics, treatment and outcomes for patients with aggressive T cell lymphomas. We report results for patients with primary refractory and relapsed disease. Methods: Primary refractory disease was defined as an evaluable best response to initial treatment (induction ± maintenance or consolidation/transplant) other than CR, and included a partial response, progressive disease, or no response/stable disease. Relapsed disease was defined as an evaluable best response to initial treatment of CR, followed by disease progression at a later date, irrespective of time to progression. Patients were included in the analysis if initial treatment began within 30 days of enrollment and treatment duration was ≥4 days. Results: Of 420 evaluable patients, 97 met the definition for primary refractory and 58 with relapsed disease. In the second-line setting, relapsed patients received single-agent therapies more often than refractory patients (52 vs. 28%; p = 0.01) and were more likely to receive single-agent regimens (74 vs. 53%; p = 0.03). The objective response rate to second-line therapy was higher in relapsed patients (61 vs. 40%; p = 0.04) as was the proportion achieving a CR (41 vs. 14%; p = 0.002). Further, relapsed patients had longer overall survival (OS) compared to refractory patients, with a median OS of 29.1 versus 12.3 months. Conclusions: Despite the availability of newer active single agents, refractory patients were less likely to receive these therapies and continue to have inferior outcomes compared to those with relapsed disease. PTCL in the real world remains an unmet medical need, and improvements in front-line therapies are needed.

2020 - Outcomes of Patients with Transformed Mycosis Fungoides: Analysis from a Prospective Multicenter US Cohort Study [Articolo su rivista]
Lansigan, F.; Horwitz, S. M.; Pinter-Brown, L. C.; Carson, K. R.; Shustov, A. R.; Rosen, S. T.; Pro, B.; Hsi, E. D.; Federico, M.; Gisselbrecht, C.; Schwartz, M.; Bellm, L. A.; Acosta, M.; Foss, F. M.
abstract

Transformed mycosis fungoides (tMF) is a rare variant of MF with an aggressive course. In this study, we describe the patient characteristics, treatments, and outcomes of 17 patients with tMF in COMPLETE: a multicenter, prospective US cohort study of peripheral T-cell lymphoma. Responses were observed with single agents, but survival remains poor. Novel treatment approaches are urgently needed to improve outcomes.

2020 - Positron-emission tomography–based staging reduces the prognostic impact of early disease progression in patients with follicular lymphoma [Articolo su rivista]
Batlevi Connie, L.; Sha, Fushen; Alperovich, Anna; Ni, Ai; Smith, Katy; Ying, Zhitao; Gerecitano John, F; Hamlin Paul, A; Horwitz, ; Steve, M.; Joffe, Erel; Kumar, Anita; Matasar Matthew, J; Moskowitz Alison, J; Moskowitz Craig, H; Noy, Ariela; Owens, Colette; Palomba, Lia; Straus, David; von Keudell, Gottfried; Zelenetz Andrew, D; Seshan Venkatraman, E; Luminari, Stefano; Marcheselli, Luigi; Federico, Massimo; Younes, Anas
abstract

Background: Previous studies reported that early progression of disease (POD) after initial therapy predicted poor overall survival (OS) in patients with follicular lymphoma (FL). Here, we investigated whether pre-treatment imaging modality had an impact on prognostic significance of POD. Methods: In this retrospective study, we identified 1088 patients with grade I–IIIA FL; of whom, 238 patients with stage II–IV disease were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), and 346 patients were treated with rituximab-based chemotherapy. Patients (N = 484) from the FOLL05 study served as an independent validation cohort. We risk-stratified patients based on pre-treatment radiographic imaging (positron-emission tomography [PET] versus computed tomography [CT]) and early POD status using event-defining and landmark analyses. A competing risk analysis evaluated the association between early POD and histologic transformation. Results: In the discovery cohort, patients with POD within 24 months (PFS24) of initiating R-CHOP therapy had a 5-year OS of 57.6% for CT-staged patients compared with 70.6% for PET-staged patients. In the validation cohort, the 5-year OS for patients with early POD was 53.9% and 100% in CT- and PET-staged patients, respectively. The risk of histologic transformation in patients whose disease progressed within one year of initiating therapy was higher in CT-staged patients than in PET-staged patients (16.7% versus 6.3%, respectively), which was associated with a 9.7-fold higher risk of death. Conclusion: In FL, pre-treatment PET staging reduced the prognostic impact of early POD compared with CT staging. Patients with early POD and no histologic transformation have an extended OS with standard therapy.

2020 - Resources‐stratified guidelines for classical Hodgkin lymphoma [Articolo su rivista]
Relecom, A.; Federico, M.; Connors, J. M.; Coiffier, B.; Biasoli, I.; Moccia, A.; Salles, G.; Mckee, T.; Miralbell, R.; Borchmann, P.; Kuruvilla, J.; Johnson, P.; Cavalli, F.; Delavy, M.; Dietrich, P. -Y.; Flahault, A.
abstract

Hodgkin lymphoma is a haematological malignancy predominantly affecting young adults. Hodgkin lymphoma is a highly curable disease by current treatment standards. Latest treatment guidelines for Hodgkin lymphoma however imply access to diagnostic and treatment modalities that may not be available in settings with restricted healthcare resources. Considerable discrepancies in Hodgkin lymphoma patient survival exist, with poorer outcomes reported in resources‐constrained settings. Resources‐stratified guidelines for diagnosis, staging and treatment of Hodgkin lymphoma were derived in an effort to optimize patient outcome provided a given setting of available resources. These guidelines were derived based on the framework of the Breast Health Global Initiative stratifying resource levels in basic, core, advanced and maximal categories.

2020 - Survival outcomes for extranodal natural-killer T-cell lymphoma – Authors' reply [Abstract in Rivista]
Fox, C. P.; Civallero, M.; Federico, M.; Kim, W. S.
abstract

2020 - Survival outcomes of patients with extranodal natural-killer T-cell lymphoma: a prospective cohort study from the international T-cell Project [Articolo su rivista]
Fox, C. P.; Civallero, M.; Ko, Y. -H.; Manni, M.; Skrypets, T.; Pileri, S.; Kim, S. J.; Cabrera, M. E.; Shustov, A. R.; Chiattone, C. S.; Horwitz, S. M.; Dlouhy, I.; Spina, M.; Hitz, F.; Montoto, S.; Nagler, A.; Martinez, V.; De Souza, C. A.; Fernandez-Alvarez, R.; Ballova, V.; Gabus, R.; Inghirami, G.; Federico, M.; Kim, W. S.
abstract

Background: Extranodal natural killer (NK) T-cell lymphoma (ENKTL) is a unique clinicopathological entity, typically associated with poor survival outcomes. Most published data have come from east Asian study groups, with little information available from international cohorts. The effects of treatment advances on routine clinical practice across continental territories has not been clear. We aimed to improve understanding of the clinical characteristics and outcomes of patients with ENKTL. Methods: We did a substudy of patients with ENKTL from the T-cell Project, a global prospective cohort study. The T-cell Project registered consecutively diagnosed adults (>18 years) with newly diagnosed, untreated mature T-cell or NK lymphomas (WHO 2001 or 2008 classifications) from 74 centres in 13 countries (in Asia, Europe, North America, and South America). In total, 1695 patients with mature T-cell or NK lymphomas were enrolled between Oct 12, 2006 and Feb 28, 2018 in the T-cell Project. The first patient with ENKTL was enrolled on Feb 15, 2007, and the last on May 26, 2017. Data on baseline characteristics, first-line treatment, treatment response, and survival outcomes were recorded in a central database (locked March 30, 2019). The primary outcome was 5-year overall survival. The T-cell Project is registered on ClinicalTrials.gov, NCT01142674. Findings: 166 patients were diagnosed with ENKTL, comprising 11% of 1553 eligible registered cases and distributed across 40 participating centres in four continents. At a median follow-up of 44 months (IQR 20–61), overall survival at 5 years was 54% (95% CI 44–63) in patients with nasal disease (n=98) and 34% (27–46) in patients with extranasal disease (n=68). Interpretation: To our knowledge, this study presents the largest international cohort of patients with ENKTL. We describe a clinically significant improvement in the survival of patients with ENKTL treated in routine clinical practice over the past decade, likely to be attributable to the increasing use of treatment protocols specific for ENKTL. Funding: The Fondazione Cassa di Risparmio di Modena, the Associazione Angela Serra per la Ricerca sul Cancro, the Fondazione Italiana Linfomi, Allos Therapeutics, Spectrum Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro, and the National Cancer Institute at the National Institutes of Health.

2019 - Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial [Articolo su rivista]
Poeschel, V.; Held, G.; Ziepert, M.; Witzens-Harig, M.; Holte, H.; Thurner, L.; Borchmann, P.; Viardot, A.; Soekler, M.; Keller, U.; Schmidt, C.; Truemper, L.; Mahlberg, R.; Marks, R.; Hoeffkes, H. -G.; Metzner, B.; Dierlamm, J.; Frickhofen, N.; Haenel, M.; Neubauer, A.; Kneba, M.; Merli, F.; Tucci, A.; de Nully Brown, P.; Federico, M.; Lengfelder, E.; di Rocco, A.; Trappe, R.; Rosenwald, A.; Berdel, C.; Maisenhoelder, M.; Shpilberg, O.; Amam, J.; Christofyllakis, K.; Hartmann, F.; Murawski, N.; Stilgenbauer, S.; Nickelsen, M.; Wulf, G.; Glass, B.; Schmitz, N.; Altmann, B.; Loeffler, M.; Pfreundschuh, M.
abstract

Background: Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis. Methods: This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18–60 years, with stage I–II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0–1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1·4 mg/m2, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1–5. Rituximab was given at a dose of 375 mg/m2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of −5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421. Findings: Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42–100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94–99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy. Interpretation: In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population. Funding: Deutsche Krebshilfe.

2019 - Outcome of transformed follicular lymphoma worsens according to the timing of transformation and to the number of previous therapies. A retrospective multicenter study on behalf of Fondazione Italiana Linfomi (FIL) [Articolo su rivista]
Rusconi, Chiara; Anastasia, Antonella; Chiarenza, Annalisa; Marcheselli, Luigi; Cavallo, Federica; Rattotti, Sara; Botto, Barbara; Ferrari, Angela; Nassi, Luca; Pagani, Chiara; Meli, Erika; Arcaini, Luca; Federico, Massimo; Rossi, Giuseppe
abstract

Optimal treatment for transformed follicular lymphoma (tFL) is not fully defined. Clinical characteristics and treatments that impact on post-transformation outcome of 176 biopsy-proven tFL were analysed. Transformation occurred at initial diagnosis in 52% (Group 1) and after a FL diagnosis in 48% (Group 2). Five-year overall survival was 84% for Group 1 and 51% for Group 2 (P < 0·001). In Group 1, 5-year progression-free survival was superior after rituximab maintenance compared to observation only (94% vs. 53%, P = 0·024). In Group 2, an inverse trend was found between survival and both a higher number of pre-transformation treatment lines and a short time-to-transformation.

2019 - Single agents vs combination chemotherapy in relapsed and refractory peripheral T-cell lymphoma: Results from the comprehensive oncology measures for peripheral T-cell lymphoma treatment (COMPLETE) registry [Articolo su rivista]
Stuver, R. N.; Khan, N.; Schwartz, M.; Acosta, M.; Federico, M.; Gisselbrecht, C.; Horwitz, S. M.; Lansigan, F.; Pinter-Brown, L. C.; Pro, B.; Shustov, A. R.; Foss, F. M.; Jain, S.
abstract

Single agents have demonstrated activity in relapsed and refractory (R/R) peripheral T-cell lymphoma (PTCL). Their benefit relative to combination chemotherapy remains undefined. Patients with histologically confirmed PTCL were enrolled in the Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) registry. Eligibility criteria included those with R/R disease who had received one prior systemic therapy and were given either a single agent or combination chemotherapy as first retreatment. Treatment results for those with R/R disease who received single agents were compared to those who received combination chemotherapy. The primary endpoint was best response to retreatment. Fifty-seven patients met eligibility criteria. At first retreatment, 46% (26/57) received combination therapy and 54.5% (31/57) received single agents. At median follow up of 2 years, a trend was seen towards increased complete response rate for single agents versus combination therapy (41% vs 19%; P = .02). There was also increased median overall survival (38.9 vs 17.1 months; P = .02) and progression-free survival (11.2 vs 6.7 months; P = .02). More patients receiving single agents received hematopoietic stem-cell transplantation (25.8% vs 7.7%, P = .07). Adverse events of grade 3 or 4 occurred more frequently in those receiving combination therapy, although this was not statistically significant. The data confirm the unmet need for better treatment in R/R PTCL. Despite a small sample, the analysis shows greater response and survival in those treated with single agents as first retreatment in R/R setting, while maintaining the ability to achieve transplantation. Large, randomized trials are needed to identify the best strategy.

2019 - The outcome of peripheral T-cell lymphoma patients failing first-line therapy: A report from the prospective international T-cell project [Articolo su rivista]
Bellei, M.; Federico, M.
abstract

Abstract not available

2019 - The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study [Articolo su rivista]
Park, Steven I.; Horwitz, Steven M.; Foss, Francine M.; Pinter-Brown, Lauren C.; Carson, Kenneth R.; Rosen, Steven T.; Pro, Barbara; Hsi, Eric D.; Federico, Massimo; Gisselbrecht, Christian; Schwartz, Marc; Bellm, Lisa A.; Acosta, Mark; Advani, Ranjana H.; Feldman, Tatyana; Lechowicz, Mary Jo; Smith, Sonali M.; Lansigan, Frederick; Tulpule, Anil; Craig, Michael D.; Greer, John P.; Kahl, Brad S.; Leach, Joseph W.; Morganstein, Neil; Casulo, Carla; Shustov, Andrei R.
abstract

Background: The role of autologous stem cell transplantation (ASCT) in the first complete remission (CR1) of peripheral T-cell lymphomas (PTCLs) is not well defined. This study analyzed the impact of ASCT on the clinical outcomes of patients with newly diagnosed PTCL in CR1. Methods: Patients with newly diagnosed, histologically confirmed, aggressive PTCL were prospectively enrolled into the Comprehensive Oncology Measures for Peripheral T-Cell Lymphoma Treatment (COMPLETE) study, and those in CR1 were included in this analysis. Results: Two hundred thirteen patients with PTCL achieved CR1, and 119 patients with nodal PTCL, defined as anaplastic lymphoma kinase–negative anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or PTCL not otherwise specified, were identified. Eighty-three patients did not undergo ASCT, whereas 36 underwent consolidative ASCT in CR1. At the median follow-up of 2.8 years, the median overall survival was not reached for the entire cohort of patients who underwent ASCT, whereas it was 57.6 months for those not receiving ASCT (P =.06). ASCT was associated with superior survival for patients with advanced-stage disease or intermediate-to-high International Prognostic Index scores. ASCT significantly improved overall and progression-free survival for patients with AITL but not for patients with other PTCL subtypes. In a multivariable analysis, ASCT was independently associated with improved survival (hazard ratio, 0.37; 95% confidence interval, 0.15-0.89). Conclusions: This is the first large prospective cohort study directly comparing the survival outcomes of patients with nodal PTCL in CR1 with or without consolidative ASCT. ASCT may provide a benefit in specific clinical scenarios, but the broader applicability of this strategy should be determined in prospective, randomized trials. These results provide a platform for designing future studies of previously untreated PTCL.

2018 - Absolute monocyte count at diagnosis could improve the prognostic role of early FDG-PET in classical Hodgkin lymphoma patients [Articolo su rivista]
Bari, Alessia; Marcheselli, Luigi; Marcheselli, Raffaella; Pozzi, Samantha; Cox, Maria Christina; Baldessari, Cinzia; Ferri, Paola; Gobbi, Paolo; Baldini, Luca; Tadmor, Tamar; Musto, Pellegrino; Federico, Massimo; Sacchi, Stefano
abstract

Recently published international guidelines suggested that positron emission tomography (PET)-computed tomography (CT) could be utilized for response assessment using the Deauville criteria in fluorodeoxyglucose (FDG)-avid lym- phomas (Meignan et al, 2012). Interim PET (I-PET) scan- ning seems highly predictive of treatment failure in Hodgkin Lymphoma (HL) patients. We recently showed that the absolute monocyte count (AMC) has prognostic value in patients with classical HL (cHL) (Tadmor et al, 2015). Here, we show that the com- bined use of I-PET and AMC at diagnosis enables a more accurate projection of patient outcome in cHL. The present study is an ancillary branch of the analysis reported by Tadmor et al, (2015). Patients with histopatho- logical diagnosis of cHL previously enrolled in the Gruppo Italiano Studio Linfomi trials were eligible if data on all clini- cal and laboratory features and treatments, reported I-PET results, treatment response and follow-up were available. Response was defined according to the revised International Working Group guidelines (Cheson et al, 1999). An absolute lymphocyte count <06 9 10 9 /l and AMC > 075 9 10 9 /l were used as cut-off points. I-PET was performed after 2 cycles of treatment. A positive or negative I-PET was defined by the local investigators’ interpretation of the nuclear physi- cian’s scan report, which was based on a visual qualitative assessment. The principal end-point of the study was the impact of I-PET and AMC on progression-free survival (PFS); their impact on overall survival (OS) was the secondary end-point. Survival functions were estimated using the Kaplan–Meier method. Statistical comparisons between curves were per- formed with log-rank test, and the effect of the covariate was reported as hazard ratios (HR), from Cox regression. All patients had a diagnosis of cHL; 76% of cases had the nodular sclerosis (NS) subtype. Seventy-six patients (64%) were treated with classical ABVD (doxorubicin, bleomycin, vincristine, dacarbazine), and 23 (19%) and 19 (16%) with the more intensive BEACOPP (bleomycin, etoposide, doxoru- bicin, cyclophosphamide, vincristine, procarbazine, pred- nisone) and COPPEBVCAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, bleomycin) regimens (Federico et al, 2009), respectively. Of the entire cohort, 104 patients (88%) achieved complete remission. Twenty-six patients had a positive I-PET (22%) and 28 (24%) had AMC > 075 9 10 9 /l at diagnosis. The median follow-up of the entire cohort was 88 months (range 5–142 months). The estimated 5-year OS was 91% (95% confidence interval [CI]: 84–95%). The 5-year PFS was 80% (95% CI: 71–86%). Patients with positive I-PET showed a worse PFS compared to patients with negative I-PET (51% and 88%, respectively; HR 587 [95% CI: 256–135]). Patients with AMC > 075 9 10 9 /l at diagnosis had a worse PFS compared to patients with AMC ≤ 075 9 10 9 /l (58% and 87%, respectively; HR 373 [95% CI: 161–864]). Multi- ple Cox proportional hazards (PH) regression, adjusted for International Prognostic Score 3–7, confirmed the prognostic role of I-PET (HR 532 [95% CI: 230–123]; P < 0001) and AMC >075 9 10 9 /l (HR 319 [95% CI: 132–768]; P = 0010). Figure 1A, B shows the PFS for I-PET and AMC, and Table I shows the uni- and multivariate Cox PH regres- sion for PFS. The prognostic role of I-PET and AMC on OS was also confirmed. Given the strong predictive value of both I-PET and AMC, we stratified patients by positive or negative I-PET and AMC > 075 9 10 9 /l or ≤075 9 10 9 /l into 3 groups with different levels of risk. The low risk level (negative I- PET and AMC ≤ 075 9 10 9 /l; n = 73, 62%) had a 5-year PFS of 90% (95% CI: 80–96%)

2018 - Combination of rituximab and nonpegylated liposomal doxorubicin (R-NPLD) as front-line therapy for aggressive non-Hodgkin lymphoma (NHL) in patients 80 years of age or older: a single-center retrospective study [Articolo su rivista]
Ricciuti, Giuseppina; Finolezzi, Erica; Luciani, Stefania; Ranucci, Elena; Federico, Massimo; Di Nicola, Marta; Zecca, Isaia Antonio Luca; Angrilli, Francesco
abstract

The incidence of non-Hodgkin lymphoma in patients 80 years of age or older is 50 times higher than in 20- to 24-year-olds. Very elderly patients are often not treated with standard immunochemotherapy because of poor performance status, comorbidities, and toxicity concerns. We retrospectively analyzed data for 29 patients diagnosed with diffuse large B-cell lymphoma or grade 3B follicular lymphoma and treated with rituximab in combination with nonpegylated liposomal doxorubicin between January 2010 and August 2015. The median age was 84 years. The overall 3-year survival, cause-specific survival, and progression-free survival rates were 46%, 55%, and 44%, respectively. Among prognostic factors, only the achievement of complete remission strongly correlated with overall survival, cause-specific survival, and progression-free survival rates. Treatment caused very mild toxicity, without treatment-related hospitalization or toxic deaths.

2018 - Do We Need Maintenance with Anti-CD20 Antibody after First-Line Therapy for All Newly Diagnosed Follicular Lymphoma Patients? [Articolo su rivista]
Federico, Massimo; Tarantino, Vittoria; Filonenko, Kateryna; Dondi, Alessandra
abstract

2018 - Efficacy of bendamustine and rituximab in splenic marginal zone lymphoma: results from the phase II BRISMA/IELSG36 study [Articolo su rivista]
Iannitto, Emilio; Bellei, Monica; Amorim, Sandy; Ferreri, Andrés J. M.; Marcheselli, Luigi; Cesaretti, Marina; Haioun, Corinne; Mancuso, Salvatrice; Bouabdallah, Krimo; Gressin, Remy; Tripodo, Claudio; Traverse-Glehen, Alexandra; Baseggio, Lucile; Zupo, Simonetta; Stelitano, Caterina; Castagnari, Barbara; Patti, Caterina; Alvarez, Isabel; Liberati, Anna Marina; Merli, Michele; Gini, Guido; Cabras, Maria Giuseppina; Dupuis, Jean; Tessoulin, Benoit; Perrot, Aurore; Re, Francesca; Palombi, Francesca; Gulino, Alessandro; Zucca, Emanuele; Federico, Massimo; Thieblemont, Catherine
abstract

Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine-rituximab as first-line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open-label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two-stage method. The primary endpoint was complete response rate. Fifty-six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m2 days 1, 2) and rituximab (375 mg/m2 day 1) every 28 days for six cycles (B-R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression-free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81–98), 90% (95% CI 77–96) and 96% (95% CI 84–98), respectively. Toxicity was mostly haematological. Neutropenia grade ≥3 was recorded in 43% of patients; infections and febrile neutropenia in 5·4% and 3·6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off-study because of toxicity and one patient died from infection. In conclusion, B-R resulted in a very effective first-line regimen for SMZL. Based on the results achieved in the BRISMA trial, B-R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients.

2018 - Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study [Articolo su rivista]
Robak, T.; Jin, J.; Pylypenko, H.; Verhoef, G.; Siritanaratkul, N.; Drach, J.; Raderer, M.; Mayer, J.; Pereira, J.; Tumyan, G.; Okamoto, R.; Nakahara, S.; Hu, P.; Appiani, C.; Nemat, S.; Cavalli, F.; Van Hoof, A.; Sheliga, A.; Teixeira, A.; Tomita, A.; Rocafiguera, A. O.; Suvorov, A.; Kuzmin, A.; Khojasteh, A.; Mezlini, A.; Golenkov, A.; Bosly, A.; Belch, A.; Van De Velde, A.; Illes, A.; Mukhopadhyay, A.; Meddeb, B.; De Prijck, B.; Garichochea, B.; Undar, B.; Gabarron, C.; Cao, C.; Souza, C.; Farber, C.; Won Suh, C.; Burcoveanu, C. I.; Cebotaru, C. L.; Truica, C. -L.; Maruyama, D.; Belada, D.; Ben Yehuda, D.; Udovitsa, D.; Dolores, ; Morra, E.; Spath-Schwalbe, E.; Gonzalez-Barca, E.; Osmanov, E.; Capote, F. J.; Offner, F.; Cardenas, G.; Hess, G.; Manikhas, G.; Babu, G.; Rekhtman, G.; Rossi, G.; Marques, H.; Bumbea, H.; Wang, H.; Huang, H.; Choi, I.; Bulavina, I.; Lysenko, I.; Avivi, I.; Kryachok, I.; Zaucha, J. M.; Novak, J.; Diaz, J.; Demeter, J.; Alexeeva, J.; Zhu, J.; Vilchevskaya, K.; Ishizawa, K.; Mauricio, K.; Tobinai, K.; Ando, K.; Abdulkadryrov, K.; Shih, L. -Y.; Kuzina, L.; Gumus, M.; De Wit, M.; Capra, M.; Marques, M.; Golubeva, M.; Ojeda-Uribe, M.; Kyselyova, M.; Taniwaki, M.; Federico, M.; Crump, M.; Baccarani, M.; Ogura, M.; Egyed, M.; Udvardy, M.; Kurosawa, M.; Uike, N.; Khuageva, N.; Shpilberg, O.; Gladkov, O.; Samoilova, O.; Serduk, O.; Santi, P.; Zachee, P.; Kaplan, P.; Stoia, R.; Gressin, R.; Arranz, R.; Greil, R.; Grosicki, S.; Cancelado, S.; Nair, S.; Le Gouill, S.; Van Steenweghen, S.; Yoon, S. -S.; Chuncharune, S.; Scheider, T.; Shimoyama, T.; Liu, T.; Kinoshita, T.; Uchida, T.; Bunworasate, U.; Vitolo, U.; Pavlov, V.; Phooshkooru, V. R.; Lima, V.; Merkulov, V.; Nawarawong, W.; Hong, X.; Ke, X.; Terui, Y.; Tee Goh, Y.; Maeda, Y.; Shi, Y.; Dunaev, Y.; Lorie, Y.; Wang, Z.; Shen, Z.; Borbenyi, Z.; Gasztonyi, Z.; Masliak, Z.
abstract

Background: In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. Methods: LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II–IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00722137, and is closed to new participants with follow-up completed. Findings: Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1–94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51–0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. Interpretations: Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. Funding: Janssen Research & Development.

2018 - Genomic alterations at the basis of treatment resistance in metastatic breast cancer: Clinical applications [Articolo su rivista]
Toss, Angela; Piacentini, Federico; Cortesi, Laura; Artuso, Lucia; Bernardis, Isabella; Parenti, Sandra; Tenedini, Elena; Ficarra, Guido; Maiorana, Antonino; Iannone, Anna; Omarini, Claudia; Moscetti, Luca; Cristofanilli, Massimo; Federico, Massimo; Tagliafico, Enrico
abstract

The standard of care for breast cancer has gradually evolved from empirical treatments based on clinical-pathological characteristics to the use of targeted approaches based on the molecular profile of the tumor. Consequently, an increasing number of molecularly targeted drugs have been developed. These drugs target specific alterations, called driver mutations, which confer a survival advantage to cancer cells. To date, the main challenge remains the identification of predictive biomarkers for the selection of the optimal treatment. On this basis, we evaluated a panel of 25 genes involved in the mechanisms of targeted treatment resistance, in 16 primary breast cancers and their matched recurrences, developed during treatment. Overall, we found a detection rate of mutations higher than that described in the literature. In particular, the most frequently mutated genes were ERBB2 and those involved in the PI3K/AKT/mTOR and the MAPK signaling pathways. The study revealed substantial discordances between primary tumors and metastases, stressing the need for analysis of metastatic tissues at recurrence. We observed that 85.7% of patients with an early-stage or locally advanced primary tumor showed at least one mutation in the primary tumor. This finding could explain the subsequent relapse and might therefore justify more targeted adjuvant treatments. Finally, the mutations detected in 50% of relapsed tissues could have guided subsequent treatment choices in a different way. This study demonstrates that mutation events may be present at diagnosis or arise during cancer treatment. As a result, profiling primary and metastatic tumor tissues may be a major step in defining optimal treatments.

2018 - Hodgkin lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up [Articolo su rivista]
Eichenauer, D A; Aleman, B M P; André, M; Federico, M; Hutchings, M; Illidge, T; Engert, A; Ladetto, M
abstract

not available

2018 - Long-Term Results of the FOLL05 Trial Comparing R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Symptomatic Follicular Lymphoma [Articolo su rivista]
Luminari, Stefano; Ferrari, Angela; Manni, Martina; Dondi, Alessandra; Chiarenza, Annalisa; Merli, Francesco; Rusconi, Chiara; Tarantino, Vittoria; Tucci, Alessandra; Vitolo, Umberto; Kovalchuk, Sofia; Angelucci, Emanuele; Pulsoni, Alessandro; Arcaini, Luca; Angrilli, Francesco; Gaidano, Gianluca; Stelitano, Caterina; Bertoldero, Giovanni; Cascavilla, Nicola; Salvi, Flavia; Ferreri, Andrés J M; Vallisa, Daniele; Marcheselli, Luigi; Federico, Massimo
abstract

Purpose The FOLL05 trial compared R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-FM (rituximab plus fludarabine and mitoxantrone) regimens without rituximab maintenance as initial therapy for patients with advanced-stage follicular lymphoma (FL). A previous analysis with a median follow-up of 34 months showed a superior 3-year time to treatment failure, the primary study end point, with R-CHOP and R-FM versus R-CVP and showed R-CHOP to have a better risk-benefit ratio in terms of toxicity than R-FM. We report a post hoc analysis of this trial after a median follow-up of 7 years. Patients and Methods Of the 534 enrolled patients, 504 were evaluable. At the time of analysis, the median follow-up was 84 months (range, 1 to 119 months). Results The 8-year time to treatment failure and progression-free survival rates were 44% (95% CI, 39% to 49%) and 48% (95% CI, 43% to 53%), respectively. The hazard ratio for progression-free survival adjusted by FL International Prognostic Index 2 versus R-CVP was 0.73 for R-CHOP (95% CI, 0.54 to 0.98; P = .037) and 0.67 for R-FM (95% CI, 0.50 to 0.91; P = .009). The 8-year overall survival (OS) rate was 83% (95% CI, 79% to 87%), with no significant differences among study arms. Overall, we observed a higher risk of dying as a result of causes unrelated to lymphoma progression with R-FM versus R-CVP. Conclusion With an 83% 8-year OS rate, long-term follow-up of the FOLL05 trial confirms the favorable outcome of patients with advanced-stage FL treated with immunochemotherapy. The three study arms had similar OS but different activity and toxicity profiles. Patients initially treated with R-CVP had a higher risk of lymphoma progression compared with those receiving R-CHOP, as well as a higher risk of requiring additional therapy.

2018 - Peripheral T cell lymphoma, not otherwise specified (PTCL-NOS). A new prognostic model developed by the International T cell Project Network [Articolo su rivista]
Federico, Massimo; Bellei, Monica; Marcheselli, Luigi; Schwartz, Marc; Manni, Martina; Tarantino, Vittoria; Pileri, Stefano; Ko, Young-Hyeh; Cabrera, Maria E.; Horwitz, Steven; Kim, Won S.; Shustov, Andrei; Foss, Francine M.; Nagler, Arnon; Carson, Kenneth; Pinter-Brown, Lauren C.; Montoto, Silvia; Spina, Michele; Feldman, Tatyana A.; Lechowicz, Mary J.; Smith, Sonali M.; Lansigan, Frederick; Gabus, Raul; Vose, Julie M.; Advani, Ranjana H.
abstract

Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL-NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL-NOS were retained for study. At a median follow-up of 46 months, the median overall survival (OS) and progression-free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1–2), and high risk (HiR, 74 patients, 24%, score 3–4), having a 3-year OS of 76% [95% confidence interval 61–88], 43% [35–51], and 11% [4–21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes.

2018 - Peripheral T-Cell Lymphomas: Incorporating New Developments in Diagnostics, Prognostication, and Treatment Into Clinical Practice-PART 1: PTCL-NOS, FTCL, AITL, ALCL [Articolo su rivista]
Zing, Natalia Pin Chuen; Fischer, Thais; Zain, Jasmine; Federico, Massimo; Rosen, Steven T
abstract

Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of diseases, with low incidence and unique epidemiology and pathobiology; they are usually clinically aggressive, with poor outcomes. There have been significant advances in our understanding of the molecular and signaling alterations seen in these malignancies. These observations have led to novel therapeutic strategies that have had a meaningful impact on outcomes. This two-part series highlights the most important aspects of PTCLs and describes current treatment options and investigative opportunities. Part 1 will cover PTCL not otherwise specified, follicular T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large-cell lymphoma (ALCL), and breast implant-associated ALCL. Part 2 will cover extranodal natural killer/T-cell lymphoma, enteropathy-associated T-cell lymphoma, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, adult T-cell leukemia/lymphoma, and hepatosplenic T-cell lymphoma.

2018 - Peripheral T-Cell Lymphomas: Incorporating New Developments in Diagnostics, Prognostication, and Treatment Into Clinical Practice-PART 2: ENKTL, EATL, Indolent T-Cell LDP of the GI Tract, ATLL, and Hepatosplenic T-Cell Lymphoma [Articolo su rivista]
Zing, Natalia Pin Chuen; Fischer, Thais; Zain, Jasmine; Federico, Massimo; Rosen, Steven T
abstract

The World Health Organization classification for peripheral T-cell lymphomas (PTCLs) continues to evolve based on genetic and clinical distinctions of each entity. In Part 1, an overview was provided of PTCL not otherwise specified, follicular T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma (ALCL), and breast implant-associated ALCL. In Part 2, this review is extended to extranodal natural killer (NK)/T-cell lymphoma, enteropathy-associated T-cell lymphoma, indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, adult T-cell leukemia/lymphoma, and hepatosplenic T-cell lymphoma. Each NK/T-cell malignancy has its own signature, requiring knowledge of the appropriate diagnostic, prognostic, and therapeutic considerations when caring for afflicted individuals. Future directions will depend on discoveries that further our understanding of each disease and clinical trials that test the latest treatment options.

2018 - Prognostic model for high-tumor-burden follicular lymphoma integrating baseline and end-induction PET: a LYSA/FIL study [Articolo su rivista]
Cottereau, Anne Ségolène; Versari, Annibale; Luminari, Stefano; Dupuis, Jehan; Chartier, Loïc; Casasnovas, René-Olivier; Berriolo-Riedinger, Alina; Menga, Massimo; Haioun, Corinne; Tilly, Hervé; Tarantino, Vittoria; Federico, Massimo; Salles, Gilles; Trotman, Judith; Meignan, Michel
abstract

Both total metabolic tumor volume (TMTV), computed on baseline positron emission tomography (PET), and end of induction (EOI) PET are imaging biomarkers showing promise for early risk stratification in patients with high-tumor-burden follicular lymphoma. A model was built incorporating these 2 factors in 159 patients from three prospective trials: 2 Lymphoma Study Association (LYSA) studies and 1 Fondazione Italiana Linfomi (FIL) trial. Median follow up was 64 months. High TMTV (>510 cm3) and positive EOI PET were independent, significant risk factors for progression. Their combination stratified the population into 3 risk groups: patients with no risk factors (n 5 102; 64%) had a 5-year progression-free survival (PFS) of 67% vs 33% (hazard ratio [HR], 2.9; 95% confidence interval [CI], 1.8-4.9) for patients with 1 risk factor (n 5 44; 27%) and only 23% (HR, 4.6; 95% CI, 2.3-9.2) for patients with both risk factors (n 5 13; 8%). 2-year PFS was respectively 90% vs 61% (HR, 4.8; 95% CI, 2.2-10.4) and 46% (HR, 8.1; 95%CI, 3.1-21.3). This model enhances the prognostic value of PET staging and response assessment, identifying a subset of patients with a very high risk of progression and early treatment failure at 2 years. (Blood. 2018;131(22): 2449-2453)

2018 - Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial [Articolo su rivista]
Cottereau, Anne-Ségolène; Versari, Annibale; Loft, Annika; Casasnovas, Olivier; Bellei, Monica; Ricci, Romain; Bardet, Stéphane; Castagnoli, Antonio; Brice, Pauline; Raemaekers, John; Deau, Bénédicte; Fortpied, Catherine; Raveloarivahy, Tiana; Van Zele, Emelie; Chartier, Loic; Borght, Thierry Vander; Federico, Massimo; Hutchings, Martin; Ricardi, Umberto; Andre, Marc; Meignan, Michel
abstract

We tested baseline positron emission tomography (PET)/computed tomography (CT) as a measure of total tumor burden to better identify high-risk patients with early-stage Hodgkin lymphoma (HL). Patients with stage I-II HL enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET and interim PET (iPET2) after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. iPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale (DS). The prognostic value of TMTV was evaluated and compared with baseline characteristics, staging classifications, and iPET2. A total of 258 patients were eligible: 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 progression-free survival (PFS) and 12 overall survival (OS) events. TMTV was a prognosticator of PFS (P &lt; .0001) and OS (P 5 .0001), with 86% and 84% specificity, respectively. Five-year PFS and OS were 71% and 83% in the high-TMTV (&gt;147 cm3) group (n 5 46), respectively, vs 92% and 98% in the low-TMTV group (£147 cm3). In multivariable analysis including iPET2, TMTV was the only baseline prognosticator compared with the current staging systems proposed by the European Organization for Research and Treatment of Cancer/Groupe d’Etude des Lymphomes de l’Adulte, German Hodgkin Study Group, or National Comprehensive Cancer Network. TMTV and iPET2 were independently prognostic and, combined, identified 4 risk groups: low (TMTV£1471DS1-3; 5-year PFS, 95%), low-intermediate (TMTV&gt;1471DS1-3; 5-year PFS, 81.6%), high-intermediate (TMTV£1471DS4-5; 5-year PFS, 50%), and high (TMTV&gt;1471DS4-5; 5-year PFS, 25%). TMTV improves baseline risk stratification of patients with early-stage HL compared with current staging systems and the predictive value of early PET response as well. (Blood. 2018;131(13):1456-1463)

2018 - Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial [Articolo su rivista]
Rambaldi, A.; Morra, E.; Federico, Massimo; Majolino, I.; Balzarotti, M.; Semenzato, G.; Canales Albendea, M. A.; Penalver Parraga, F. J.; Kruger, A.; Culligan, D.; Dyer, M.; Pettengell, R.; Seymour, J.; Gribben, J.; Al-Ismail, S.; Al-Refaie, F.; Blesing, N.; Macnamara, C.; O'Callaghan, A.; Haynes, A.; Follows, G.; Johnson, R.; Cunningham, D.; Bowles, K.; Collins, G.; Gallop-Evans, E.; Robinson, S.; Subash, C.; Bailey, J.; Holden, V.; Neidhart, J.; De Oliveira, M.; Tezcan, H.; Kim, K.; Kambhampati, S.; Lanier, K.; Mcclean, J.; Tobinai, K.; Hatake, K.; Ogura, M.; Uchida, T.; Ando, K.; Kinoshita, T.; Hohler, T.; Stauder, H.; Kirsch, A.; Koenigsmann, M.; Kremers, S.; Illmer, T.; Witzens-Harig, M.; La Rosee, P.; Durig, J.; Kneba, M.; Hensel, M.; Fuxius, S.; Bergmann, L.; Hubel, K.; Buske, C.; Marks, R.; Wulf, G.; Lerchenmueller, C.; Schmits, R.; Reinwald, M.; Lengfelder, E.; Scott, F.; Chou, T.; Taniwaki, M.; Yoshida, I.; Ishizawa, K.; Uike, N.; Uoshima, N.; Kamitsuji, Y.; Iida, S.; Ohmine, K.; Nosaka, K.; Ide, K.; Ishikawa, T.; Desjardins, P.; Finn, N.; Zhu, J.; Li, W.; Yu, L.; Ren, H.; Shi, Y. K.; Wu, G.; Hong, X.; Zhang, Q.; Feng, J.; Zhan, R.; Lin, T.; Leppa, S.; Costello, R.; Tempescul, A.; Sanhes, L.; Tournilhac, O.; Kirchen, H.; Hebart, H.; Weide, R.; Jentsch-Ullrich, K.; Avivi, I.; Nagler, A.; Gurion, R.; Shpilberg, O.; Leoni, P.; Baldini, L.; Samoylova, O.; Myasnikov, A.; Tan, T. -D.; Chang, H.; Kumagai, K.; Tsukamoto, N.; Tsukasaki, K.; Beatty, P.; Usui, N.; Izutsu, K.; Murayama, T.; Ichinohe, T.; Kubo, K.; Ishida, F.; Beck, J. T.; Griesinger, F.; Osmanov, D.; Dakhil, S.; Clavert, A.; Maruyama, D.; Terui, Y.; Yamamoto, K.; Eigendorff, E.; Kobayashi, T.; Ichikawa, S.; Choi, I.; Wada, K.; Kikukawa, Y.; Matsuoka, M.; Yoshino, T.; Minami, Y.
abstract

Background: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET–CT responses after first-line immunochemotherapy in the GALLIUM study. Methods: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1–3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968. Findings: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6–69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0–79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2–51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9–90·8) in PET complete responders and 72·0% (63·1–79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3–0·6, p&lt;0·0001). According to Lugano 2014 criteria, 2·5-year progression-free survival in complete metabolic responders was 87·4% (95% CI 83·7–90·2) and in non-complete metabolic responders was 54·9% (40·5–67·3; HR 0·2, 95% CI 0·1–0·3, p&lt;0·0001). Interpretation: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional s

2018 - Rituximab and the risk of transformation of follicular lymphoma: a retrospective pooled analysis [Articolo su rivista]
Federico, Massimo; Caballero Barrigón, María Dolores; Marcheselli, Luigi; Tarantino, Vittoria; Manni, Martina; Sarkozy, Clementine; Alonso-Álvarez, Sara; Wondergem, Marielle; Cartron, Guillaume; Lopez-Guillermo, Armando; Issa, Djamila; Morschhauser, Franck; Alcoceba, Miguel; Kimby, Eva; Rusconi, Chiara; Chamuleau, Martine; Holte, Harald; Lockmer, Sandra; Montoto, Silvia; Gomes da Silva, Maria; Aurer, Igor; Zucca, Emanuele; Paszkiewicz-Kozik, Ewa; Minoia, Carla; Skrypets, Tetiana; Blaker, Yngvild Nuvin; Salles, Gilles; Coiffier, Bertrand
abstract

Background: Histological transformation of follicular lymphoma to aggressive lymphoma is a serious event with a substantial effect on patient outcome. The aim of the Aristotle study was to assess the effect of rituximab on the risk of histological transformation and its outcome. Methods: 11 cooperative groups or institutions across Europe contributed data to this study. Eligible patients (≥18 years) had histologically confirmed follicular lymphoma grade 1, 2, or 3a, diagnosed between Jan 2, 1997, and Dec 20, 2013. Histological transformation was defined as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy. The primary endpoints were the cumulative hazard of histological transformation and survival after transformation. Findings: Information was available for 10 001 patients with follicular lymphoma, 8116 of whom were eligible for analysis. 509 histological transformations were reported. After a median follow-up of 87 months (range 1–221; 2·5–97·5th percentile 5–160), the 10-year cumulative hazard of histological transformation was 7·7% (95% CI 6·9–8·5). The 10-year cumulative hazard of histological transformation was 5·2% (95% CI 4·5–6·2) in patients who received rituximab and 8·7% (7·2–10·6) in those who did not (hazard ratio [HR] 0·73, 95% CI 0·58–0·90; p=0·004). The 10-year cumulative hazard of histological transformation was 5·9% (95% CI 5·0–7·0) for patients who received induction rituximab only and 3·6% (95% CI 2·3–5·5) for those treated with induction and maintenance rituximab (HR 0·55, 95% CI 0·37–0·81; p=0·003). This finding was confirmed in a multivariate analysis (p=0·016). 287 deaths were recorded in 509 patients with histological transformation, resulting in a 10-year survival after transformation of 32% (95% CI 26–38). Survival after transformation did not differ between patients not exposed to rituximab and those who received rituximab in induction only (HR 0·94, 95% CI 0·69–1·28; p=0·70), and those who received rituximab in induction and maintenance (0·96, 0·58–1·61; p=0·88). Interpretation: The risk of histological transformation as a first event can be significantly reduced by the use of rituximab. These findings support the need to inform patients using rituximab nowadays that the risk of transformation is lower than it was before the introduction of rituxumab. Funding: Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, Spanish Group of Lymphoma and Bone Marrow Transplantation.

2018 - The outcome of peripheral t-cell lymphoma patients failing first-line therapy: A report from the prospective, international t-cell project [Articolo su rivista]
Bellei, Monica; Foss, Francine M.; Shustov, Andrei R.; Horwitz, Steven M.; Marcheselli, Luigi; Kim, Won Seog; Cabrera, Maria E.; Dlouhy, Ivan; Nagler, Arnon; Advani, Ranjana H.; Pesce, Emanuela A.; Ko, Young-Hyeh; Martinez, Virginia; Montoto, Silvia; Chiattone, Carlos; Moskowitz, Alison; Spina, Michele; Biasoli, Irene; Manni, Martina; Federico, Massimo
abstract

This analysis explored factors influencing survival of patients with primary refractory and relapsed peripheral T-cell lymphomas enrolled in the prospective International T-cell Project. We analyzed data from 1020 patients with newly diagnosed disease, enrolled between September 2006 and December 2015. Out of 937 patients who received first-line treatment, 436 (47%) were identified as refractory and 197 (21%) as relapsed. Median time from the end of treatment to relapse was 8 months (range 2-73). Overall, 75 patients (8%) were consolidated with bone marrow transplantation, including 12 refractory and 22 relapsed patients. After a median follow up of 38 months (range 1-96 months) from documentation of refractory/relapsed disease, 440 patients had died. The median overall survival (OS) was 5.8 months; 3-year overall survival rates were 21% and 28% for refractory and relapsed patients, respectively (P<0.001). Patients receiving or not salvage bone marrow transplantation had a 3-year survival of 48% and 18%, respectively (P<0.001). In a univariate Cox regression analysis, refractory disease was associated with a higher risk of death (HR=1.43, P=0.001), whereas late relapse (>12 months, HR 0.57, P=0.001) and salvage therapy with transplantation (HR=0.36, P<0.001) were associated with a better OS. No difference was found in OS with respect to histology. This study accurately reflects outcomes for patients treated according to standards of care worldwide. Results confirm that peripheral T-cell lymphomas patients had dismal outcome after relapse or progression. Patients with chemotherapy sensitive disease who relapsed after more than 12 months might benefit from consolidation bone marrow transplantation. (Registered at clinicaltrials.gov identifier: 01142674).

2018 - Transformed follicular lymphoma [Articolo su rivista]
Fischer, Thais; Zing, Natalia Pin Chuen; Chiattone, Carlos Sergio; Federico, Massimo; Luminari, Stefano
abstract

Follicular Lymphoma (FL) is the second most common type of non-Hodgkin lymphoma and is considered to be the prototype of indolent lymphomas. Histologic transformation into an aggressive lymphoma, which is expected to occur at a rate of 2 to 3% each year, is associated with rapid progression, treatment resistance, and poor prognosis. Recent modifications to the physiopathologic mechanism of transformed follicular lymphoma (t-FL) have been proposed, including genetic and epigenetic mechanisms as well as a role for the microenvironment. Although t-FL is considered a devastating complication, as it is associated with treatment-refractory disease and a dismal outcome, recent data in the rituximab era have suggested that not only is the prognosis less severe than reported in the previous literature but the risk of transformation is also lower. Thus, this study aimed to review the most recent research on t-FL in an attempt to better understand the clinical meaning of transformation from FL to diffuse large B cell lymphoma (DLBCL) and the impact of current treatment strategies on the curability of this intriguing subentity of lymphoma.

2017 - A prospective cohort study of patients with peripheral T-cell lymphoma in the United States [Articolo su rivista]
Carson, Kenneth R.; Horwitz, Steven M.; Pinter Brown, Lauren C.; Rosen, Steven T.; Pro, Barbara; Hsi, Eric D.; Federico, Massimo; Gisselbrecht, Christian; Schwartz, Marc; Bellm, Lisa A.; Acosta, Mark A.; Shustov, Andrei R.; Advani, Ranjana H.; Feldman, Tatyana A.; Lechowicz, Mary Jo; Smith, Sonali M.; Lansigan, Frederick; Tulpule, Anil; Craig, Michael D.; Greer, John P.; Kahl, Brad S.; Leach, Joseph W.; Morganstein, Neil; Casulo, Carla; Park, Steven I.; Foss, Francine M.
abstract

BACKGROUND: Long-term survival in patients with aggressive peripheral T-cell lymphoma (PTCL) is generally poor, and there currently is no clear consensus regarding the initial therapy used for these diseases. Herein, the authors analyzed treatment patterns and outcomes in a prospectively collected cohort of patients with a new diagnosis of nodal PTCL in the United States. METHODS: Comprehensive Oncology Measures for Peripheral T-cell Lymphoma Treatment (COMPLETE) is a prospective multicenter cohort study designed to identify the most common prevailing treatment patterns used for patients newly diagnosed with PTCL in the United States. Patients with nodal PTCL and completed records regarding baseline characteristics and initial therapy were included in this analysis. All statistical tests were 2-sided. RESULTS: Of a total of 499 patients enrolled, 256 (51.3%) had nodal PTCL and completed treatment records. As initial therapy, patients received doxorubicin-containing regimens (41.8%), regimens containing doxorubicin plus etoposide (20.9%), other etoposide regimens (15.8%), other single-agent or combination regimens (19.2%), and gemcitabine-containing regimens (2.1%). Survival was found to be statistically significantly longer for patients who received doxorubicin (log-rank P=.03). After controlling for disease histology and International Prognostic Index, results demonstrated a trend toward significance in mortality reduction in patients who received doxorubicin compared with those who did not (hazard ratio, 0.71; 95% confidence interval, 0.48-1.05 [P=.09]). CONCLUSIONS: To the authors' knowledge, there is no clear standard of care in the treatment of patients with PTCL in the United States. Although efforts to improve frontline treatments are necessary, anthracyclines remain an important component of initial therapy for curative intent. Cancer 2016.

2017 - Analysis of Peripheral T-cell Lymphoma Diagnostic Workup in the United States [Articolo su rivista]
Hsi, Eric D; Horwitz, Steven M.; Carson, Kenneth R.; Pinter Brown, Lauren C.; Rosen, Steven T.; Pro, Barbara; Federico, Massimo; Gisselbrecht, Christian; Schwartz, Marc; Bellm, Lisa A.; Acosta, Mark; Collie, Angela M.; Gruver, Aaron M.; Grzywacz, Bartosz J.; Turakhia, Samir; Shustov, Andrei R.; Advani, Ranjana H.; Feldman, Tatyana; Lechowicz, Mary Jo; Smith, Sonali M.; Lansigan, Frederick; Tulpule, Anil; Craig, Michael D.; Greer, John P.; Kahl, Brad S.; Leach, Joseph W.; Morganstein, Neil; Casulo, Carla; Park, Steven I.; Foss, Francine M.
abstract

Micro-Abstract With increased understanding of the unique entities of peripheral T-cell lymphoma (PTCL), subtype-specific approaches are emerging, and more precise diagnoses are becoming increasingly important. Using data from a large prospective cohort study, we examined the diagnostic patterns of PTCL in the United States. We found that the workup for PTCL varies widely and often lacks important phenotypic information to fully characterize the lymphoma.

2017 - Data quality in rare cancers registraton: The report of the RARECARE data quality study [Articolo su rivista]
Trama, A.; Marcos-Gragera, R.; Perez, M. J. S.; van der Zwan, J. M.; Ardanaz, E.; Bouchardy, C.; Melchor, J. M.; Martinez, C.; Capocaccia, R.; Vicentini, M.; Siesling, S.; Gatta, G.; Zielonk, N.; Van Eycken, E.; Henau, K.; Magi, M.; Bouvier, A. M.; Jooste, V.; Faivre, J.; Maynadie, M.; Manivet, I.; Comber, H.; Deady, S.; Bellu, F.; Dal Cappello, T.; Ferretti, S.; Vercelli, M.; Quaglia, A.; Federico, M.; Cirilli, C.; Fusco, M.; Michiara, M.; Sgargi, P.; Giacomin, A.; Tumino, R.; Cilia, S.; Spata, E.; Mangone, L.; Cinzia, S.; Falcini, F.; Giorgetti, S.; Piffer, S.; Franchini, S.; Crocetti, E.; Caldarella, A.; Tagliabue, G.; Zambon, P.; Fiore, A. R.; Dei Tos, A. P.; De Angelis, R.; England, K.; Gozdz, S.; Mezyk, R.; Zwierko, M.; Bielska-Lasota, M.; Slowinski, J.; Primic-Zakelj, M.; Skrlec, F.; Mateos, A.; Bidaurrazaga, J.; Galceran, J.; Diaz Garcia, J. M.; Martinez-Garcia, C.; Sanchez Perez, M. J.; Adolfsson, J.; Usel, M.; Ess, S. M.; Spitale, A.; Bordoni, A.; Konzelmann, I.; Visser, O.; Otter, R.; Siesling, S.
abstract

Purpose: Rare cancers represent 22% of all tumors in Europe; however, the quality of the data of rare cancers may not be as good as the quality of data for common cancer. The project surveillance of rare cancers in Europe (RARECARE) had, among others, the objectve of assessing rare cancer data quality in populaton-based cancer registries (CRs). Eight rare cancers were considered: mesothelioma, liver angiosarcoma, sarcomas, tumors of oral cavity, CNS tumors, germ cell tumors, leukemia, and malignant digestve endocrine tumors. Methods: We selected data on 18,000 diagnoses and revised, on the basis of the pathologic and clinical reports (but not on pathologic specimens), unspecified morphology and topography codes originally atributed by CR officers and checked the quality of follow-up of long-term survivors of poor prognosis cancers. Results: A total of 38 CRs contributed from 13 European countries. The majority of unspecified morphology and topography cases were confirmed as unspecified. The few unspecified cases that, after the review, changed to a more specific diagnosis increased the incidence of the common cancer histotypes. For example, 11% of the oral cavity epithelial cancers were reclassified from unspecified to more specific diagnoses: 8% were reclassified as squamous cell carcinoma (commoner) and only 1% as adenocarcinoma (rarer). The revision confirmed the majority of long-term survivors revealing a relatve high proporton of mesothelioma long-term survivors. The majority of appendix carcinoids changed behavior from malignant to borderline lesions. Conclusions: Our study suggests that the problem of poorly specified morphology and topography cases is mainly one of difficulty in reaching a precise diagnosis. The awareness of the importance of data quality for rare cancers should increase among registrars, pathologists, and clinicians.

2017 - Early Positron Emission Tomography Response-Adapted Treatment in Stage I and II Hodgkin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial [Articolo su rivista]
André, Marc P. E; Girinsky, Théodore; Federico, Massimo; Reman, Oumédaly; Fortpied, Catherine; Gotti, Manuel; Casasnovas, Olivier; Brice, Pauline; van der Maazen, Richard; Re, Alessandro; Edeline, Véronique; Fermé, Christophe; van Imhoff, Gustaaf; Merli, Francesco; Bouabdallah, Réda; Sebban, Catherine; Specht, Lena; Stamatoullas, Aspasia; Delarue, Richard; Fiaccadori, Valeria; Bellei, Monica; Raveloarivahy, Tiana; Versari, Annibale; Hutchings, Martin; Meignan, Michel; Raemaekers, John
abstract

Purpose Patients who receive combined modality treatment for stage I and II Hodgkin lymphoma (HL) have an excellent outcome. Early response evaluation with positron emission tomography (PET) scan may improve selection of patients who need reduced or more intensive treatments. Methods We performed a randomized trial to evaluate treatment adaptation on the basis of early PET (ePET) after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in previously untreated-according to European Organisation for Research and Treatment of Cancer criteria favorable (F) and unfavorable (U)-stage I and II HL. The standard arm consisted of ABVD followed by involved-node radiotherapy (INRT), regardless of ePET result. In the experimental arm, ePET-negative patients received ABVD only (noninferiority design), whereas ePET-positive patients switched to two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc) and INRT (superiority design). Primary end point was progression-free survival (PFS). Results Of 1,950 randomly assigned patients, 1,925 received an ePET-361 patients (18.8%) were positive. In ePET-positive patients, 5-year PFS improved from 77.4% for standard ABVD + INRT to 90.6% for intensification to BEACOPPesc + INRT (hazard ratio [HR], 0.42; 95% CI, 0.23 to 0.74; P = .002). In ePET-negative patients, 5-year PFS rates in the F group were 99.0% versus 87.1% (HR, 15.8; 95% CI, 3.8 to 66.1) in favor of ABVD + INRT; the U group, 92.1% versus 89.6% (HR, 1.45; 95% CI, 0.8 to 2.5) in favor of ABVD + INRT. For both F and U groups, noninferiority of ABVD only compared with combined modality treatment could not be demonstrated. Conclusion In stage I and II HL, PET response after two cycles of ABVD allows for early treatment adaptation. When ePET is positive after two cycles of ABVD, switching to BEACOPPesc + INRT significantly improved 5-year PFS. In ePET-negative patients, noninferiority of ABVD only could not be demonstrated: risk of relapse is increased when INRT is omitted, especially in patients in the F group.

2017 - Effect of the addition of rituximab to salvage chemotherapy prior to autologous stem cell transplant in aggressive CD20+ lymphoma: a cohort comparison from the NCIC Clinical Trials Group Study LY.12* [Articolo su rivista]
Baetz, Tara; Chen, Bingshu E.; Couban, Stephen; Tom Kouroukis, C.; Buckstein, Rena; Kuruvilla, John; Howson Jan, Kang; Szwajcer, David; Federico, Massimo; Meyer, Ralph M.; Djurfeldt, Marina S.; Hay, Annette E.; Shepherd, Lois; Crump, Michael
abstract

The impact of the addition of rituximab to salvage chemotherapy prior to autologous stem cell transplant (ASCT) was evaluated in a retrospective subgroup analysis of NCIC CTG LY.12. Among 414 patients who relapsed following R-CHOP, 96 received salvage chemotherapy alone [R − cohort]; and 318 received rituximab with chemotherapy [R + cohort] following a protocol amendment. The R−cohort had a higher proportion of patients with PS ≥2 and relapse &lt;1 year after R-CHOP. The response rate (45.6% vs. 25.0%, p = 0.0003), CR/CRu (15.7% vs. 4.2%, p = 0.003) and transplantation rate (51.9% vs. 31.3%, p = 0.0004) was higher in the R + cohort. Event-free (27% vs. 22%, p = 0.0954) and overall survival at four years (43% vs. 31%; p = 0.045) were greater in the R + cohort when the patients with best response SD/PD to R-CHOP were excluded. Addition of rituximab to salvage therapy before ASCT appears to improve the response rate, transplantation rate, and overall survival in patients with CD20+ lymphoma who responded to R-CHOP.

2017 - Evaluation of Transvaginal Ultrasound plus CA-125 Measurement and Prophylactic Salpingo-Oophorectomy in Women at Different Risk Levels of Ovarian Cancer: The Modena Study Group Cohort Study [Articolo su rivista]
Cortesi, Laura; De Matteis, Elisabetta; Toss, Angela; Marchi, Isabella; Medici, Veronica; Contu, Giannina; Xholli, Anjeza; Grandi, Giovanni; Cagnacci, Angelo; Federico, Massimo
abstract

Objective: To evaluate the effectiveness of transvaginal ultrasound (TVU) and serum CA-125 measurement in women at different risk of developing ovarian cancer/fallopian tube cancer (OC/FTC) and the incidence of primary peritoneal cancer (PPC) after risk-reducing salpingo-oophorectomy (RRSO). Methods: Between 2002 and 2014, 661 women at different risk of OC/FTC/PPC due to a family history or BRCA1/2 gene mutation were offered TVU and CA-125 measurement or RRSO as prevention strategies. The detection rate of OC/FTC/PPC was evaluated, and the sensitivity and specificity for CA-125 measurement and TVU were calculated. Survival and event analysis was performed for diagnosed patients. Results: After a median follow-up of 112 months, 12 OC/FTC/PPC cases were detected (2.6/1,000 persons/year). The screening sensitivity was 70%, with 73% for BRCA carriers. Six (50%) of 12 cancers were stage I or II. Among 41 women who underwent RRSO, 2 BRCA1 carriers developed a PPC (4.9%). At 61-month follow-up, overall and event-free survival were 75 and 64%, respectively. Conclusions: The cancer detection rate in women with BRCA mutation or a strong family history supports the effectiveness of our surveillance program for early diagnosis. Screening for women at lower risk of OC/FTC is not recommended. A residual risk of PPC after RRSO remains for BRCA1 carriers.

2017 - International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017) [Articolo su rivista]
Younes, A; Hilden, P; Coiffier, B; Hagenbeek, A; Salles, G; Wilson, W; Seymour, J. F; Kelly, K; Gribben, J; Pfreunschuh, M; Morschhauser, F; Schoder, H; Zelenetz, A. D; Rademaker, J; Advani, R; Valente, N; Fortpied, C; Witzig, T. E; Sehn, L. H; Engert, A; Fisher, R. I; Zinzani, P. L; Federico, Massimo; Hutchings, M; Bollard, C; Trneny, M; Elsayed, Y. A; Tobinai, K; Abramson, J. S; Fowler, N; Goy, A; Smith, M; Ansell, S; Kuruvilla, J; Dreyling, M; Thieblemont, C; Little, R. F; Aurer, I; Van Oers, M. H. J; Takeshita, K; Gopal, A; Rule, S; de Vos, S; Kloos, I; Kaminski, M. S; Meignan, M; Schwartz, L. H; Leonard, J. P; Schuster, S. J; Seshan, V. E.
abstract

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on 18-Fluoro-deoxyglucose positron emission tomography (FDG-PET) or bidimensional tumor measurements on computerized tomography (CT) scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47,828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials, and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

2017 - Neutrophil-lymphocyte ratio at diagnosis is an independent prognostic factor in patients with nodular sclerosis Hodgkin lymphoma: Results of a large multicenter study involving 990 patients [Articolo su rivista]
Marcheselli, Raffaella; Bari, Alessia; Tadmor, Tamar; Marcheselli, Luigi; Cox, Maria Christina; Pozzi, Samantha; Ferrari, Angela; Baldini, Luca; Gobbi, Paolo; Aviv, Ariel; Pugliese, Giuseppe; Federico, Massimo; Polliack, Aaron; Sacchi, Stefano
abstract

Several studies have demonstrated the prognostic value of neutrophil-lymphocyte ratio (NLR) in patients with solid tumors and non-Hodgkin lymphoma. In contrast, there is only sparse data on its prognostic role in patients with classical Hodgkin lymphoma (cHL). The aim of our study was to establish whether NLR could serve as an independent prognostic factor in a cohort of 990 patients with nodular sclerosis (NS)-cHL. After analysis of the log hazard ratio (HR) as a function of NLR, we chose the value 6 as cutoff. Patients with NLR &gt;6 had a worse progression-free survival and overall survival compared to those with NLR ≤6; 84% vs 75% and 92% vs 88%, at 5 years, with an HR of 1.65 and 1.82, respectively. Multivariate analysis showed that the risk remained high with HR 1.44 and HR 1.54 in progression-free survival and overall survival, respectively. In summary, our study shows that NLR is a robust and independent prognostic parameter in NS-cHL, both in early and advanced disease. It is inexpensive and simple to apply. Thus, we conclude that NLR, possibly in combination with the international prognostic score and absolute monocyte count, is a useful guide for physicians treating NS-cHL patients.

2017 - Pitfalls and major issues in the histologic diagnosis of peripheral T-cell lymphomas: Results of the central review of 573 cases from the T-Cell Project, an international, cooperative study [Articolo su rivista]
Bellei, Monica; Sabattini, Elena; Pesce, Emanuela Anna; Ko, Young Hyeh; Kim, Won Seog; Cabrera, Maria Elena; Martinez, Virginia; Dlouhy, Ivan; Paes, Roberto Pinto; Barrese, Tomas; Vassallo, Josè; Tarantino, Vittoria; Vose, Julie; Weisenburger, Dennis; Rüdiger, Thomas; Federico, Massimo; Pileri, Stefano
abstract

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of neoplasms that are derived from post-thymic lymphoid cells at different stages of differentiation with different morphological patterns, phenotypes and clinical presentations. PTCLs are highly diverse, reflecting the diverse cells from which they can originate and are currently sub-classified using World Health Organization (WHO) 2008 criteria. In 2006 the International T-Cell Lymphoma Project launched the T-Cell Project, building on the retrospective study previously carried on by the network, with the aim to prospectively collect accurate data to improve knowledge on this group of lymphomas. Based on previously published reports from International Study Groups it emerged that rendering a correct classification of PTCLs is quite difficult because the relatively low prevalence of these diseases results in a lack of confidence by most pathologists. This is the reason why the T-Cell Project requested the availability of diagnostic material from the initial biopsy of each patient registered in the study in order to have the initial diagnosis centrally reviewed by expert hematopathologists. In the present report the results of the review process performed on 573 cases are presented. Overall, an incorrect diagnosis was centrally recorded in 13.1% cases, including 8.5% cases centrally reclassified with a subtype eligible for the project and 4.6% cases misclassified and found to be disorders other than T-cell lymphomas; 2.1% cases were centrally classified as T-Cell disorders not included in the study population. Thus, the T-Cell Project confirmed the difficulties in providing an accurate classification when a diagnosis of PTCLs is suspected, singled out the major pitfalls that can bias a correct histologic categorization and confirmed that a centralized expert review with the application of adequate diagnostic algorithms is mandatory when dealing with these tumours.

2017 - Reply to H.J.A. Adams et al and E. Laffon et al [Articolo su rivista]
Meignan, Michel; Cottereau, Anne Ségolène; Versari, Annibale; Chartier, Loïc; Dupuis, Jehan; Boussetta, Sami; Grassi, Ilaria; Casasnovas, René Olivier; Haioun, Corinne; Tilly, Hervé; Tarantino, Vittoria; Dubreuil, Julien; Federico, Massimo; Salles, Gilles; Luminari, Stefano; Trotman, Judith
abstract

not available

2017 - Reply to j.a. vargo et al, h.j.a. adams et al, e. hindié et al, and s. kothari et al [Articolo su rivista]
André, Marc P. E.; Federico, Massimo; Fortpied, Catherine; Girinsky, Théodore; Meignan, Michel; Raemaekers, John
abstract

not available

2017 - Secondary malignant neoplasms, progression-free survival and overall survival in patients treated for Hodgkin lymphoma: A systematic review and meta-analysis of randomized clinical trials [Articolo su rivista]
Eichenauer, Dennis A.; Becker, Ingrid; Monsef, Ina; Chadwick, Nicholas; De Sanctis, Vitaliana; Federico, Massimo; Fortpied, Catherine; Gianni, Alessandro M.; Henry-Amar, Michel; Hoskin, Peter; Johnson, Peter; Luminari, Stefano; Bellei, Monica; Pulsoni, Alessandro; Sydes, Matthew R.; Valagussa, Pinuccia; Viviani, Simonetta; Engert, Andreas; Franklin, Jeremy
abstract

Treatment intensification to maximize disease control and reduced intensity approaches to minimize the risk of late sequelae have been evaluated in newly diagnosed Hodgkin lymphoma. The influence of these interventions on the risk of secondary malignant neoplasms, progression-free survival and overall survival is reported in the meta-analysis herein, based on individual patient data from 9498 patients treated within 16 randomized controlled trials for newly diagnosed Hodgkin lymphoma between 1984 and 2007. Secondary malignant neoplasms were meta-analyzed using Peto’s method as time-to-event outcomes. For progression-free and overall survival, hazard ratios derived from each trial using Cox regression were combined by inverse-variance weighting. Five study questions (combined-modality treatment vs. chemotherapy alone; more extended vs. involved-field radiotherapy; radiation at higher doses vs. radiation at 20 Gy; more vs. fewer cycles of the same chemotherapy protocol; standard-dose chemotherapy vs. intensified chemotherapy) were investigated. After a median follow-up of 7.4 years, dose-intensified chemotherapy resulted in better progression-free survival rates (P=0.007) as compared with standard-dose chemotherapy, but was associated with an increased risk of therapy-related acute myeloid leukemia/myelodysplastic syndromes (P=0.0028). No progression-free or overall survival differences were observed between combined-modality treatment and chemotherapy alone, but more secondary malignant neoplasms were seen after combined-modality treatment (P=0.010). For the remaining three study questions, outcomes and secondary malignancy rates did not differ significantly between treatment strategies. The results of this meta-analysis help to weigh up efficacy and secondary malignancy risk for the choice of first-line treatment for Hodgkin lymphoma patients. However, final conclusions regarding secondary solid tumors require longer follow-up.

2017 - The histology of ovarian cancer: worldwide distribution and implications for international survival comparisons (CONCORD-2) [Articolo su rivista]
Matz, M.; Coleman, M. P.; Sant, M.; Chirlaque, M. D.; Visser, O.; Gore, M.; Allemani, C.; Bouzbid, S.; Hamdi-Cherif, M.; Zaidi, Z.; Bah, E.; Swaminathan, R.; Nortje, S. H.; C. Stefan, D.; El Mistiri, M. M.; Bayo, S.; Malle, B.; Manraj, S. S.; Sewpaul-Sungkur, R.; Fabowale, A.; Ogunbiyi, O. J.; Bradshaw, D.; Somdyala, N. I. M.; Abdel-Rahman, M.; Jaidane, L.; Mokni, M.; Kumcher, I.; Moreno, F.; Gonzalez, M. S.; Laura, E. A.; Espinola, S. B.; Calabrano, G. H.; Carballo Mazzoleni, G.; Giacomin, A.; Bella, F.; Castaing, M.; Sutera, A.; Gola, G.; Ferretti, S.; Serraino, D.; Zucchetto, A.; Lillini, R.; Vercelli, M.; Busco, S.; Pannozzo, F.; Vitarelli, S.; Ricci, P.; Pascucci, C.; Autelitano, M.; Cirilli, C.; Federico, M.; Fusco, M.; Vitale, M. F.; Usala, M.; Cusimano, R.; Mazzucco, W.; Michiara, M.; Sgargi, P.; Maule, M. M.; Sacerdote, C.; Tumino, R.; Di Felice, E.; Vicentini, M.; Falcini, F.; Cremone, L.; Budroni, M.; Cesaraccio, R.; Contrino, M. L.; Tisano, F.; Fanetti, A. C.; Maspero, S.; Candela, G.; Scuderi, T.; Gentilini, M. A.; Piffer, S.; Rosso, S.; Sacchetto, L.; Caldarella, A.; La Rosa, F.; Stracci, F.; Contiero, P.; Tagliabue, G.; Dei Tos, A. P.; Zorzi, M.; Zanetti, R.; Baili, P.; Berrino, F.; Gatta, G.; Capocaccia, R.; De Angelis, R.; Liepina, E.
abstract

Objective Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. Methods The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995–2009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included. We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. Results During 2005–2009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. Conclusions The distribution of ovarian cancer histology varies widely worldwide. Type I epithelial, germ cell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions.

2017 - Time to publish: challenging the performance of cooperative group lymphoma trials [Articolo su rivista]
Federico, Massimo; Trotman, Judith; Dreyling, Martin
abstract

not available

2017 - Worldwide comparison of ovarian cancer survival: Histological group and stage at diagnosis (CONCORD-2) [Articolo su rivista]
Matz, M.; Coleman, M. P.; Carreira, H.; Salmeron, D.; Chirlaque, M. D.; Allemani, C.; Bouzbid, S.; Hamdi-Cherif, M.; Zaidi, Z.; Bah, E.; Swaminathan, R.; Nortje, S. H.; El Mistiri, M. M.; Bayo, S.; Malle, B.; Manraj, S. S.; Sewpaul-Sungkur, R.; Fabowale, A.; Ogunbiyi, O. J.; Bradshaw, D.; Somdyala, N. I. M.; Stefan, D. C.; Abdel-Rahman, M.; Jaidane, L.; Mokni, M.; Kumcher, I.; Moreno, F.; Gonzalez, M. S.; Laura, E. A.; Espinola, S. B.; Calabrano, G. H.; Carballo Quintero, B.; Fita, R.; Garcilazo, D. A.; Giacciani, P. L.; Diumenjo, M. C.; Laspada, W. D.; Green, M. A.; Lanza, M. F.; Ibanez, S. G.; Lima, C. A.; Lobo de Oliveira, E.; Daniel, C.; Scandiuzzi, C.; De Souza, P. C. F.; Melo, C. D.; Del Pino, K.; Laporte, C.; Curado, M. P.; de Oliveira, J. C.; Veneziano, C. L. A.; Veneziano, D. B.; Latorre, M. R. D. O.; Tanaka, L. F.; Azevedo e Silva, G.; Galaz, J. C.; Moya, J. A.; Herrmann, D. A.; Vargas, S.; Herrera, V. M.; Uribe, C. J.; Bravo, L. E.; Arias-Ortiz, N. E.; Jurado, D. M.; Yepez, M. C.; Galan, Y. H.; Torres, P.; Martinez-Reyes, F.; Perez-Meza, M. L.; Jaramillo, L.; Quinto, R.; Cueva, P.; Yepez, J. G.; Torres-Cintron, C. R.; Tortolero-Luna, G.; Alonso, R.; Barrios, E.; Nikiforuk, C.; Shack, L.; Coldman, A. J.; Woods, R. R.; Noonan, G.; Turner, D.; Kumar, E.; Zhang, B.; McCrate, F. R.; Ryan, S.; Hannah, H.; Dewar, R. A. D.; MacIntyre, M.; Lalany, A.; Ruta, M.; Marrett, L.; Nishri, D. E.; McClure, C.; Vriends, K. A.; Bertrand, C.; Louchini, R.; Robb, K. I.; Stuart-Panko, H.; Demers, S.; Wright, S.; George, J. T.; Shen, X.; Brockhouse, J. T.; O'Brien, D. K.; Ward, K. C.; Almon, L.; Bates, J.; Rycroft, R.; Mueller, L.; Phillips, C.; Brown, H.; Cromartie, B.; Schwartz, A. G.; Vigneau, F.; MacKinnon, J. A.; Wohler, B.; Bayakly, A. R.; Clarke, C. A.; Glaser, S. L.; West, D.; Green, M. D.; Hernandez, B. Y.; Johnson, C. J.; Jozwik, D.; Charlton, M. E.; Lynch, C. F.; Huang, B.; Tucker, T. C.; Deapen, D.; Liu, L.; Hsieh, M. C.; Wu, X. C.; Stern, K.; Gershman, S. T.; Knowlton, R. C.; Alverson, J.; Copeland, G. E.; Rogers, D. B.; Lemons, D.; Williamson, L. L.; Hood, M.; Hosain, G. M.; Rees, J. R.; Pawlish, K. S.; Stroup, A.; Key, C.; Wiggins, C.; Kahn, A. R.; Schymura, M. J.; Leung, G.; Rao, C.; Giljahn, L.; Warther, B.; Pate, A.; Patil, M.; Schubert, S. S.; Rubertone, J. J.; Slack, S. J.; Fulton, J. P.; Rousseau, D. L.; Janes, T. A.; Schwartz, S. M.; Bolick, S. W.; Hurley, D. M.; Richards, J.; Whiteside, M. A.; Nogueira, L. M.; Herget, K.; Sweeney, C.; Martin, J.; Wang, S.; Harrelson, D. G.; Keitheri Cheteri, M. B.; Farley, S.; Hudson, A. G.; Borchers, R.; Stephenson, L.; Espinoza, J. R.; Weir, H. K.; Edwards, B. K.; Wang, N.; Yang, L.; Chen, J. S.; Song, G. H.; Gu, X. P.; Zhang, P.; Ge, H. M.; Zhao, D. L.; Zhang, J. H.; Zhu, F. D.; Tang, J. G.; Shen, Y.; Wang, J.; Li, Q. L.; Yang, X. P.; Dong, J.; Li, W.; Cheng, L. P.; Chen, J. G.; Huang, Q. H.; Huang, S. Q.; Guo, G. P.; Wei, K.; Chen, W. Q.; Zeng, H.; Demetriou, A. V.; Pavlou, P.; Mang, W. K.; Ngan, K. C.; Kataki, A. C.; Krishnatreya, M.; Jayalekshmi, P. A.; Sebastian, P.; Sapkota, S. D.; Verma, Y.; Nandakumar, A.; Suzanna, E.; Keinan-Boker, L.; Silverman, B. G.; Ito, H.; Nakagawa, H.; Hattori, M.; Kaizaki, Y.; Sugiyama, H.; Utada, M.; Katayama, K.; Narimatsu, H.; Kanemura, S.; Koike, T.; Miyashiro, I.; Yoshii, M.; Oki, I.; Shibata, A.; Matsuda, T.; Nimri, O.; Ab Manan, A.; Bhoo-Pathy, N.; Tuvshingerel, S.; Chimedsuren, O.; Al Khater, A. H. M.; Al-Eid, H.; Jung, K. W.; Won, Y. J.; Chiang, C. J.; Lai, M. S.; Suwanrungruang, K.; Wiangnon, S.; Daoprasert, K.; Pongnikorn, D.; Geater, S. L.; Sriplung, H.; Eser, S.; Yakut, C. I.; Hackl, M.; Muhlbock, H.; Oberaigner, W.; Zborovskaya, A. A.; Aleinikova, O. V.; Henau, K.; Van Eycken, L.; Dimitrova, N.; Valerianova, Z.; Sekerija, M.; Zvolsky, M.; Engholm, G.; Storm, H.; Innos, K.; Magi, M.; Malila, N.; Seppa, K.; Jegu, J.; Velten, M.; Cornet, E.; Troussard, X.; Bouvier, A. M.; Faivre, J.; Guizard, A. V.; Bouvier, V.; Launoy, G.; Arveux, P.; M
abstract

Objective Ovarian cancer comprises several histological groups with widely differing levels of survival. We aimed to explore international variation in survival for each group to help interpret international differences in survival from all ovarian cancers combined. We also examined differences in stage-specific survival. Methods The CONCORD programme is the largest population-based study of global trends in cancer survival, including data from 60 countries for 695,932 women (aged 15–99&nbsp;years) diagnosed with ovarian cancer during 1995–2009. We defined six histological groups: type I epithelial, type II epithelial, germ cell, sex cord-stromal, other specific non-epithelial and non-specific morphology, and estimated age-standardised 5-year net survival for each country by histological group. We also analysed data from 67 cancer registries for 233,659 women diagnosed from 2001 to 2009, for whom information on stage at diagnosis was available. We estimated age-standardised 5-year net survival by stage at diagnosis (localised or advanced). Results Survival from type I epithelial ovarian tumours for women diagnosed during 2005–09 ranged from 40 to 70%. Survival from type II epithelial tumours was much lower (20–45%). Survival from germ cell tumours was higher than that of type II epithelial tumours, but also varied widely between countries. Survival for sex-cord stromal tumours was higher than for the five other groups. Survival from localised tumours was much higher than for advanced disease (80% vs. 30%). Conclusions There is wide variation in survival between histological groups, and stage at diagnosis remains an important factor in ovarian cancer survival. International comparisons of ovarian cancer survival should incorporate histology.

2017 - Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries [Articolo su rivista]
Bonaventure, A.; Harewood, R.; Stiller, C. A.; Gatta, G.; Clavel, J.; Stefan, D. C.; Carreira, H.; Spika, D.; Marcos-Gragera, R.; Peris-Bonet, R.; Pineros, M.; Sant, M.; Kuehni, C. E.; Murphy, M. F. G.; Coleman, M. P.; Allemani, C.; Bouzbid, S.; Hamdi-Cherif, M.; Zaidi, Z.; Bah, E.; Swaminathan, R.; Nortje, S. H.; El Mistiri, M. M.; Bayo, S.; Malle, B.; Manraj, S. S.; Sewpaul-Sungkur, R.; Fabowale, ; Bradshaw, D.; Somdyala, N. I. M.; Abdel-Rahman, M.; Jaidane, L.; Mokni, M.; Kumcher, I.; Moreno, F.; Gonzalez, M. S.; Laura, E. A.; Espinola, S. B.; Calabrano, G. H.; Carballo Quintero, B.; Fita, R.; Garcilazo, D. A.; Giacciani, P. L.; Diumenjo, M. C.; Laspada, W. D.; Green, M. A.; Lanza, M. F.; Ibanez, S. G.; Lima, C. A.; de Oliveira, E. L.; Daniel, C.; Scandiuzzi, C.; De Souza, P. C. F.; Melo, C. D.; Del Pino, K.; Laporte, C.; Curado, M. P.; de Oliveira, J. C.; Veneziano, C. L. A.; Veneziano, D. B.; Alexandre, T. S.; Verdugo, A. S.; Azevedo e Silva, G.; Galaz, J. C.; Moya, J. A.; Herrmann, D. A.; Vargas, S.; Herrera, V. M.; Uribe, C. J.; Bravo, L. E.; Arias-Ortiz, N. E.; Jurado, D. M.; Yepez, M. C.; Galan, Y. H.; Torres, P.; Martinez-Reyes, F.; Perez-Meza, M. L.; Jaramillo, L.; Quinto, R.; Cueva, P.; Yepez, J. G.; Torres-Cintron, C. R.; Tortolero-Luna, G.; Alonso, R.; Barrios, E.; Nikiforuk, C.; Shack, L.; Coldman, A. J.; Woods, R. R.; Noonan, G.; Turner, D.; Kumar, E.; Zhang, B.; Mccrate, F. R.; Ryan, S.; Hannah, H.; Dewar, R. A. D.; Macintyre, M.; Lalany, A.; Ruta, M.; Marrett, L.; Nishri, D. E.; Mcclure, C.; Vriends, K. A.; Bertrand, C.; Louchini, R.; Robb, K. I.; Stuart-Panko, H.; Demers, S.; Wright, S.; George, J. T.; Shen, X.; Brockhouse, J. T.; O'Brien, D. K.; Ward, K. C.; Almon, L.; Bates, J.; Rycroft, R.; Mueller, L.; Phillips, C.; Brown, H.; Cromartie, B.; Schwartz, A. G.; Vigneau, F.; Mackinnon, J. A.; Wohler, B.; Bayakly, A. R.; Clarke, C. A.; Glaser, S. L.; West, D.; Green, M. D.; Hernandez, B. Y.; Johnson, C. J.; Jozwik, D.; Charlton, M. E.; Lynch, C. F.; Huang, B.; Tucker, T. C.; Deapen, D.; Liu, L.; Hsieh, M. C.; Wu, X. C.; Stern, K.; Gershman, S. T.; Knowlton, R. C.; Alverson, J.; Copeland, G. E.; Rogers, D. B.; Lemons, D.; Williamson, L. L.; Hood, M.; Hosain, G. M.; Rees, J. R.; Pawlish, K. S.; Stroup, A.; Key, C.; Wiggins, C.; Kahn, A. R.; Schymura, M. J.; Leung, G.; Rao, C.; Giljahn, L.; Warther, B.; Pate, A.; Patil, M.; Schubert, S. S.; Rubertone, J. J.; Slack, S. J.; Fulton, J. P.; Rousseau, D. L.; Janes, T. A.; Schwartz, S. M.; Bolick, S. W.; Hurley, D. M.; Richards, J.; Whiteside, M. A.; Nogueira, L. M.; Herget, K.; Sweeney, C.; Martin, J.; Wang, S.; Harrelson, D. G.; Cheteri, M. K.; Farley, S.; Hudson, A. G.; Borchers, R.; Stephenson, L.; Espinoza, J. R.; Weir, H. K.; Edwards, B. K.; Wang, N.; Yang, L.; Chen, J. S.; Song, G. H.; Gu, X. P.; Zhang, P.; Ge, H. M.; Zhao, D. L.; Zhang, J. H.; Zhu, F. D.; Tang, J. G.; Shen, Y.; Wang, J.; Li, Q. L.; Yang, X. P.; Dong, J.; Li, W.; Cheng, L. P.; Chen, J. G.; Huang, Q. H.; Huang, S. Q.; Guo, G. P.; Wei, K.; Chen, W. Q.; Zeng, H.; Demetriou, A. V.; Pavlou, P.; Mang, W. K.; Ngan, K. C.; Kataki, A. C.; Krishnatreya, M.; Jayalekshmi, P. A.; Sebastian, P.; Sapkota, S. D.; Verma, Y.; Nandakumar, A.; Suzanna, E.; Keinan-Boker, L.; Silverman, B. G.; Ito, H.; Nakagawa, H.; Hattori, M.; Kaizaki, Y.; Sugiyama, H.; Utada, M.; Katayama, K.; Narimatsu, H.; Kanemura, S.; Koike, T.; Miyashiro, I.; Yoshii, M.; Oki, I.; Shibata, A.; Matsuda, T.; Nimri, O.; Ab Manan, A.; Pathy, N. B.; Chimedsuren, O.; Tuvshingerel, S.; Al Khater, A. H. M.; Al-Eid, H.; Jung, K. W.; Won, Y. J.; Chiang, C. J.; Lai, M. S.; Suwanrungruang, K.; Wiangnon, S.; Daoprasert, K.; Pongnikorn, D.; Geater, S. L.; Sriplung, H.; Eser, S.; Yakut, C. I.; Hackl, M.; Muhlbock, H.; Oberaigner, W.; Zborovskaya, A. A.; Aleinikova, O. V.; Henau, K.; Van Eycken, L.; Dimitrova, N.; Valerianova, Z.; Sekerija, M.; Zvolsky, M.; Engholm, G.; Storm, H.; Innos, K.; Magi, M.; Malila, N.; Seppa, K.; Jegu, J.; Velten, M.; Cornet, E.;
abstract

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0–14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995–99, 2000–04, and 2005–09), sex, and age at diagnosis (&lt;1, 1–4, 5–9, and 10–14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995–99, 5-year age-standardised net survival for all lymphoid leukaemias combined ranged from 10·6% (95% CI 3·1–18·2) in the Chinese registries to 86·8% (81·6–92·0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005–09, when age-standardised survival for lymphoid leukaemias ranged from 52·4% (95% CI 42·8–61·9) in Cali, Colombia, to 91·6% (89·5–93·6) in the German registries, and for AML ranged from 33·3% (18·9–47·7) in Bulgaria to 78·2% (72·0–84·3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000–04 and 2005–09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1–4 and 5–9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood cancer survival. Funding Canadian Partnership Against Cancer, Cancer Focus Northern Ireland, Cancer Institute New South Wales, Cancer Research UK, US Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, and the University of Kentucky.

2016 - A progression-risk score to predict treatment-free survival for early stage chronic lymphocytic leukemia patients [Articolo su rivista]
Gentile, M; Shanafelt, Td; Cutrona, G; Molica, S; Tripepi, G; Alvarez, I; Mauro, F. R; Di Renzo, N; Di Raimondo, F; Vincelli, I; Todoerti, K; Matis, S; Musolino, C; Fabris, S; Vigna, E; Levato, L; Zupo, S; Angrilli, F; Consoli, U; Festini, G; Longo, G; Cortelezzi, A; Arcari, A; Federico, Massimo; Mannina, D; Recchia, Ag; Neri, A; Kay, Ne; Ferrarini, M; Morabito, F.
abstract

Several phenotypic, molecular and chromosomal markers of chronic lymphocytic leukemia (CLL) cells have been identified that are significantly associated with patient prognosis.1, 2, 3, 4, 5, 6 However, these markers used singularly are inaccurate predictors of outcome for individual patients. Recent efforts have focused on combining markers to predict either treatment-free survival (TFS)4, 7, 8 or overall survival (OS),9, 10, 11 however, further effort is worthwhile to determine how to combine prognostic parameters, optimize risk stratification, simplify calculations and/or identify new prognostic variables.

2016 - Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma [Articolo su rivista]
Johnson, Peter; Federico, Massimo; Kirkwood, Amy; Fosså, Alexander; Berkahn, Leanne; Carella, Angelo; D'Amore, Francesco; Enblad, Gunilla; Franceschetto, Antonella; Fulham, Michael; Luminari, Stefano; O'Doherty, Michael; Patrick, Pip; Roberts, Thomas; Sidra, Gamal; Stevens, Lindsey; Smith, Paul; Trotman, Judith; Viney, Zaid; Radford, John; Barrington, Sally
abstract

BACKGROUND: We tested interim positron-emission tomography-computed tomography (PET-CT) as a measure of early response to chemotherapy in order to guide treatment for patients with advanced Hodgkin's lymphoma. METHODS: Patients with newly diagnosed advanced classic Hodgkin's lymphoma underwent a baseline PETCT scan, received two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy, and then underwent an interim PET-CT scan. Images were centrally reviewed with the use of a 5-point scale for PET findings. Patients with negative PET findings after two cycles were randomly assigned to continue ABVD (ABVD group) or omit bleomycin (AVD group) in cycles 3 through 6. Those with positive PET findings after two cycles received BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Radiotherapy was not recommended for patients with negative findings on interim scans. The primary outcome was the difference in the 3-year progression-free survival rate between randomized groups, a noninferiority comparison to exclude a difference of 5 or more percentage points. RESULTS: A total of 1214 patients were registered; 937 of the 1119 patients (83.7%) who underwent an interim PET-CT scan according to protocol had negative findings. With a median follow-up of 41 months, the 3-year progression-free survival rate and overall survival rate in the ABVD group were 85.7% (95% confidence interval [CI], 82.1 to 88.6) and 97.2% (95% CI, 95.1 to 98.4), respectively; the corresponding rates in the AVD group were 84.4% (95% CI, 80.7 to 87.5) and 97.6% (95% CI, 95.6 to 98.7). The absolute difference in the 3-year progression-free survival rate (ABVD minus AVD) was 1.6 percentage points (95% CI, -3.2 to 5.3). Respiratory adverse events were more severe in the ABVD group than in the AVD group. BEACOPP was given to the 172 patients with positive findings on the interim scan, and 74.4% had negative findings on a third PET-CT scan; the 3-year progression-free survival rate was 67.5% and the overall survival rate 87.8%. A total of 62 patients died during the trial (24 from Hodgkin's lymphoma), for a 3-year progression-free survival rate of 82.6% and an overall survival rate of 95.8%. CONCLUSIONS: Although the results fall just short of the specified noninferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects than with continued ABVD but not significantly lower efficacy.

2016 - Age-adjusted international prognostic index is a predictor of survival in gastric diffuse B-cell non-Hodgkin lymphoma patients [Articolo su rivista]
Delamain, Marcia Torresan; da Silva, Maria Gomes; Miranda, Eliana Cristina Martins; Desterro, Joana; Luminari, Stefano; Fedina, Anna; Merli, Francesco; Chiattone, Carlos Sergio; Pagnano, Katia Borgia Barbosa; Federico, Massimo; de Souza, Carmino Antonio
abstract

Background The clinical course of gastric lymphoma is heterogeneous and clinical symptoms and some factors have been related to prognosis. Objective The present study aims to identify prognostic factors in gastric diffuse B-cell non-Hodgkin lymphoma diagnosed and treated in different countries. Methods A consecutive series of gastric diffuse B-cell non-Hodgkin lymphoma patients diagnosed and treated in Brazil, Portugal and Italy, between February 2008 and December 2014 was evaluated. Results Of 104 patients, 57 were female and the median age was 69 years (range: 28–88). The distribution of the age-adjusted international prognostic index was 12/95 (13%) high risk, 20/95 (21%) high-intermediate risk and 63/95 (66%) low/low-intermediate risk. Symptoms included abdominal pain (63/74), weight loss (57/73), dysphagia (37/72) and nausea/vomiting (37/72). Bulky disease was found in 24% of the cases, anemia in 33 of 76 patients and bleeding in 22 of 72 patients. The median follow-up time was 25 months (range: 1–77 months), with 1- and 5-year survival rates of 79% and 76%, respectively. The multivariate Cox Regression identified the age-adjusted international prognostic index as a predictor of death (hazard risk: 3.62; 95% confidence interval: 2.21–5.93; p-value &lt;0.0001). Conclusions This series identified the age-adjusted international prognostic index as predictive of mortality in patients treated with conventional immunochemotherapy.

2016 - Baseline Metabolic Tumor Volume Predicts Outcome in High-Tumor-Burden Follicular Lymphoma: A Pooled Analysis of Three Multicenter Studies [Articolo su rivista]
Meignan, Michel; Cottereau, Anne Ségolène; Versari, Annibale; Chartier, Loïc; Dupuis, Jehan; Boussetta, Sami; Grassi, Ilaria; Casasnovas, René Olivier; Haioun, Corinne; Tilly, Hervé; Tarantino, Vittoria; Dubreuil, Julien; Federico, Massimo; Salles, Gilles; Luminari, Stefano; Trotman, Judith
abstract

Identifying patients at high risk of progression and early death among those with high-tumor-burden follicular lymphoma (FL) is unsatisfactory with current prognostic models. This study aimed to determine the prognostic impact of the total metabolic tumor volume (TMTV) measured at baseline with [(18)F]fluorodeoxyglucose/positron emission tomography-computed tomography ([(18)F]FDG/PET-CT) scans and its added value to these models.

2016 - Brentuximab vedotin followed by ABVD +/- radiotherapy in patients with previously untreated Hodgkin lymphoma: final results of a pilot phase II study [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Pellegrini, Cinzia; Merli, Francesco; Pesce, Emanuela Anna; Chauvie, Stephane; Gandolfi, Letizia; Capodanno, Isabella; Salati, Massimiliano; Argnani, Lisa; Zinzani, Pier Luigi
abstract

N/A

2016 - G-CSF use in patients receiving first-line chemotherapy for non-Hodgkin’s lymphoma (NHL) and granulocyte-colony stimulating factors (G-CSF) as observed in clinical practice in Italy [Articolo su rivista]
Vitolo, Umberto; Angrili, Francesco; Decosta, Lucy; Wetten, Sally; Federico, Massimo
abstract

Treatment of non-Hodgkin lymphoma (NHL) requires chemotherapy regimens with significant risk of febrile neutropenia (FN). For patients at ≥20% FN risk, guidelines recommend primary prophylaxis (PP) with granulocyte-colony stimulating factor (G-CSF). This study assessed whether G-CSF use in NHL was in line with recommendations in routine practice. This was a retrospective, observational study of adult NHL patients receiving first-line (R)CHOP-like chemotherapy and G-CSF support between June 2010 and 2012, in Italy. The primary outcome was whether G-CSF was provided as PP, which was defined as G-CSF initiation on days 1–3 after chemotherapy, ≥3 days’ use for daily G-CSFs and continued prophylaxis from cycle 1 across all cycles. Secondary prophylaxis was defined as continued prophylaxis from cycle 2 or later, and all other use was defined as Suboptimal. The analysis included 199 patients, 61% of whom had diffuse large B cell lymphoma and 21% follicular lymphoma. (R)CHOP-21 was given to 52% of patients and (R)CHOP-14 to 32%. Overall, 29% of patients received PP, while two-thirds received Suboptimal G-CSF. Of patients receiving daily G-CSF, 3% received PP and 94% received Suboptimal use; with pegfilgrastim, 65% received PP and 26% Suboptimal use. FN occurred in 13 patients (7%) and grade 3/4 neutropenia in 43%. Chemotherapy dose delays occurred in 22% and dose reductions in 18% of patients. Delivery of G-CSF, particularly daily G-CSFs, was not in accordance with guideline or product label recommendations in a large proportion of NHL patients receiving chemotherapy in Italy.

2016 - Increased incidence of breast cancer in postmenopausal women with high body mass index at the modena screening program [Articolo su rivista]
Sebastiani, F.; Cortesi, L.; Sant, M.; Lucarini, V.; Cirilli, C.; De Matteis, E.; Marchi, I.; Negri, R.; Gallo, E.; Federico, M.
abstract

Purpose: We conducted a study to evaluate the relationship between body mass index (BMI) and the risk of breast cancer (BC) and outcome in a population of 14,684 women aged 55 to 69 years eligible to participate in the Mammography Screening Program (MSP) in the Province of Modena, Italy. Methods: The study population was drawn from women who underwent mammography screening between 2004 and 2006 in the Province of Modena. Women were subdivided into obese, overweight, and normal-weight categories according to BMI and followed until July 31, 2010, to evaluate the BC incidence. The clinicopathological characteristics of BC were also evaluated in different groups of patients classified according to BMI. After BC diagnosis, patients were followed for a median period of 65 (range, 2–104) months. Second events (recurrences and second tumors) were recorded, and the 5-year event-free survival (EFS) was calculated. Results: After a period of 73 months, 366 cases of BC were diagnosed. Compared with normal-weight women, obese women had a significantly higher incidence of BC (relative risk [RR], 1.32; p= 0.040) (RR=1), larger tumors (27% of tumors were larger than T2 size), and more nodal involvement (38.5% of tumors were node-positive). Furthermore, a significantly higher rate of total events was seen in obese women compared with overweight and normal-weight patients, respectively (17.9% vs. 11.4% vs. 10.8%, p=0.032). The 5-year EFS was 89.0%, 89.0%, and 80.0% for normal-weight, overweight, and obese patients, respectively. Conclusion: We observed a significantly higher risk of BC in obese women among those eligible to participate in the MSP in the Province of Modena. Finally, obese women had more second events and poorer EFS compared to nono bese women.

2016 - Interim PET-CT scan in advanced Hodgkin's lymphoma [Articolo su rivista]
Johnson, P.; Trotman, J.; Federico, Massimo
abstract

abstract not available

2016 - Khorana score and histotype predict the incidence of early venous thromboembolism (VTE) in Non Hodgkin Lymphoma (NHL). A pooled data analysis of twelve clinical trials of Fondazione Italiana Linfomi (FIL) [Abstract in Rivista]
Santi, R. M; Ceccarelli, M; Catania, G; Monagheddu, C; Evangelista, A; Bernocco, E; Monaco, F; Federico, Massimo; Vitolo, U; Cortelazzo, S; Cabras, M. G; Spina, M; Baldini, L; Boccomini, C; Chiappella, A; Bari, Alessia; Luminari, Stefano; Calabrese, M; Levis, A; Visco, C; Contino, L; Ciccone, G; Ladetto, M.
abstract

Recent studies show that the risk of VTE in NHL pts is similar to that observed in high risk solid tumors (i.e. pancreatic, ovarian cancer). VTE in NHL occurs in most cases within three months from diagnosis and can have substantial impact on treatment delivery and outcome as well as on quality of life. However few data are available on potential predictors.

2016 - Long-term results of the HD2000 trial comparing ABVD versus BEACOPP versus COPP-EBV-CAD in untreated patients with advanced hodgkin lymphoma: A study by fondazione Italiana Linfomi [Articolo su rivista]
Merli, Francesco; Luminari, Stefano; Gobbi, Paolo G.; Cascavilla, Nicola; Mammi, Caterina; Ilariucci, Fiorella; Stelitano, Caterina; Musso, Maurizio; Baldini, Luca; Galimberti, Sara; Angrilli, Francesco; Polimeno, Giuseppe; Scalzulli, Potito Rosario; Ferrari, Angela; Marcheselli, Luigi; Federico, Massimo
abstract

Purpose The randomized HD2000 trial compared six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), four escalated plus two standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and six cycles of COPPEBV- CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin; CEC) in patients with advanced-stage Hodgkin lymphoma. After a median follow-up of 42 months, patients who received BEACOPP were reported to have experienced better progression-free survival (PFS) but not better overall survival (OS) results than those receiving ABVD. Wehere report a post hoc analysis of this trial after a median follow-up of 10 years. Patients and Methods Three hundred seven patients were enrolled, 295 of whom were evaluable. At the time of our analysis, the median follow-up for the entire group was 120 months (range, 4 to 169 months). Results The 10-year PFS results for the ABVD, BEACOPP, and CEC arms were 69%, 75%, and 76%, respectively; corresponding OS results were 85%, 84%, and 86%. Overall, 13 second malignancies were reported: one in the ABVD arm and six each in the BEACOPP and CEC arms. The cumulative risk of developing secondmalignancies at 10 years was 0.9%, 6.6%, and 6% with ABVD, BEACOPP, and CEC, respectively; the risk with either BEACOPP or CEC was significantly higher than that reported with ABVD (P = .027 and .02, respectively). Conclusion With these mature results, we confirm that patients with advanced Hodgkin lymphoma have similar OS results when treated with ABVD, BEACOPP, or CEC. However, with longer follow-up, we were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality rates resulting from second malignancies observed after treatment with BEACOPP and CEC.

2016 - PET-CT for staging and early response: Results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study [Articolo su rivista]
Barrington, Sally F; Kirkwood, Amy A.; Franceschetto, Antonella; Fulham, Michael J.; Roberts, Thomas H.; Almquist, Helén; Brun, Eva; Hjorthaug, Karin; Viney, Zaid N.; Pike, Lucy C.; Federico, Massimo; Luminari, Stefano; Radford, John; Trotman, Judith; Fosså, Alexander; Berkahn, Leanne; Molin, Daniel; D'Amore, Francesco; Sinclair, Donald A.; Smith, Paul; O'Doherty, Michael J.; Stevens, Lindsey; Johnson, Peter W.
abstract

International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design.PET-CTwasreported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2scans. TheRATHLand PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a k (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice.

2016 - Positron emission tomography response and minimal residual disease impact on progression-free survival in patients with follicular lymphoma. A subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi [Articolo su rivista]
Luminari, Stefano; Galimberti, Sara; Versari, Annibale; Biasoli, Irene; Anastasia, Antonella; Rusconi, Chiara; Ferrari, Angela; Petrini, Mario; Manni, Martina; Federico, Massimo
abstract

The aim of the present study was to analyze the prognostic role of combined PET and BCL2/IGH analysis, performed at the EOT, in a subset study of the phase III trial FOLL05 (NCT00774826), in which patients with FL were randomized to R-CVP (rituximab plus cyclophosphamide, vincristine and prednisone), R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) or R-FM (rituximab plus fludarabine and mitoxantrone).6 This study was conducted in compliance with the Declaration of Helsinki, was approved by the appropriate research ethics committee, and required each patient to provide written informed consent.

2016 - Prospective validation of predictive value of abdominal computed tomography scan on time to first treatment in Rai 0 chronic lymphocytic leukemia patients: results of the multicenter O-CLL1-GISL study [Articolo su rivista]
Gentile, Massimo; Cutrona, Giovanna; Molica, Stefano; Ilariucci, Fiorella; Mauro, Francesca R; Di Renzo, Nicola; Di Raimondo, Francesco; Vincelli, Iolanda; Todoerti, Katia; Matis, Serena; Musolino, Caterina; Fabris, Sonia; Lionetti, Marta; Levato, Luciano; Zupo, Simona; Angrilli, Francesco; Consoli, Ugo; Festini, Gianluca; Longo, Giuseppe; Cortelezzi, Agostino; Musto, Pellegrino; Federico, Massimo; Neri, Antonino; Ferrarini, Manlio; Morabito, Fortunato
abstract

We performed an external and multicentric validation of the predictive value of abdominal computed tomography (aCT) on time to first treatment (TTFT) in early stage chronic lymphocytic leukemia (CLL) patients. METHODS: aCT was performed at diagnosis in 181 Rai 0 patients enrolled in the O-CLL1-GISL trial (clinicaltrial.gov ID:NCT00917549). RESULTS: Fifty-five patients showed an abnormal aCT. Patients with an abnormal aCT showed a significantly shorter TTFT than those with normal aCT (P < 0.0001). At multivariate analysis, aCT (P = 0.011), β-2 microglobulin (P = 0.019), and CD38 expression (P = 0.047) correlated with TTFT. Following IWCLL 2008 criteria, 112 (61.9%) cases remained at Rai 0, while 69 (38.1%) satisfied the criteria of clinical monoclonal B-cell lymphocytosis (cMBL). Reclassified Rai 0 patients with an abnormal aCT showed a significantly shorter TTFT than those with a normal aCT (P < 0.0001). At multivariate analysis, only aCT (P = 0.011) correlated with TTFT. Eleven cMBL cases (15.9%) showed an abnormal aCT and were reclassified as small lymphocytic lymphomas (SLL); nonetheless, TTFT was similar for cMBLs and SLLs. CONCLUSION: Our results confirm the ability of the abnormal aCT to predict progression in early stage cases.

2016 - Reply to T.P. Vassilakopoulos et al [Articolo su rivista]
Merli, Francesco; Federico, Massimo; Luminari, Stefano
abstract

Lettera di risposta all'articolo "Long-term results of the HD2000 trial comparing ABVD versus BEACOPP versus COPP-EBV-CAD in untreated patients with advanced hodgkin lymphoma: A study by fondazione Italiana Linfomi" pubblicato sulla medesima rivista

2016 - STRATEGIES TO PREDICT TREATMENT RESPONSE AND SELECT THERAPIES IN METASTATIC BREAST CANCER PATIENTS USING A NEXT GENERATION SEQUENCING MULTI-GENE PANEL [Abstract in Atti di Convegno]
Toss, Angela; Cortesi, Laura; Artuso, Lucia; Tenedini, Elena; Bernardis, Isabella; Ficarra, G; Piacentini, Federico; Federico, Massimo; Tagliafico, Enrico
abstract

The standard of care for many patients with advanced breast cancer (BC )is gradually evolving from empirical treatment based on clinicalpathological characteristics to the use of targeted approaches based on the molecular profile of the tumor. In the last decade, an increasing number of molecularly targeted drugs have been developed for the treatment of metastatic BC. These drugs target specific molecular abnormalities that confer to cancer cells a survival advantage. Interestingly, the ability to perform multigene testing for a range of molecular alterations may provide an opportunity to clarify the mechanisms of treatment response, to find the strategies to overcome treatment resistance and thus, to identify patients who are more likely to develop relapse and who may be candidates for matched targeted therapies. The main aim of this study is to find prognostic and predictive molecular biomarkers for the management of metastatic BC patients in clinical practice.

2016 - STRATEGIES TO PREDICT TREATMENT RESPONSE AND SELECT THERAPIES IN METASTATIC BREAST CANCER PATIENTS USING A NEXT GENERATION SEQUENCING (NGS) MULTI-GENE PANEL [Poster]
Toss, Angela; Cortesi, Laura; Artuso, Lucia; Tenedini, Elena; Bernardis, Isabella; Parenti, Sandra; Ficarra, Guido; Piacentini, Federico; Federico, Massimo; Tagliafico, Enrico
abstract

The standard of care for many patients with advanced breast cancer (BC )is gradually evolving from empirical treatment based on clinicalpathological characteristics to the use of targeted approaches based on the molecular profile of the tumor. In the last decade, an increasing number of molecularly targeted drugs have been developed for the treatment of metastatic BC. These drugs target specific molecular abnormalities that confer to cancer cells a survival advantage [1]. Interestingly, the ability to perform multigene testing for a range of molecular alterations may provide an opportunity to clarify the mechanisms of treatment response, to find the strategies to overcome treatment resistance and thus, to identify patients who are more likely to develop relapse and who may be candidates for matched targeted therapies [2-3]. The main aim of this study is to find prognostic and predictive molecular biomarkers for the management of metastatic BC patients in clinical practice. MATERIALS AND METHODS The amplicon-sequencing analyses took advantage of the Ion AmpliSeq™ technology (Thermo Fisher, Waltham, MA, USA). A custom panel was designed with the help of the Designer online tool (www.ampliseq.com), which was employed to generate optimized primers encompassing the coding DNA sequences (with 100bp of exon padding and the UTRs regions) of 25 genes in the Human Reference Genome (hg19); these genes were selected searching and screening scientific literature for treatments resistance in BC and are reported in Table 1. Primer pairs were divided into two pools to optimize multiplex PCR conditions and the coverage, that assessed to 89.02%. The customized Ion AmpliSeq panel was employed on samples from 7 primary BC samples and matched metastatic sites (3 skin, 3 lymph node and 1 lung metastases). They were all processed using the Ion AmpliSeq Library Kit 2.0, starting from 15 nanograms of FFPE extracted DNA/pool. Samples were barcoded with the Ion Express Kit to optimize matched patients pooling on the same 318 Chip v2 sequencing chip. The template-positive Ion Sphere Particles were sequenced on a Personal Genome Machine (Thermo Fisher, Waltham, MA, USA). RESULTS The mutation profiles of paired primary and secondary tumors of the seven patients enrolled in this study are presented in Table 2. Ten different genes (PTEN, PIK3CA, mTOR, ERBB2, ERBB3, MET, INPP4B, MAP2K1, CDK6, KRAS) in 6 different patients showed possible damaging variants as shown in Table 2. • Four patients (number 1, 3, 5 and 6) showed no additional or different mutations in secondary tumors if compared to primary samples. • In patient number 2, the metastatic site presented new mutations if compared to the primary tumor. • Finally in patient number 4 and 7 we did not detect in metastases some of the mutations found in the primary tumor. DISCUSSION In 5 patients (71,4%) the mutational status of primary tumor could explain treatment resistance and thus predict relapse, in one patient the mutational status of the new subclones could be relevant for guiding differently the subsequent treatment choices. In 2 patients (28,5%) we were not able to detect in metastases some of the mutations found in the primary tumor. This could be explained by considering the clonal evolution of metastases. These preliminary data suggest that the multi-gene panel analysis of primary and secondary tumors may help clinicians: • in discriminating BC patients HR+ and/or HER2+ with mutations predicting an increased risk of adjuvant treatment resistance and thus relapse • in guiding treatment selection strategies in the metastatic setting. The study is still open and we are currently recruiting other patients.

2016 - The 68Ge phantom-based FDG-PET site qualification program for clinical trials adopted by FIL (Italian Foundation on Lymphoma) [Articolo su rivista]
Chauvie, Stephane; Bergesio, Fabrizio; Fioroni, Federica; Brambilla, Marco; Biggi, Alberto; Versari, Annibale; Guerra, Luca; Storto, Giovanni; Musto, Pellegrino; Luminari, Stefano; Cabras, Maria G.; Balzarotti, Monica; Rigacci, Luigi; Martelli, Maurizio; Vitolo, Umberto; Federico, Massimo; Gallamini, Andrea
abstract

Purpose: The quantitative assessment of Positron Emission Tomography (PET) scans using standardized uptake value and derived parameters proved to be superior to traditional qualitative assessment in several retrospective or mono-centric prospective reports. Since different scanners give different quantitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of quantitative PET in prospective multi-centre clinical trials and in every-day clinical life. Methods: We set up, under the auspices of Italian Foundation on Lymphoma (FIL), a CTQ program consisting of the PET/CT scan acquisition and analysis of 18F and 68Ge NEMA/IEC image quality phantoms for the reduction of inter-scanner variability. Variability was estimated on background activity concentration (BAC) and sphere to background ratio (SBR). Results: The use of a 68Ge phantom allowed reducing the inter-scanner variability among different scanners from 74.0% to 20.5% in BAC and from 63.3% to 17.4% in SBR compared to using the 18F phantom. The CTQ criteria were fulfilled at first round in 100% and 28% of PET scanners with 68Ge and 18F respectively. Conclusions: The 68Ge phantom proved a reliable tool for PET scanner qualification, able to significantly reduce the potential sources of error while increasing the reproducibility of PET derived quantitative parameter measurement.

2015 - Absolute monocyte count and lymphocyte-monocyte ratio predict outcome in nodular sclerosis Hodgkin lymphoma: Evaluation based on data from 1450 patients [Articolo su rivista]
Tadmor, Tamar; Bari, Alessia; Marcheselli, Luigi; Sacchi, Stefano; Aviv, Ariel; Baldini, Luca; Gobbi, Paolo G.; Pozzi, Samantha; Ferri, Paola; Cox, Maria Christina; Cascavilla, Nicola; Iannitto, Emilio; Federico, Massimo; Polliack, Aaron
abstract

Objective: To verify whether absolute monocyte count (AMC) and lymphocyte-monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL). Patients and Methods: Data were collected from 1450 patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007. Results: The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm3, and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm(3) was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm(3) was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm(3) or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm3 was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm(3) or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio [HR], 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm(3). Conclusion: This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice.

2015 - Brentuximab Vedotin in CD30-Positive Lymphomas: A SIE, SIES, and GITMO Position Paper [Articolo su rivista]
Zinzani, Pier Luigi; Corradini, Paolo; Gianni, Alessandro M.; Federico, Massimo; Santoro, Armando; Vitolo, Umberto; Barosi, Giovanni; Tura, Sante
abstract

Brentuximab vedotin (BV) is approved for the treatment of patients with relapsed or refractory CD30-positive Hodgkin lymphoma, and relapsed or refractory systemic anaplastic large-cell lymphoma. Several uncertainties remain regarding the optimal use of the drug in its approved indications as well as outside them. This article reports recommendations on the use of BV issued during a consensus project, sponsored by the Italian Society of Hematology (SIE) and its affiliate societies, Società Italiana di Ematologia Sperimentale (SIES) and Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Scientific evidence on BV was evaluated by a panel of experts, and consensus was developed by group discussion for key questions selected according to the clinical relevance. The following key issues were addressed: testing CD30 positivity to assess eligibility to BV; assessing practice indications of BV in Hodgkin lymphoma and systemic anaplastic large-cell lymphoma; providing pretreatment evaluation of patients candidates to BV; monitoring the response to BV; managing patients treated with BV; and assessing the role of BV in other CD30-positive lymphomas.

2015 - Cancer incidence, mortality, and survival in Eastern Libya: Updated report from the Benghazi Cancer Registry [Articolo su rivista]
El Mistiri, Mufid; Salati, Massimiliano; Marcheselli, Luigi; Attia, Adel; Habil, Salah; Alhomri, Faraj; Spika, Devon; Allemani, Claudia; Federico, Massimo
abstract

Purpose: Despite the increasing burden of cancer occurred over recent years in the African continent, epidemiologic data from Northern Africa area have been so far sparse or absent. We present most recently available data from the Benghazi Cancer Registry concerning cancer incidence and mortality as well as the most comprehensive survival data set so far generated for cases diagnosed during 2003 to 2005 in Eastern Libya. Methods: We collected and analyzed data on cancer incidence, mortality and survival that were obtained over a 3-year study period from January 1st 2003 to December 31st 2005 from the Benghazi Cancer Registry. Results: A total of 3307 cancer patients were registered among residents during the study period. The world age-standardized incidence rate for all sites was 135.4 and 107.1 per 100,000 for males and females, respectively. The most common malignancies in men were cancers of lung (18.9%), colorectum (10.4%), bladder (10.1%), and prostate (9.4%); among women, they were breast (23.2%), colorectum (11.2%), corpus uteri (6.7%), and leukemia (5.1%). A total of 1367 deaths for cancer were recorded from 2003 to 2005; the leading causes of cancer death were cancers of the lung (29.3%), colorectum (8.2%), and brain (7.3%) in males and cancers of breast (14.8%), colorectum (10.6%), and liver (7%) in females. The 5-year relative survival for all cancer combined was 22.3%; survival was lower in men (19.8%) than in women (28.2%). Conclusions: This study provides an updated report on cancer incidence, mortality, and survival, in Eastern Libya which may represent a useful tool for planning future interventions toward a better cancer control.

2015 - Changes in cervical cancer incidence following the introduction of organized screening in italy [Articolo su rivista]
Serraino, Diego; Gini, Andrea; Taborelli, Martina; Ronco, Guglielmo; Giorgi Rossi, Paolo; Zappa, Marco; Crocetti, Emanuele; Franzo, Antonella; Falcini, Fabio; Visioli, Carmen Beatriz; Stracci, Fabrizio; Zorzi, Manuel; Federico, Massimo; Michiara, Maria; Fusco, Mario; Ferretti, Stefano; Pannozzo, Fabio; Tisano, Francesco; Zanetti, Roberto; Zucchetto, Antonella
abstract

OBJECTIVE: To quantify the impact of organized cervical screening programs (OCSPs) on incidence of invasive cervical cancer (ICC), comparing rates before and after OCSPs' activation. METHODS: This population-based investigation, using individual data from cancer registries and OCSPs, included 3557 women diagnosed with ICC at age 25-74 years in 1995-2008. The year of OCSPs' full-activation was defined as the year when at least 40% of target women had been invited. Incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs) were calculated as the ratios between age-standardized incidence rates observed in periods after OCSPs' full-activation vs those observed in the preceding quinquennium. RESULTS: ICC incidence rates diminished with time since OCSPs' full-activation: after 6-8 years, the IRR was 0.75 (95%CI: 0.67-0.85). The reduction was higher for stages IB-IV (IRR=0.68, 95%CI: 0.58-0.80), squamous cell ICCs (IRR=0.74, 95%CI: 0.64-0.84), and particularly evident among women aged 45-74 years. Conversely, incidence rates of micro-invasive (stage IA) ICCs increased, though not significantly, among women aged 25-44 years (IRR=1.34, 95%CI: 0.91-1.96). Following OCSPs' full-activation, micro-invasive ICCs were mainly and increasingly diagnosed within OCSPs (up to 72%). CONCLUSION(S): Within few years from activation, organized screening positively impacted the already low ICC incidence in Italy and favored down-staging.

2015 - Dismal outcome of t-cell lymphoma patients failing first-line treatment: results of a population-based study from the Modena Cancer Registry [Articolo su rivista]
Biasoli, Irene; Cesaretti, Marina; Bellei, Monica; Maiorana, Antonino; Bonacorsi, Goretta; Quaresima, Micol; Salati, Massimiliano; Federico, Massimo; Luminari, Stefano
abstract

We conducted a population-based study to establish the outcome of T-cell lymphoma (TCL) patients failing systemic first-line therapy. All TCL patients failing first-line systemic therapy in the province of Modena were identified from Modena Cancer Registry between 1997 and 2010. A total of 53 patients were analysed. Regarding the type of failure, 18 patients relapsed, and 35 progressed during first treatment. Among relapsed patients, the median time from date of response to relapse after first treatment was 6.2 months (range 1.87-102). A total of 18 patients (34%) died before receiving salvage treatment, 21 received platinum or gemcitabine-containing regimens (7 addressed to autologous stem cell transplant (ASCT)), 12 other CT regimens; 2 received radiotherapy (RT). The median survival after relapse (SAR) was 2.5 months. After a median follow-up for living patients after failure of 35 months (range 8-111 months), 44 patients died, and the cause of death was found to be lymphoma progression in all (98%) but one of them. The median SAR was 2.5 months. The 3-year SAR was 19%. Univariate and multivariate Cox regression analyses for SAR were performed. In multivariate analysis, performance status and type of failure were associated with a higher risk of death after relapse. The outcome of TCL patients failing first-line therapy is poor. Only a few cases that could receive ASCT had promising chances of long remission. There is urgent need for novel agents for patients requiring second-line treatment. Copyright © 2014 John Wiley & Sons, Ltd.

2015 - FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor [Articolo su rivista]
Peterlongo, Paolo; Catucci, Irene; Colombo, Mara; Caleca, Laura; Mucaki, Eliseos; Bogliolo, Massimo; Marin, Maria; Damiola, Francesca; Bernard, Loris; Pensotti, Valeria; Volorio, Sara; Dall'Olio, Valentina; Meindl, Alfons; Bartram, Claus; Sutter, Christian; Surowy, Harald; Sornin, Valérie; Dondon, Marie Gabrielle; Eon Marchais, Séverine; Stoppa Lyonnet, Dominique; Andrieu, Nadine; Sinilnikova, Olga M.; Mitchell, Gillian; James, Paul A.; Thompson, Ella; Marchetti, Marina; Verzeroli, Cristina; Tartari, Carmen; Capone, Gabriele Lorenzo; Putignano, Anna Laura; Genuardi, Maurizio; Medici, Veronica; Marchi, Isabella; Federico, Massimo; Tognazzo, Silvia; Matricardi, Laura; Agata, Simona; Dolcetti, Riccardo; Puppa, Lara Della; Cini, Giulia; Gismondi, Viviana; Viassolo, Valeria; Perfumo, Chiara; Mencarelli, Maria Antonietta; Baldassarri, Margherita; Peissel, Bernard; Roversi, Gaia; Silvestri, Valentina; Rizzolo, Piera; Spina, Francesca; Vivanet, Caterina; Tibiletti, Maria Grazia; Caligo, Maria Adelaide; Gambino, Gaetana; Tommasi, Stefania; Pilato, Brunella; Tondini, Carlo; Corna, Chiara; Bonanni, Bernardo; Barile, Monica; Osorio, Ana; Benitez, Javier; Balestrino, Luisa; Ottini, Laura; Manoukian, Siranoush; Pierotti, Marco A.; Renieri, Alessandra; Varesco, Liliana; Couch, Fergus J.; Wang, Xianshu; Devilee, Peter; Hilbers, Florentine S.; van Asperen, Christi J.; Viel, Alessandra; Montagna, Marco; Cortesi, Laura; Diez, Orland; Balmaña, Judith; Hauke, Jan; Schmutzler, Rita K.; Papi, Laura; Pujana, Miguel Angel; Lázaro, Conxi; Falanga, Anna; Offit, Kenneth; Vijai, Joseph; Campbell, Ian; Burwinkel, Barbara; Kvist, Anders; Ehrencrona, Hans; Mazoyer, Sylvie; Pizzamiglio, Sara; Verderio, Paolo; Surralles, Jordi; Rogan, Peter K.; Radice, Paolo
abstract

Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p. Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p. Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.

2015 - FLORENCE: A randomized, double-blind, phase III pivotal study of febuxostat versus allopurinol for the prevention of tumor lysis syndrome (TLS) in patients with hematologic malignancies at intermediate to high TLS risk [Articolo su rivista]
Spina, Michele; Nagy, Z.; Ribera, J. M.; Federico, Massimo; Aurer, I.; Jordan, K.; Borsaru, G.; Pristupa, A. S.; Bosi, A.; Grosicki, S.; Glushko, N. L.; Ristic, D.; Jakucs, J.; Montesinos, P.; Mayer, J.; Rego, E. M.; Baldini, S.; Scartoni, S.; Capriati, A.; Maggi, C. A.; Simonelli, C.
abstract

Background: Serum uric acid (sUA) control is of key relevance in tumor lysis syndrome (TLS) prevention as it correlates with both TLS and renal event risk. We sought to determine whether febuxostat fixed dose achieves a better sUA control than allopurinol while preserving renal function in TLS prevention. Patients and methods: Patients with hematologic malignancies at intermediate to high TLS risk grade were randomized to receive febuxostat or allopurinol, starting 2 days before induction chemotherapy, for 7-9 days. Study treatment was blinded, whereas daily dose (low/standard/high containing allopurinol 200/300/600 mg, respectively, or fixed febuxostat 120 mg) depended on the investigator's choice. The co-primary end points, sUA area under curve (AUC sUA1-8) and serum creatinine change, were assessed from baseline to day 8 and analyzed through analysis of covariance with two-sided overall significance level of 5%. Secondary end points included treatment responder rate, laboratory and clinical TLS incidence and safety. Results: A total of 346 patients (82.1% intermediate TLS risk; 82.7% assigned to standard dose) were randomized. Mean AUC sUA1-8 was 514.0 ± 225.71 versus 708.0 ± 234.42 mgxh/dl (P < 0.0001) in favor of febuxostat. Mean serum creatinine change was -0.83 ± 26.98% and -4.92 ± 16.70% for febuxostat and allopurinol, respectively (P = 0.0903). No differences among secondary efficacy end points were detected. Drug-related adverse events occurred in 6.4% of patients in both arms. Conclusion: In the largest adult trial carried out in TLS prevention, febuxostat achieved a significant superior sUA control with one fixed dose in comparison to allopurinol with comparable renal function preservation and safety profile. Clinical trial registration: NCT01724528.

2015 - Global surveillance of cancer survival 1995-2009: Analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2) [Articolo su rivista]
Allemani, C.; Weir, H. K.; Carreira, H.; Harewood, R.; Spika, D.; Wang, X. -S.; Bannon, F.; Ahn, J. V.; Johnson, C. J.; Bonaventure, A.; Marcos-Gragera, R.; Stiller, C.; Azevedo E Silva, G.; Chen, W. -Q.; Ogunbiyi, O. J.; Rachet, B.; Soeberg, M. J.; You, H.; Matsuda, T.; Bielska-Lasota, M.; Storm, H.; Tucker, T. C.; Coleman, M. P.; Bouzbid, S.; Hamdi-Cherif, M.; Zaidi, Z.; Bah, E.; Swaminathan, R.; Nortje, S. H.; Stefan, C. D.; El Mistiri, M. M.; Bayo, S.; Malle, B.; Manraj, S. S.; Sewpaul-Sungkur, R.; Fabowale, A.; Bradshaw, D.; Somdyala, N. I. M.; Abdel-Rahman, M.; Jaidane, L.; Mokni, M.; Kumcher, I.; Moreno, F.; Gonzalez, M. S.; Laura, E.; Pugh, F. V.; Torrent, M. E.; Carballo Quintero, B.; Fita, R.; Garcilazo, D.; Giacciani, P. L.; Diumenjo, M. C.; Laspada, W. D.; Green, M. A.; Lanza, M. F.; Ibanez, S. G.; Lima, C. A.; Lobo, E.; Daniel, C.; Scandiuzzi, C.; De Souza, P. C. F.; Del Pino, K.; Laporte, C.; Curado, M. P.; de Oliveira, J. C.; Veneziano, C. L. A.; Veneziano, D. B.; Alexandre, T. S.; Verdugo, A. S.; Koifman, S.; Galaz, J. C.; Moya, J. A.; Herrmann, D. A.; Jofre, A. M.; Uribe, C. J.; Bravo, L. E.; Lopez Guarnizo, G.; Jurado, D. M.; Yepes, M. C.; Galan, Y. H.; Torres, P.; Martinez-Reyes, F.; Jaramillo, L.; Quinto, R.; Cueva, P.; Yepez, J.; Torres-Cintron, C. R.; Tortolero-Luna, G.; Alonso, R.; Barrios, E.; Russell, C.; Shack, L.; Coldman, A. J.; Woods, R. R.; Noonan, G.; Turner, D.; Kumar, E.; Zhang, B.; Mccrate, F. R.; Ryan, S.; Hannah, H.; Dewar, R. A. D.; Macintyre, M.; Lalany, A.; Ruta, M.; Marrett, L.; Nishri, D. E.; Vriends, K. A.; Bertrand, C.; Louchini, R.; Robb, K. I.; Stuart-Panko, H.; Demers, S.; Wright, S.; George, J.; Shen, X.; Brockhouse, J. T.; O'Brien, D. K.; Almon, L.; Young, J. L.; Bates, J.; Rycroft, R.; Mueller, L.; Phillips, C.; Ryan, H.; Walrath, J.; Schwartz, A.; Vigneau, F.; Mackinnon, J. A.; Wohler, B.; Bayakly, R.; Ward, K. C.; Davidson-Allen, K.; Glaser, S.; West, D.; Green, M. D.; Hernandez, B. Y.; Lynch, C. F.; Mckeen, K. M.; Huang, B.; Deapen, D.; Liu, L.; Hsieh, M. C.; Wu, X. C.; Stern, K.; Gershman, S. T.; Knowlton, R. C.; Copeland, G.; Spivak, G.; Rogers, D. B.; Lemons, D.; Williamson, L. L.; Hood, M.; Jerry, H.; Hosain, G. M.; Rees, J. R.; Pawlish, K. S.; Stroup, A.; Key, C.; Wiggins, C.; Kahn, A. R.; Schymura, M. J.; Leung, G.; Rao, C.; Giljahn, L.; Warther, B.; Pate, A.; Patil, M.; Shipley, D. K.; Esterly, M.; Otto, R. D.; Fulton, J. P.; Rousseau, D. L.; Janes, T. A.; Schwartz, S. M.; Bolick, S. W.; Hurley, D. M.; Tenney, R. A.; Whiteside, M. A.; Hakenewerth, A.; Williams, M. A.; Herget, K.; Sweeney, C.; Martin, J.; Wang, S.; Harrelson, M. G.; Keitheri Cheteri, M. B.; Hudson, A. G.; Borchers, R.; Stephenson, L.; Espinoza, J. R.; Edwards, B. K.; Wang, N.; Yang, L.; Chen, J. S.; Song, G. H.; Gu, X. P.; Zhang, P.; Ge, H. M.; Zhao, D. L.; Zhang, J. H.; Zhu, F. D.; Tang, J. G.; Shen, Y.; Wang, J.; Li, Q. L.; Yang, S. P.; Dong, J. M.; Li, W. W.; Cheng, L. P.; Chen, J. G.; Huang, Q. H.; Huang, S. Q.; Guo, G. P.; Wei, K.; Chen, W. Q.; Zeng, H.; Demetriou, A. V.; Pavlou, P.; Mang, W. K.; Ngan, K. C.; Kataki, A. C.; Krishnatreya, M.; Jayalekshmi, P. A.; Sebastian, P.; Sapkota, S. D.; Verma, Y.; Nandakumar, A.; Suzanna, E.; Keinan-Boker, L.; Silverman, B. G.; Ito, H.; Hattori, M.; Sugiyama, H.; Utada, M.; Katayama, K.; Natsui, S.; Nishino, Y.; Koike, T.; Ioka, A.; Nakata, K.; Kosa, K.; Oki, I.; Shibata, A.; Nimri, O.; Ab Manan, A.; Bhoo Pathy, N.; Ochir, C.; Tuvshingerel, S.; Al Khater, A. M.; Al-Eid, H.; Jung, K. W.; Won, Y. J.; Park, S.; Chiang, C. J.; Lai, M. S.; Suwanrungruang, K.; Wiangnon, S.; Daoprasert, K.; Pongnikorn, D.; Geater, S. L.; Sriplung, H.; Eser, S.; Yakut, C. I.; Hackl, M.; Zielonke, N.; Muhlbock, H.; Oberaigner, W.; Pineros, M.; Zborovskaya, A. A.; Henau, K.; Van Eycken, L.; Dimitrova, N.; Valerianova, Z.; Sekerija, M.; Znaor, A.; Zvolsky, M.; Engholm, G.; Aareleid, T.; Magi, M.; Malila, N.; Seppa, K.; Velten, M.; Cornet, E.; Troussard, X.; Bouvier, A. M.; Faivre, J.; Gu
abstract

Background Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. Methods Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75 000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. Findings 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. Interpretation International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems. Funding Canadian Partnership Against Cancer (Toronto, Canada), Cancer Focus Northern Ireland (Belfast, UK), Cancer Institute New South Wales (Sydney, Australia), Cancer Research UK (London, UK), Centers for Disease Control and Prevention (Atlanta, GA, USA), Swiss Re (London, UK), Swiss Cancer Research foundation (Bern, Switzerland), Swiss Cancer League (Bern, Switzerland), and University of Kentucky (Lexington, KY, USA).

2015 - KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence [Articolo su rivista]
Joensuu, Heikki; Rutkowski, Piotr; Nishida, Toshirou; Steigen, Sonja E.; Brabec, Peter; Plank, Lukas; Nilsson, Bengt; Braconi, Chiara; Bordoni, Andrea; Magnusson, Magnus K.; Sufliarsky, Jozef; Federico, Massimo; Jonasson, Jon G.; Hostein, Isabelle; Bringuier, Pierre Paul; Emile, Jean Francois
abstract

Purpose: Mutated KIT and platelet-derived growth factor alpha gene (PDGFRA ) drive GI stromal tumor (GIST) oncogenesis, but the clinical significance of their single mutations is known incompletely. Patients and Methods: We identified 11 population-based series of patients with GIST through a literature search and pooled individual data from 3,067 patients treated with macroscopically complete tumor excision. Mutation analysis was done from 1,505 tumors. We analyzed associations between KIT and PDGFRA mutations and recurrence-free survival (RFS) in the subsets in which patients were treated with surgery alone. Results: We identified 301 different single mutations in KIT and 33 in PDGFRA. Patients with PDGFRA mutations had more favorable RFS than those with KIT mutations (hazard ratio, 0.34; P = .004). Only one of the 35 GISTs with KIT exon 11 duplication mutations recurred. Patients with deletions of only one codon of KIT exon 11 had better RFS than those with another deletion type, and some KIT exon 11 substitution mutations (Trp557Arg, Val559Ala, and Leu576Pro) were also associated with favorable RFS. Patients with an identical mutation had greatly variable outcomes depending on the standard prognostic factors, notably, mitotic count. Commonly used risk stratification schemes tended to overestimate the risk for recurrence in subgroups with prognostically favorable mutations. Conclusion: GISTs with an identical KIT or PDGFRA mutation may have widely varying risks for recurrence. Most of the patients with PDGFRA mutations and those with KIT exon 11 duplication mutation or deletion of one codon have favorable RFS with surgery alone and are usually not candidates for adjuvant therapy.

2015 - Precision medicine in diffuse large B-cell lymphoma: Hitting the target [Articolo su rivista]
Vermaat, Joost S.; Pals, Steven T.; Younes, Anas; Dreyling, Martin; Federico, Massimo; Aurer, Igor; Radford, John; Kersten, Marie José
abstract

Abstract not available

2015 - Prognostic roles of absolute monocyte and absolute lymphocyte counts in patients with advanced-stage follicular lymphoma in the rituximab era: an analysis from the FOLL05 trial of the Fondazione Italiana Linfomi [Articolo su rivista]
Marcheselli, Luigi; Bari, Alessia; Anastasia, Antonella; Botto, Barbara; Puccini, Benedetta; Dondi, Alessandra; Carella, Angelo M; Alvarez, Isabel; Chiarenza, Annalisa; Arcari, Annalisa; Salvi, Flavia; Federico, Massimo
abstract

Recently, in an attempt to improve the discrimination power of the international prognostic index (IPI), patients with diffuse large B-cell lymphoma were evaluated to determine the prognostic roles of peripheral blood absolute monocyte count (AMC) and absolute lymphocyte count (ALC). Here, we analysed data of 428 patients with follicular lymphoma (FL) enrolled in a prospective, randomized trial (FOLL05 study) conducted by Fondazione Italiana Linfomi, to assess the impact of AMC and ALC on progression-free survival (PFS). All patients had been treated with one of three treatment combinations: (i) rituximab (R) plus cyclophosphamide, vincristine and prednisone; (ii) R plus cyclophosphamide, doxorubicin, vincristine and prednisone or (iii) R plus mitoxantrone and fludarabine. We showed that only AMC was a powerful predictor of PFS, and possibly overall survival, in patients with FL treated with combination chemotherapy regimens that contained R. The AMC can be used alone as a novel, simple factor that can predict survival outcome in patients with FL, independent of the immunochemotherapy regimen. It may therefore be widely used by clinicians, due to its simplicity and broad applicability. Additionally, it can be combined with other factors that determine the IPI or FLIPI, to increase the discriminating ability of these indices.

2015 - Risk of second primary malignancy in breast cancer survivors: A nested population-based case-control study [Articolo su rivista]
Marcheselli, Raffaella; Marcheselli, Luigi; Cortesi, Laura; Bari, Alessia; Cirilli, Claudia; Pozzi, Samantha; Ferri, Paola; Napolitano, Martina; Federico, Massimo; Sacchi, Stefano
abstract

Purpose: Evolving therapies have improved the prognoses of patients with breast cancer; and currently, the number of long-term survivors is continuously increasing. However, these patients are at increased risk of developing a second cancer. Thus, late side effects are becoming an important issue. In this study, we aimed to investigate whether patient and tumor characteristics, and treatment type correlate with secondary tumor risk. Methods: This case-control study included 305 patients with a diagnosed second malignancy after almost 6 months after the diagnosis of primary breast cancer and 1,525 controls (ratio 1:5 of cases to controls) from a population-based cohort of 6,325 women. The control patients were randomly selected from the cohort and matched to the cases according to age at diagnosis, calendar period of diagnosis, disease stage, and time of follow-up. Results: BRCA1 or BRCA2 mutation, human epidermal growth factor receptor 2 (HER2)+ status, chemotherapy, and radiotherapy were related to increased risk of developing a second cancer, whereas hormonotherapy showed a protective effect. Chemotherapy, radiotherapy, and estrogenic receptor level <10% increased the risk of controlateral breast cancer. HER2+ status increased the risk of digestive system and thyroid tumors, while BRCA1 or BRCA2 mutation increased the risk of cancer in the genital system. Conclusion: Breast cancer survivors are exposed to an excess of risk of developing a second primary cancer. The development of excess of malignancies may be related either to patient and tumor characteristics, such as BRCA1 or BRCA2 mutation and HER2+ status, or to treatments factors.

2015 - Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone as first-line treatment for splenic marginal zone lymphoma: a Fondazione Italiana Linfomi phase II study [Articolo su rivista]
Iannitto, Emilio; Luminari, Stefano; Tripodo, Claudio; Mancuso, Salvatrice; Cesaretti, Marina; Marcheselli, Luigi; Merli, Francesco; Stelitano, Caterina; Carella, Angelo Michele; Fragasso, Alberto; Montechiarello, Elisa; Ricciuti, Giuseppina; Pulsoni, Alessandro; Paulli, Marco; Franco, Vito; Federico, Massimo
abstract

Rituximab provides high response rates and effective disease palliation in patients with splenic marginal zone lymphoma (SMZL). We conducted a phase II trial in SMZL patients that were either untreated or were splenectomised, but had shown disease progression within 1 year after splenectomy. Treatment consisted of 6 courses of rituximab with cyclophosphamide, vincristine, non-pegilated liposomal doxorubicin and prednisone (R-COMP). Fifty-one patients were eligible for the analysis. The overall response rate was 84%. The 6-years progression free survival and overall survival was 54% and 72%, respectively. Toxicity was substantial (grade ≥3 neutropenia: 26%; grade ≥3 infections: 8%). Of the 15 deaths, 2 occurred on treatment (one sepsis and one pneumonia). Six deaths were due to lymphoma progression, 4 to secondary neoplasia, 1 to sepsis, 1 to pneumonia and one to splenectomy complications. R-COMP should be restricted to patients with bulky disease associated with symptoms or to patients with possible histological transformation.

2015 - T-cell lymphomas: where we are and where we a re moving forward [Articolo su rivista]
Bellei, Monica; Conte, Luana; Tarantino, Vittoria; Federico, Massimo
abstract

Mature T-Cell Lymphomas (PTCLs) represent a heterogeneous group of haematological malignancies, with a fairly poor outcome. Due to their rarity, PTCLs are very poorly understood and information useful to develop more rational therapeutic approaches and substantially improve the prognosis are limited. The T-Cell Project (TCP), launched a prospective collection of accurate data coming from patients with newly diagnosed PTCLs, with the aim of improving knowledge on these rare diseases. From Sept 2006 to Jan 2016, 1,439 cases have been registered by 74 Institutions world-wide. PTCL-NOS emerged as the most frequent subtype (36%). Combination chemotherapy was the preferred approach (90%), anthracycline-containing regimens being the favourite (84%). Consolidative ASCT was reported in 7%, with different geographic distribution. After induction therapy 54% achieved a CR and 18% a PR. After a median follow-up of 35 months, 5-yr OS and PFS were 44% and 33%, respectively. The ALCL, ALK+ showed the best 5-yr OS (73%). The TCP is the largest ongoing prospective registry; and is now moving forward to the establishment of a large biorepository. This exceptional position could allow to build future treatment platforms predicated on our biological understanding of the disease, which we anticipate will lead to the development of subtype specific treatments.

2015 - The genotype of MLH1 identifies a subgroup of follicular lymphoma patients who do not benefit from doxorubicin: FIL-FOLL study [Articolo su rivista]
Rossi, Davide; Bruscaggin, Alessio; La Cava, Piera; Galimberti, Sara; Ciabatti, Elena; Luminari, Stefano; Rigacci, Luigi; Tucci, Alessandra; Pulsoni, Alessandro; Bertoldero, Giovanni; Vallisa, Daniele; Rusconi, Chiara; Spina, Michele; Arcaini, Luca; Angrilli, Francesco; Stelitano, Caterina; Merli, Francesco; Gaidano, Gianluca; Federico, Massimo; Palumbo, Giuseppe A.
abstract

Though most follicular lymphoma biomarkers rely on tumor features, the host genetic background may also be relevant for outcome. Here we aimed at verifying the contribution of candidate polymorphisms of FCγ receptor, DNA repair and detoxification genes to prognostic stratification of follicular lymphoma treated with immunochemotherapy. The study was based on 428 patients enrolled in the FOLL05 prospective trial that compared three standard-of-care regimens (rituximab-cyclophosphamide-vincristine-prednisone versus rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone versus rituximab-fludarabine-mitoxantrone) for the first line therapy of advanced follicular lymphoma. Polymorphisms were genotyped on peripheral blood DNA samples. The primary endpoint was time to treatment failure. Polymorphisms of FCGR2A and FCGR3A, which have been suggested to influence the activity of rituximab as a single agent, did not affect time to treatment failure in the pooled analysis of the three FOLL05 treatment arms that combined rituximab with chemotherapy (P=0.742, P=0.252, respectively). These results were consistent even when the analysis was conducted by intention to treat, indicating that different chemotherapy regimens and loads did not interact differentially with the FCGR2A and FCGR3A genotypes. The genotype of MLH1, which regulates the genotoxic effect of doxorubicin, significantly affected time to treatment failure in patients in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone arm (P=0.001; q<0.1), but not in arms in which patients did not receive doxorubicin (i.e., the rituximab-cyclophosphamide-vincristine-prednisone and rituximab-fludarabine-mitoxantrone arms). The impact of MLH1 on time to treatment failure was independent after adjusting for the Follicular Lymphoma International Prognostic Index and other potential confounding variables by multivariate analysis. These data indicate that MLH1 genotype is a predictor of failure to benefit from rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone treatment in advanced follicular lymphoma and confirm that FCGR2A and FCGR3A polymorphisms have no impact when follicular lymphoma is treated with rituximab plus chemotherapy (clinicaltrials.gov identifier: NCT00774826).

2015 - The more patients you treat, the more you cure: managing cardiotoxicity in the treatment of aggressive non-Hodgkin lymphoma [Articolo su rivista]
Zinzani, P. L.; Federico, Massimo; Oliva, S.; Pinto, A.; Rigacci, L.; Specchia, G.; Tucci, A.; Vitolo, U.
abstract

Athracycline-based regimens remain the gold standard for the treatment of lymphomas, even if their use can be limited by associated cardiac toxicity, especially in elderly patients. Although most patients with aggressive non-Hodgkin lymphoma (NHL) are elderly, they may envisage long-term life expectancy. Thus, there is a need for therapeutic strategies that can overcome the impact of anthracycline cardiotoxicity. A better understanding of its pathogenetic mechanisms, the identification of risk factors of cardiac dysfunction, and appropriate therapy should prove useful in this setting. A comparable efficacy and reduced cardiotoxicity even in frail and elderly patients have been shown with the use of non-pegylated liposomal doxorubicin, when substituted for conventional doxorubicin in standard chemotherapy regimens for NHL. In the coming years, the goal will be to apply these advancements to the treatment of patients with NHL, to ensure adequate therapy in patients currently denied conventional intensive chemotherapy because of age or comorbidities

2015 - The use of anthracycline at first-line compared to alkylating agents or nucleoside analogs improves the outcome of salvage treatments after relapse in follicular lymphoma The REFOLL study by the Fondazione Italiana Linfomi [Articolo su rivista]
Rossi, Giuseppe; Marcheselli, Luigi; Dondi, Alessandra; Bottelli, Chiara; Tucci, Alessandra; Luminari, Stefano; Arcaini, Luca; Merli, Michele; Pulsoni, Alessandro; Boccomini, Carola; Puccini, Benedetta; Micheletti, Moira; Martinelli, Giovanni; Rossi, Andrea; Zilioli, Vittorio Ruggero; Bozzoli, Valentina; Balzarotti, Monica; Bolis, Silvia; Cabras, Maria Giuseppina; Federico, Massimo
abstract

Follicular lymphoma (FL) patients experience multiple remissions and relapses and commonly receive multiple treatment lines. A crucial question is whether anthracyclines should be used at first-line or whether they would be better "reserved" for relapse and whether FL outcome can be optimized by definite sequences of treatments. Randomized trials can be hardly designed to address this question. In this retrospective multi-institutional study, time-to-next-treatment after first relapse was analyzed in 510 patients who had received either alkylating agents- or anthracycline- or nucleoside analogs-based chemotherapy with/without rituximab at first-line and different second-line therapies. After a median of 42 months, median time-to-next-treatment after relapse was 41 months (CI95%:34-47 months). After adjustment for covariates, first-line anthracycline-based chemotherapy with/without rituximab was associated with better time-to-next-treatment after any salvage than alkylating agents-based chemotherapy with/without rituximab or nucleoside analogs-based chemotherapy with/without rituximab (HR:0.74, P = 0.027). The addition of rituximab to first-line chemotherapy had no significant impact (HR:1.22, P = 0.140). Autologs stem cell transplantation performed better than any other salvage treatment (HR:0.53, P < 0.001). First-line anthracycline-based chemotherapy significantly improved time-to-next-treatment even in patients receiving salvage autologs stem cell transplantation (P = 0.041). This study supports the concept that in FL previous treatments significantly impact on the outcome of subsequent therapies. The outcome of second-line treatments, either with salvage chemoimmunotherapy or with autologs stem cell transplantation, was better when an anthracycline-containing regimen was used at first-line. Am. J. Hematol. 90:56-61, 2015. © 2014 Wiley Periodicals, Inc.

2015 - The Value and Relevance of the T Cell Lymphoma Registries and International Collaborations: the Case of COMPLETE and the T-Cell Project [Articolo su rivista]
Bellei, Monica; Nabhan, Chadi; Pesce, Emanuela Anna; Conte, Luana; Vose, Julie M.; Foss, Francine; Federico, Massimo
abstract

Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of lymphoid malignancies that portend a poor prognosis and have an undefined optimal therapeutic strategy. Data on best practices stem from prior studies that have generally included B cell lymphomas. However, the enhanced ability to diagnose PTCLs, the development of newer agents specific for PTCLs, and its increased incidence have called the scientific community to develop better strategies to combat these neoplasms. To that end, T cell lymphoma registries were developed in an attempt to answer relevant questions on the prognosis and management of PTCLs. The largest registries currently enrolling patients are the Comprehesive Oncology Measures for PeripheraL T-cEll Lymphoma TrEatment (COMPLETE) and the T-Cell Project. Despite the inherent limitations of these studies, valuable information are being collected to refine our management approaches and to aid in designing future clinical trials. This review illustrates the value of these registries and describes the critical questions that need to be answered.

2015 - Treatment of advanced-stage hodgkin lymphoma [Capitolo/Saggio]
Borchmann, P.; Federico, M.; Diehl, V.
abstract

2015 - Twenty-years experience with de novo metastatic breast cancer [Articolo su rivista]
Cortesi, Laura; Toss, Angela; Cirilli, Claudia; Marcheselli, Luigi; Braghiroli, Barbara; Sebastiani, Federica; Federico, Massimo
abstract

Although new treatments have been widely studied to improve the survival of patients with metastatic breast cancer (BC), prognosis continues to be poor with an average survival time no longer than 3 years. We carried on a population-based study with the purpose of evaluating the outcome of metastatic breast cancer in the province of Modena from 1990 to 2009. We examined the Modena Cancer Registry and evaluated the 5-year overall survival (OS) of women diagnosed with a de novo metastatic breast cancer between 1990 and 2009, defining 5 periods of 4 years each. After a median follow-up time of 29 months, the 5-year OS was 11% for years 1990-1993, 15% for years 1994-1997, 12% for years 1998-2001, 20% for years 2002-2005 and 29% for years 2006-2009 (p = 0.012). Overall, although no OS differences were noted in the first decade analyzed, a real advantage has been shown in the last two cohorts. In a multivariate analysis, the 5-year OS was significantly increased only for hormone receptor positive and HER2+ tumors, whereas chemotherapy treatments were not significant independent predictors of survival in "de novo" metastatic BC (p = 0.08). Our analysis confirms that the prognosis of de novo metastatic breast cancer has improved overtime, particularly in the last decade. Trastuzumab, LH-RH analogues and aromatase inhibitors have determined a significant clinical benefit and cost-effectiveness in metastatic breast cancer treatment.

2014 - A diachronic-comparative analysis for the identification of the most powerful prognostic index for localized diffuse large B-cell lymphoma [Articolo su rivista]
Mian, M.; Marcheselli, Luigi; Rossi, A.; Visco, C.; Chiappella, A.; Volpetti, S.; Zaja, F.; Mondello, P.; Fiegl, M.; Billio, A.; Federico, Massimo; Luminari, Stefano; Rambaldi, A.; Cortelazzo, S.
abstract

BACKGROUND: In the rituximab era, the conventional International Prognostic index (IPI) lost at least in part its predictive power, while the National Comprehensive Cancer Network-IPI (NCCN-IPI) seems to be a new and valid prognosticator. However, it has not yet been evaluated in patients with localized disease and it has not been compared with the modified IPI (mIPI) of the pre-rituximab era. In order to evaluate the different prognosticators and to assess the importance of rituximab and radiotherapy (RT), we carried out the so far largest retrospective analysis of patients with localized diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: We retrospectively assessed clinical and therapeutical data of 1405 patients treated in from 1987 to 2012 in 10 cancer centers in Italy and 1 in Austria. RESULTS: All patients underwent an anthracycline containing polychemotherapy and 254 additional rituximab. The median follow-up was 5.7 years (range 0.1-23 years). The 5-year overall survival (OS) was 75%, being significantly superior in those who underwent additional rituximab, while RT consolidation did not improve the outcome of those who received immunochemotherapy. Patients with extranodal disease benefited from the addition of rituximab, while RT did not improve OS of the immunochemotherapy subgroup. In the pre-rituximab era, the mIPI showed a better performance than the others. In rituximab-treated patients, the NCCN-IPI had the highest discriminant value and the 5-years OS varied significantly (P < 0.001) between the three risk groups and was 98% in low-risk patients, 82% in those with a low-intermediate risk and 57% among high-intermediate and high-risk cases. CONCLUSIONS: The NCCN-IPI is so far the best prognosticator for patients with localized DLBCL who underwent R-CHOP(-like). The addition of rituximab is indispensable regardless of the risk category and site of involvement, while the addition of RT should be reserved to those cases who are ineligible to rituximab.

2014 - A rapid genetic counselling and testing in newly diagnosed breast cancer is associated with high rate of risk-reducing mastectomy in BRCA1/2-positive italian women [Articolo su rivista]
Cortesi, Laura; Razzaboni, Elisabetta; Toss, Angela; DE MATTEIS, Elisabetta; Marchi, I.; Medici, Veronica; Tazzioli, Giovanni; Andreotti, Alberto; DE SANTIS, Giorgio; Pignatti, Marco; Federico, Massimo
abstract

BACKGROUND: Risk-reducing mastectomy (RRM) decreases breast cancer (BC) risk in BRCA1/2 mutation carriers by up to 95%, but the Italian attitude towards this procedure is reluctant. PATIENTS AND METHODS: This is an observational study with retrospective design, using quantitative and qualitative research methods, aimed at evaluating the attitude towards RRM by rapid genetic counselling and testing (RGCT), at the time of BC diagnosis, compared with traditional genetic counselling and testing (TGCT), after previous BC surgery. Secondary aims were to investigate patient satisfaction after RRM and the rate of occult tumour in healthy breasts. A total of 1168 patients were evaluated: 1058 received TGCT, whereas 110 underwent RGCT. RESULTS: In TGCT, among 1058 patients, 209 (19.7%) mutation carriers were identified, with the rate of RRM being 4.7% (10 of 209). Conversely in RGCT, among 110 patients, 36 resulted positive, of which, 15 (41.7%) underwent bilateral mastectomy at the BC surgery time, showing an overall good satisfaction, measured by interpretative phenomenological analysis 12 months after the intervention. CONCLUSIONS: Our study shows that RGCT in patients with a hereditary profile is associated with a high rate of RRM at the BC surgery time, this being the pathway offered within a multidisciplinary organization. KEYWORDS: BRCA1/2 mutation carriers; acceptability; genetic counselling; risk-reducing mastectomy

2014 - Breast cancer in systemic sclerosis: Results of a cross-linkage of an Italian Rheumatologic Center and a population-based Cancer Registry and review of the literature. [Articolo su rivista]
Colaci, Michele; Giuggioli, D; Vacchi, Caterina; Lumetti, Federica; Iachetta, Francesco; Marcheselli, L; Federico, Massimo; Ferri, Clodoveo
abstract

OBJECTIVE: Increased frequency of few types of cancer in systemic sclerosis (SSc) has been reported in the literature; in particular, breast carcinoma has been proposed as one of the most frequent malignancy in SSc patients, even though data are not univocal. The aim of the present study was to retrospectively evaluate the prevalence of breast cancer in our SSc series, compared with sex-/age-matched general population of the same geographical area, and the possible correlations with SSc features, including X-ray exposure for clinical investigations. A review of the world literature about this topic was also done. METHODS: Clinical records of 318 consecutive SSc patients, 31 M and 287 F, age 51.5±14.5 SD years, disease duration 10±6.5 SD years, referred to our Rheumatology Unit between January 2002 and December 2012 were evaluated. RESULTS: Twelve (3.8%) cases of breast cancer were recorded, including 11/287 females (3.8%) and 1/31 (3.2%) male patients. Considering the subgroup of 202 SSc patients resident in the Province of Modena compared with data of the local Tumor Registry, the incidence of breast cancer observed in our SSc series is significantly higher than expected (SIR 2.1; 95% interval of confidence: 1.13-3.90; p<0.01). On the whole, the comparison between SSc patients with cancer and those without did not show any significant differences with regard to SSc clinical features, including the X-ray exposure. Of note is the relatively shorter disease duration at the time of breast cancer detection (median 2.5years, range 1-21; disease duration of mean 10±6.5 SD years in the entire cohort). The review of the literature revealed that the observed incidence of breast cancer in our case series is comparable to the few studies reporting the highest percentages of this malignancy. CONCLUSIONS: A significant increase of breast cancer incidence compared to sex-age-matched general population from the same geographic area was observed. Moreover, a close temporal relationship between SSc and breast cancer onset was found, independently from clinical, serological, and instrumental features of SSc. The possible pathogenetic link between this systemic autoimmune disease and complicating breast cancer, as well as the results of previous studies, are discussed.

2014 - Cancer survival in Europe 1999-2007 by country and age: results of EUROCARE--5-a population-based study [Articolo su rivista]
De Angelis R, Sant M; Coleman, Mp; Francisci, S; Baili, P; Pierannunzio, D; Trama, A; Visser, O; Brenner, H; Ardanaz, E; Bielska Lasota, M; Engholm, G; Nennecke, A; Siesling, S; Berrino, F; M, Capocaccia R. Hackl; Zielonke, N; Oberaigner, W; Henau, K; Van Eycken, E; Dimitrova, N; Valerianova, Z; Znaor, A; Dušek, L; Zvolský, M; Engholm, G; Storm, H; Mägi, M; Aareleid, T; Malila, N; Seppä, K; Velten, M; Belot, A; Troussard, X; Launoy, G; Guizard, A; Bouvier, A; Faivre, J; Arveux, P; Maynadié, M; Woronoff, A; Robaszkiewicz, M; Baldi, I; Monnereau, A; Tretarre, B; Bossard, N; Estève, J; Colonna, M; Molinié, F; Bara, S; Schvartz, C; Lapôtre Ledoux, B; Grosclaude, P; Meyer, M; Stabenow, R; Eberle, A; Luttmann, S; Brenner, H; Nennecke, A; Engel, J; Schubert Fritschle, G; Kieschke, J; Batzler, W; Holleczek, B; Katalinic, A; Jónasson, J; Tryggvadóttir, L; Comber, H; Bulatko, A; Mazzoleni, G; Buzzoni, C; Giacomin, A; Mancuso, P; Sardo, A; Ferretti, S; Caldarella, A; Crocetti, E; Amati, C; Baili, P; Berrino, F; Bonfarnuzzo, S; Botta, L; Foschi, R; Gatta, G; Margutti, C; Minicozzi, P; Sant, M; Tereanu, C; Trama, A; Dal Maso, L; Serraino, D; Caldora, M; Capocaccia, R; Carrani, E; De Angelis, R; Francisci, S; Mallone, S; Pierannunzio, D; Roazzi, P; Rossi, S; Santaquilani, M; Tavilla, A; Busco, S; Pannozzo, F; Quaglia, A; Vercelli, M; Gennaro, V; Ricci, P; Bisanti, L; Randi, G; PONZ DE LEON, Maurizio; Federico, Massimo; Fusco, M; Vitale, M; Usala, M; Traina, A; Zarcone, M; Cusimano, R; Vitale, F; Michiara, M; Tumino, R; Di Felice, E; Rossi, P; Falcini, F; Iannelli, A; Budroni, M; Sechi, O; Piffer, S; Madeddu, A; Tisano, F; Fanetti, A; Tessandori, R; Rosso, S; Zanetti, R; Candela, P; Scuderi, T; Bianconi, F; La Rosa, F; Contiero, P; Tagliabue, G; Guzzinati, S; Zambon, P; Pildava, S; Smailyte, G; Agius, D; Micallef, R; Johannesen, T; Góźdź, S; Mężyk, R; Rachtan, J; Bębenek, M; Błaszczyk, J; Bielska Lasota, M; Forjaz de Lacerda, G; Antunes, L; Bento, M; Mayer da Silva, A; Miranda, A; Coza, D; Nicula, F; Diba, C; Primic Zakelj, M; Almar, E; Mateos, A; Bidaurrazaga, J; Larrañaga, N; Torrella Ramos, A; Díaz García, J; Jimenez Chillaron, R; Izquierdo Font, A; Marcos Gragera, R; Martinez, C; Sanchez, M; Chirlaque, M; Navarro, C; Ardanaz, E; Moreno Iribas, C; García, S; Peris Bonet, R; Carulla, M; Galceran, J; Khan, S; Lambe, M; Jundt, G; Bouchardy, C; Usel, M; Frick, H; Lorez, M; Ess, S; Herrmann, C; Bordoni, A; Spitale, A; Konzelmann, I; Lutz, J; Coebergh, J; Lemmens, V; Aben, K; Siesling, S; Otter, R; Allemani, C; Coleman, M; Rachet, B; Davies, E; Easey, N; Lawrence, G; Meechan, D; Moran, T; Rashbass, J; Roche, M; Verne, J; Wilkinson, J; Bannon, F; Gavin, A; Brewster, D; Reynolds, S.
abstract

Cancer survival is a key measure of the effectiveness of health-care systems. EUROCARE-the largest cooperative study of population-based cancer survival in Europe-has shown persistent differences between countries for cancer survival, although in general, cancer survival is improving. Major changes in cancer diagnosis, treatment, and rehabilitation occurred in the early 2000s. EUROCARE-5 assesses their effect on cancer survival in 29 European countries.

2014 - Defining the best cut-off value for lymphopenia in diffuse large B cell lymphoma treated with immuno-chemotherapy [Articolo su rivista]
Bari, Alessia; Tadmor, T.; Sacchi, Stefano; Marcheselli, Luigi; Cox, C.; Liardo, ELIANA VALENTINA; Pozzi, Samantha; Beniamini, N.; Avivi, I.; Ferrari, Angela; Baldini, L.; Falorio, S.; Gobbi, P.; Federico, Massimo; Polliack, A.
abstract

Abstract not available

2014 - Early-stage diffuse large B cell lymphoma of the head and neck: clinico-biological characterization and 18 year follow-up of 488 patients (IELSG 23 study) [Articolo su rivista]
Mian, M.; Capello, D.; Ventre, M. B.; Grazio, D.; Svaldi, M.; Rossi, A.; Tsang, R.; Gospodarowicz, M. K.; Oldani, E.; FEDERICO, Massimo; LUMINARI, Stefano; MARCHESELLI, Luigi; Pogliani, E. M.; Rossigni, F.; Cabrera, M. E.; Martelli, M.; Gutierrez Garcia, G.; Busetto, M.; Visco, C.; Fiegl, M.; Rossi, D.; Gaidano, G.; Cavalli, F.; Zucca, E.; Rambaldi, A.; Cortelazzo, S.
abstract

Abstract It is known that extranodal head and neck diffuse large B cell lymphomas (eHN-DLBCL) can affect various anatomical structures what is not well-known, however, is whether they differ in terms of clinical presentation and outcome. Clinical data of the multi-institutional series, the largest of its kind as yet, has been analysed with the aim of answering these open questions and providing long-term follow-up information. Data from 488 patients affected by stage I/II eHN-DLBCL was collected: 300 of the Waldeyer's Ring (WR), 38 of the parotid and salivary glands (PSG), 48 of the thyroid gland (TG), 53 of the nasal cavity and paranasal sinuses (NPS), 24 of the palate and oral cavity (POC) and 25 with more than one involved site. Different eHN-DLBCL arising have distinct characteristics at presentation. The intermediate high risk-modified IPI was 67 % in TG, 44 % in WR, 38 % in PSG and POC and 20 % in MS. The worst 5-year survival rate had TG-DLBCL (61 %) due to the 61 % of patients with a mIPI >1. The addition of radiotherapy (cRT) to remitters did not translate into a survival advantage (5-year disease-free survival of 67 % in the cRT group vs. 70 % in the other). Three of four central nervous system recurrences occurred in NPS-DLBCL. Survival of HN-DLBCL was inferior to nodal DLBCL. This study showed that eHN-DLBCL remitters have an inferior survival when compared to nodal DLBCL, and that the addition of cRT does not provide a survival advantage. Since the standard of care nowadays is chemo-immunotherapy, survival of these patients might have been improved.

2014 - Epidemiological overview of Hodgkin lymphoma across the Mediterranean Basin [Articolo su rivista]
Salati, Massimiliano; Cesaretti, Marina; Macchia, M.; El Mistiri, M.; Federico, Massimo
abstract

The epidemiology of Hodgkin lymphoma (HL) has always been a source of fascination to researchers due to its heterogeneous characteristics of presentation. HL is an uncommon neoplasm of B-cell origin with an incidence that varies significantly by age, sex, ethnicity, geographic location and socioeconomic status. This complex pattern was also found to be replicated among Mediterranean basin populations. HL incidence rates progressively decreased from industrialized European countries such as France (ASR=2.61) and Italy (ASR=2.39) to less developed nations such as Albania (ASR=1.34) and Bosnia Herzegovina (ASR=1.1). Regarding HL mortality we have found that countries with the lowest incidence rates show the highest number of deaths from this cancer and viceversa. Finally, a wide gap in terms of survival was showed across the Mediterranean basin with survival rates ranged from 82.3% and 85.1% among Italian men and women, to 53.3 % and 59.3% among Libyan men and women, respectively. Factors such as the degree of socio-economic development, the exposure to risk factors westernization-related, the availability of diagnostic practices along with different genetic susceptibilities to HL may explain its variation across Mediterranean countries. Furthermore, the lack of health resources decisively contribute to the poor prognosis recorded in less developed region. In the future, the introduction of appropriate and accessible treatment facilities along with an adequate number of clinical specialists in the treatment of HL and other cancers are warranted in order to improve the outcomes of affected patients and treat a largely curable type of cancer in disadvantaged regions.

2014 - Italian cancer figures, report 2014: Prevalence and cure of cancer in Italy [Articolo su rivista]
Adamo, Ms; Alessi, D; Aletta, P; Amodio, R; Andreone, S; Angelin, T; Anghinoni, E; Annulli, Ml; Arciprete, C; Artioli, Me; Autelitano, M; Baili, P; Balducci, C; Baracco, M; Baracco, S; Battisti, W; Bella, F; Bellatalla, C; Bellini, A; Belluardo, C; Benatti, P; Benedetto, G; Benfatto, L; Bernazza, E; Bianconi, F; Biavati, P; Bidoli, E; Birri, S; Bizzoco, S; Bonelli, L; Bonini, A; Borciani, E; Bordini, M; Bovo, E; Bozzani, F; Braghiroli, B; Brucculeri, Ma; Brunori, V; Bucalo, G; Bucchi, L; Bugliarello, E; Bulatko, A; Busco, S; Busso, P; Buzzoni, C; Calabrese, A; Calabretta, L; Caldarella, A; Candela, G; Cannone, G; Canu, L; Caparelli, M; Capocaccia, R; Cappelletti, M; Caprara, L; Carboni, D; Carletti, N; Caroli, S; Cascio, Ma; Cascone, G; Casella, C; Castaing, M; Cavalieri d'Oro, L; Cecconami, L; Celesia, Mv; Cena, T; Cercato, Mc; Cesaraccio, R; Chiesa, R; Cirilli, C; Cocchioni, M; Codazzi, T; Cogno, R; Colamartini, A; Colanino Ziino, A; Cometti, I; Contiero, P; Contrino, Ml; Corbinelli, A; Cordaro, C; Corti, M; Costa, A; Costarelli, D; Coviello, V; Crapanzano, G; Cremone, L; Crocetti, E; Cuccaro, F; Curatella, S; Cusimano, R; D'Alò, D; Dal Cappello, T; Dal Cin, A; Dal Maso, L; Davini, C; De Dottori, M; De Angelis, R; De Santis, E; De Valiere, E; Dei Tos, Ap; Demurtas, G; Devigili, E; Di Felice, E; di Grazia, L; Di Gregorio, C; di Norcia, R; Di Prima, A; Dinaro, Y; Distefano, R; Doa, N; Domati, F; Fabiano, S; Facchinelli, G; Falcini, F; Falk, M; Fanetti, Ac; Fattoruso, S; Federico, Massimo; Ferrari, F; Ferrari, L; Ferretti, S; Fidelbo, M; Filipazzi, L; Fiore, Ar; Fiori, G; Foca, F; Forgiarini, O; Foschi, R; Francisci, S; Frasca, G; Frassoldi, E; Fusco, M; Fusco, M; Gada, D; Garrone, E; Gasparotti, C; Gatta, G; Gatti, L; Gaudiano, C; Gennaro, V; Gentilini, Ma; Gerevini, C; Ghilardi, S; Ghisleni, S; Giacomin, A; Giavazzi, L; Gigli, A; Gilardi, F; Giorgetti, S; Giorgi Rossi, P; Giubelli, C; Giuliani, O; Giurdanella, Mc; Gola, G; Goldoni, Ca; Golizia, Mg; Greco, A; Guarda, L; Guttadauro, A; Guzzinati, S; Iachetta, F; Iannelli, A; Ieni, A; Intrieri, T; Kaleci, S; La Rosa, F; Lando, C; Lavecchia, Am; Lazzarato, F; Le Rose, L; Leone, A; Leone, R; Lonati, F; Lucchi, S; Luminari, Stefano; Macci, L; Macerata, V; Madeddu, A; Maffei, S; Maghini, A; Magnani, C; Magnani, G; Magoni, M; Mallone, S; Mameli, G; Mancini, S; Mancuso, P; Mangone, L; Manneschi, G; Mannino, R; Mannino, S; Marani, E; Marchesi, C; Mariani, F; Martorana, C; Marzola, L; Maspero, S; Maule, M; Mazzei, A; Mazzoleni, G; Mazzucco, G; Melcarne, A; Merletti, F; Merlo, E; Michiara, M; Migliari, E; Minerba, S; Minicuzzi, A; Mizzi, M; Monetti, D; Morana, G; Moroni, E; Mosso, Ml; Muni, A; Mura, F; Natali, M; Negrino, L; Nemcova, L; Nicita, C; Ocello, C; Pala, F; Palumbo, M; Panciroli, E; Panico, M; Pannozzo, F; Pascucci, C; Pasolini, A; Pastore, G; Patriarca, S; Pedroni, M; Perrotta, C; Pesce, P; Petrinelli, Am; Petrucci, C; Pezzarossi, A; Pezzuto, L; Piffer, S; Pinon, M; Pinto, A; Pintori, N; Pirani, M; Pirino, D; Pironi, V; Ponz de Leon, M; Prandi, R; Prazzoli, R; Puleio, M; Puppo, A; Quarta, F; Quattrocchi, M; Ramazzotti, V; Rashid, I; Ravaioli, A; Ravazzolo, B; Ravegnani, M; Reggiani Bonetti, L; Ricci, P; Rinaldi, E; Rizzello, R; Rognoni, M; Rollo, Pc; Roncaglia, F; Roncucci, Luca; Rosano, A; Rossi, F; Rossi, G; Rossi, M; Rossi, S; Rossini, S; Rosso, S; Rudisi, G; Ruggeri, Mg; Russo, Ag; Russo, M; Sacchettini, C; Sacchetto, L; Sacco, G; Sacerdote, C; Salvatore, S; Salvi, O; Sampietro, G; Santucci, C; Scheibel, M; Sciacca, S; Sciacchitano, C; Sciacchitano, S; Scuderi, T; Sechi, O; Seghini, P; Senatore, G; Serafini, G; Serraino, D; Sgargi, P; Sini, Gm; Sobrato, I; Soddu, M; Solimene, C; Spano, F; Spata, E; Sperduti, I; Spinosa, S; Staiti, R; Stocco, C; Stracci, F; Sunseri, R; Sutera Sardo, A; Tagliabue, G; Tamburo, L; Tamburrino, S; Taranto, V; Terracini, B; Tisano, F; Tittarelli, A; Tognazzo, S; Torrisi, A; Torrisi, A; Traina, A;
abstract

This Report intends to estimate the total number of people still alive in 2010 after cancer diagnosis in Italy, regardless of the time since diagnosis, and to project these estimates to 2015. This study is also aimed to estimate the number of already cured cancer patients, whose mortality rates have become undistinguishable from that of the general population of the same age and sex.

2014 - Management of relapsed/refractory mantle cell lymphoma: a review of current therapeutic strategies [Articolo su rivista]
Zaja, F.; Federico, Massimo; Vitolo, U.; Zinzani, P. L.
abstract

Abstract Despite recent advances in therapeutic strategies, a large proportion of patients with mantle cell lymphoma experience progression after first-line treatment. Several attempts have been performed for assessing the role of different therapies for the treatment of patients with relapsed/refractory MCL; however, a consensus on the optimal therapeutic strategy for each single patient has not been reached. Overall, clinical evidence from phase II studies show that high-dose containing regimens, stem cell transplantation, and different biological agents all have promising activity with acceptable safety profiles. Therefore, these therapies can represent suitable treatment options for patients with refractory/relapsed MCL. Among different biological agents, at present only temsirolimus was tested in a phase III study. This review discusses available evidence on the management of refractory/relapsed MCL as discussed during a consensus meeting on the current treatment strategies for MCL.

2014 - Minimal residual disease after conventional treatment significantly impacts on progression-free survival of patients with follicular lymphoma: The FIL FOLL05 trial [Articolo su rivista]
Galimberti, Sara; Luminari, Stefano; Ciabatti, Elena; Grassi, Susanna; Guerrini, Francesca; Dondi, Alessra; Marcheselli, Luigi; Ladetto, Marco; Piccaluga, Pier Paolo; Gazzola, Anna; Mannu, Claudia; Monitillo, Luigia; Mantoan, Barbara; Giudice, Ilaria Del; Starza, Irene Della; Cavalli, Marzia; Arcaini, Luca; Tucci, Alessra; Palumbo, Giuseppe Alberto; Rigacci, Luigi; Pulsoni, Alessro; Vitolo, Umberto; Boccomini, Carola; Vallisa, Daniele; Bertoldero, Giovanni; Gaidano, Gianluca; Musto, Pellegrino; Petrini, Mario; Federico, Massimo
abstract

PURPOSE: The role of the minimal residual disease (MRD) in follicular lymphoma is still debated. In this study, we assessed whether the BCL2/IGH rearrangement could have a prognostic role in patients receiving R-CHOP, R-FM, or R-CVP. EXPERIMENTAL DESIGN: DNAs from 415 patients among the 504 cases enrolled in the FOLL05 trial (NCT00774826) were centralized and assessed for the BCL2/IGH at diagnosis, at the end of treatment, and after 12 and 24 months. RESULTS: At diagnosis, the molecular marker was detected in 53% of cases. Patients without molecular marker or with a low molecular tumor burden (&lt;1 × 10(-4) copies) showed higher complete remission (CR) rate and longer progression-free survival (PFS; 3-year PFS 80% vs. 59%; P = 0.015). PFS was significantly conditioned by the PCR status at 12 and 24 months, with 3-year PFS of 66% for MRD(-) cases versus 41% for those MRD(+) at 12 months (P = 0.015), and 84% versus 50% at 24 months (P = 0.014). The MRD negativity at 12 and 24 months resulted in an improved PFS both in CR and in partial remission (PR) patients (3-year PFS = 72% for cases CR/PCR(-) vs. 32% for those CR/PCR(+) vs. 62% for those PR/PCR(-) and 25% for patients in PR/PCR(+); P = 0.001). The prognostic value of MRD at 12 and 24 months of follow-up was confirmed also in multivariate analysis. CONCLUSIONS: In this study, standardized molecular techniques have been adopted and applied on bone marrow samples from a large cohort. Data reported show that the MRD detection is a powerful independent predictor of PFS in patients with follicular lymphoma receiving conventional chemoimmunotherapy.

2014 - Monocyte count at diagnosis is a prognostic parameter in diffuse large B-cell lymphoma: a large multicenter study involving 1191 patients, in the pre and post rituximab era [Articolo su rivista]
Tadmor, T.; Bari, Alessia; Sacchi, Stefano; Marcheselli, Luigi; Liardo, ELIANA VALENTINA; Avivi, I.; Benyamini, N.; Attias, D.; Pozzi, Samantha; Cox, M. C.; Baldini, L.; Brugiatelli, M.; Federico, Massimo; Polliack, A.
abstract

In this study we assessed the prognostic significance of absolute monocyte count and selected the best cut-off value at diagnosis in a large cohort of patients with diffuse large B-cell lymphoma. Data were retrieved for therapy-naïve patients with diffuse large B-cell lymphoma followed in Israel and Italy during 1993-2010. A final cohort of 1017 patients was analyzed with a median follow up of 48 months and a 5-year overall survival rate of 68%. The best absolute monocyte count cut-off level was 630/mm(3) and the 5-year overall survival for patients with counts below this cut-off was 71%, whereas it was 59% for those with a count >630 mm(3) (P=0.0002). Of the 1017 patients, 521 (51%) were treated with chemo-immunotherapy, and in this cohort, using multivariate analysis, elevated monocyte count retained a negative prognostic value even when adjusted for International Prognostic Index (HR1.54, P=0.009). This large study shows that a simple parameter such as absolute monocyte count (>630/mm(3)) can easily be used routinely in the evaluation of newly diagnosed diffuse large B-cell lymphoma to identify high-risk patients with a worse survival in the rituximab era.

2014 - Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 Trial [Articolo su rivista]
Raemaekers, J. M. M.; Andrè, M. P. E.; Federico, Massimo; Girinsky, T.; Oumedaly, R.; Brusamolino, E.; Brice, P.; Fermè, C.; van der Maazen, R.; Gotti, M.; Bouabdallah, R.; Sebban, C. J.; Lievens, Y.; Re, A.; Stamatoullas, A.; Morschhauser, F.; Lugtenburg, P. J.; Abruzzese, E.; Olivier, P.; Casasnovas, R. O.; van Imhoff, G.; Raveloarivahy, T.; Bellei, Monica; van der Borght, T.; Bardet, S.; Versari, A.; Hutchings, M.; Melgnan, M.; Fortpied, C.
abstract

PURPOSE: Combined-modality treatment is standard treatment for patients with clinical stage I/II Hodgkin lymphoma (HL). We hypothesized that an early positron emission tomography (PET) scan could be used to adapt treatment. Therefore, we started the randomized EORTC/LYSA/FIL Intergroup H10 trial evaluating whether involved-node radiotherapy (IN-RT) could be omitted without compromising progression-free survival in patients attaining a negative early PET scan after two cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) as compared with standard combined-modality treatment. PATIENTS AND METHODS: Patients age 15 to 70 years with untreated clinical stage I/II HL were eligible. Here we report the clinical outcome of the preplanned interim futility analysis scheduled to occur after documentation of 34 events in the early PET-negative group. Because testing for futility in this noninferiority trial corresponds to testing the hypothesis of no difference, a one-sided superiority test was conducted. RESULTS: The analysis included 1,137 patients. In the favorable subgroup, 85.8% had a negative early PET scan (standard arm, one event v experimental arm, nine events). In the unfavorable subgroup, 74.8% had a negative early PET scan (standard arm, seven events v experimental arm, 16 events). The independent data monitoring committee concluded it was unlikely that we would show noninferiority in the final results for the experimental arm and advised stopping random assignment for early PET-negative patients. CONCLUSION: On the basis of this analysis, combined-modality treatment resulted in fewer early progressions in clinical stage I/II HL, although early outcome was excellent in both arms. The final analysis will reveal whether this finding is maintained over time.

2014 - Outcome of frail elderly patients with diffuse large B-cell lymphoma prospectively identified by Comprehensive Geriatric Assessment: Results from a study of the Fondazione Italiana Linfomi [Articolo su rivista]
Merli, F.; Luminari, Stefano; Rossi, G.; Mammi, Caterina; Marcheselli, Luigi; Ferrari, A.; Spina, M.; Tucci, A.; Stelitano, C.; Capodanno, I.; Fragasso, A.; Baldini, L.; Bottelli, C.; Montechiarello, E.; Fogazzi, S.; Lamorgese, C.; Cavalli, L.; Federico, Massimo
abstract

In 2003 the Fondazione Italiana Linfomi (FIL) started a clinical research program for investigating initial treatment of frail elderly patients with diffuse large B-cell lymphoma (DLBCL) identified by Comprehensive Geriatric Assessment (CGA). From 2003 to 2006, 334 elderly patients underwent CGA assessment, and 99 patients were classified as frail. Frail patients had a median age of 78 years, stage III-IV disease in 62% and age-adjusted International Prognostic Index (aaIPI) of 2-3 in 53%. Treatment consisted of several different regimens according to physician discretion. After a median follow-up of 36 months, 5-year overall survival (OS) was 28%. In multivariate analysis, aaIPI 2-3 (p = 0.005) and the presence of respiratory comorbidity (p = 0.044) were the only factors that showed independent correlation with OS. Frail patients had a poorer outcome compared with fit patients also if they were treated with rituximab-containing combination chemotherapy (hazard ratio 2.37, 95% confidence interval 1.48-3.78; p &lt; 0.001). CGA is a valid tool to prospectively identify frail subjects among elderly patients with DLBCL.

2014 - Prognostic value of PET-CT after first-line therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies [Articolo su rivista]
Trotman, J.; Luminari, Stefano; Boussetta, S.; Versari, A.; Dupuis, J.; Tychyl, C.; Marcheselli, Luigi; Berriolo Riedinger, A.; Franceschetto, Antonella; Julian, A.; Ricard, F.; Guerra, L.; Haioun, C.; Biasoli, I.; Tilly, H.; Federico, Massimo; Salles, G.; Meignan, M.
abstract

Background The value of 18F-fluorodeoxyglucose (FDG) PET-CT (PET) imaging in response assessment after first-line rituximab chemotherapy for follicular lymphoma has been documented. We analysed the application of the five-point Deauville scale (5PS; used to score FDG uptake on PET images) in a large cohort derived from three studies, to assess the correlation between post-induction PET status and survival in patients with follicular lymphoma. Methods In this pooled analysis, we used data from three multicentre prospective studies of first-line rituximab chemotherapy for patients with high-tumour-burden follicular lymphoma (the PRIMA study, the PET-Folliculaire study, and the Fondazione Italiana Linfomi FOLL05 study). Patients included in this analysis received at least six cycles of rituximab and chemotherapy before response assessment with conventional contrast-enhanced CT and PET low-dose CT (PET). We included only patients who had a PET scan within 3 months of the last dose of induction rituximab. Patient data, including conventional CT-based response assessment, were recorded for all patients undergoing PET review. Scans undergoing central PET review were scored independently by three reviewers according to the 5PS. The primary endpoints were progression-free survival and overall survival according to the 5PS score of post-induction PET scan (ie, positive [≥4 points] or negative [<4 points]), analysed in the central review population. Findings Between Dec 24, 2004, and Sept 22, 2010, 439 of the patients enrolled in the three studies underwent local PET assessment, 246 of whom had centrally reviewed post-induction scans. 41 (17%) of 246 patients had a positive post-induction PET scan according to a cutoff of 4 or higher on the 5PS, with substantial reporter concordance. With a median follow-up of 54·8 months (IQR 39·7–68·5; range 7·7–90·1), the hazard ratio (HR) for progression-free survival for patients with a positive PET scan versus those with a negative PET scan was 3·9 (95% CI 2·5–5·9; p<0·0001), and for overall survival was 6·7 (2·4–18·5; p=0·0002). For patients with a positive PET scan, 23·2% (95% CI 11·1–37·9) of patients were progression free at 4 years compared with 63·4% (55·9–70·0) of those who had a negative PET scan (p<0·0001); 4-year overall survival was 87·2% (95% CI 71·9–94·5) versus 97·1% (93·2–98·8), respectively (p<0·0001). Conventional CT-based response (ie, complete response or unconfirmed complete response vs partial response) was weakly predictive of progression-free survival (HR 1·7 [95% CI 1·1–2·5]; p=0·017). Interpretation PET-CT rather than contrast-enhanced CT scanning should be considered as a new standard for response assessment of follicular lymphoma in clinical practice, and could help guide response-adapted therapy. Funding Groupe d'Etude des Lymphomes de l'Adulte (Paris, France), now LYSA (Lymphoma Study Association), Direction de la Recherche Clinique de l'Assistance Publique–Hôpitaux de Paris, Fondazione Italiana Linfomi, and the Italian Ministry of Health.

2014 - Prospective validation of a risk score based on biological markers for predicting progression free survival in Binet stage A chronic lymphocytic leukemia patients: results of hte multicenter O-CLL 1-GISL study [Articolo su rivista]
Gentile, M.; Cutrona, G.; Mosca, L.; Matis, S.; Fabris, S.; Lionetti, M.; Ilariucci, F.; Zupo, S.; Musolino, C.; Levato, L.; Molica, S.; Di Raimondo, F.; Vincelli, I.; Di Renzo, N.; Pesce, Emanuela Anna; Angrilli, F.; Federico, Massimo; Neri, A.; Ferrarini, M.; Morabito, F.
abstract

A risk score based on three biological features (CD38, ZAP-70, and IGHV mutational status) was previously developed to predict progression-free survival (PFS) in untreated Binet A CLL patients. Here we perform a score validation analysis in a prospective and independent cohort of patients. Biological markers (CD38, ZAP-70, and IGHV mutational status) and gene expression profiles (GEP) of leukemic cells from CLL patients included in a prospective multicenter observational study (O-CLL1-GISL protocol, clinicaltrial.gov ID:NCT00917549) were used to assess the value and reproducibility of this score. To date, 468 Binet A patients were classified as low- (0 positive marker), intermediate- (1 positive marker), or high-risk (2 or 3 positive markers) using the progression risk score. The 3-year PFS probability was 91.7%, 82.9%, and 57.4% for low-, intermediate-, and high-risk (P < 0.0001) cases, respectively. These values were similar to those found in the original cohort. At Cox multivariate analysis, Rai stage, absolute lymphocyte count, progression risk score, and β-2 microglobulin maintained an independent prognostic impact on PFS. This score remained a predictor of progression when analysis was limited to 371 Rai 0 cases (P < 0.0001). Finally, the cells from the different CLL risk groups showed differences in their gene expression patterns. These results confirm the ability of this progression risk score to predict PFS among Binet A patients. The utility of the score was also extended by demonstrating that it retains prognostic value when applied exclusively to Rai 0 patients. Specific transcriptional patterns were significantly associated with risk groups

2014 - Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12 [Articolo su rivista]
Crump, Michael; Kuruvilla, John; Couban, Stephen; Macdonald, David A; Kukreti, Vishal; Kouroukis, C. Tom; Rubinger, Morel; Buckstein, Rena; Imrie, Kevin R; Federico, Massimo; Di Renzo, Nicola; Howson Jan, Kang; Baetz, Tara; Kaizer, Leonard; Voralia, Michael; Olney, Harold J; Turner, A. Robert; Sussman, Jonathan; Hay, Annette E; Djurfeldt, Marina S; Meyer, Ralph M; Chen, Bingshu E; Shepherd, Lois E.
abstract

PURPOSE: For patients with relapsed or refractory aggressive lymphoma, we hypothesized that gemcitabine-based therapy before autologous stem-cell transplantation (ASCT) is as effective as and less toxic than standard treatment. PATIENTS AND METHODS: We randomly assigned 619 patients with relapsed/refractory aggressive lymphoma to treatment with gemcitabine, dexamethasone, and cisplatin (GDP) or to dexamethasone, cytarabine, and cisplatin (DHAP). Patients with B-cell lymphoma also received rituximab. Responding patients proceeded to stem-cell collection and ASCT. Coprimary end points were response rate after two treatment cycles and transplantation rate. The noninferiority margin for the response rate to GDP relative to DHAP was set at 10%. Secondary end points included event-free and overall survival, treatment toxicity, and quality of life. RESULTS: For the intention-to-treat population, the response rate with GDP was 45.2%; with DHAP the response rate was 44.0% (95% CI for difference, -9.0% to 6.7%), meeting protocol-defined criteria for noninferiority of GDP (P = .005). Similar results were obtained in a per-protocol analysis. The transplantation rates were 52.1% with GDP and 49.3% with DHAP (P = .44). At a median follow-up of 53 months, no differences were detected in event-free survival (HR, 0.99; stratified log-rank P = .95) or overall survival (HR, 1.03; P = .78) between GDP and DHAP. Treatment with GDP was associated with less toxicity (P &lt; .001) and need for hospitalization (P &lt; .001), and preserved quality of life (P = .04). CONCLUSION: For patients with relapsed or refractory aggressive lymphoma, in comparison with DHAP, treatment with GDP is associated with a noninferior response rate, similar transplantation rate, event-free survival, and overall survival, less toxicity and hospitalization, and superior quality of life.

2014 - The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL) [Articolo su rivista]
Luminari, Stefano; Biasoli, I.; Versari, A.; Rattotti, S.; Battelli, C.; Rusconi, C.; Merli, F.; Spina, M.; Ferreri, A. J.; Zinzani, P. L.; Gallamini, A.; Franceschetto, Antonella; Boccomini, C.; Franceschetti, S.; Salvi, F.; Raimondo, F. D.; Carella, A. M.; Quaresima, Micol; Balzarotti, M.; Musto, P.; Federico, Massimo
abstract

BACKGROUND: [18F]fluorodeoxyglucose-positron emission tomography (PET) is emerging as a strong diagnostic and prognostic tool in follicular lymphoma (FL) patients. PATIENTS AND METHODS: In a subset analysis of the FOLL05 trial (NCT00774826), we investigated the prognostic role of post-induction PET (PI-PET) scan. Patients were eligible to this study if they had a PI-PET scan carried out within 3 months from the end of induction immunochemotherapy. Progression-free survival (PFS) was the primary study end point. RESULTS: A total of 202 patients were eligible and analysed for this study. The median age was 55 years (range 33-75). Overall, PI-PET was defined as positive in 49 (24%) patients. Conventional response assessment with CT scan was substantially modified by PET: 15% (22/145) of patients considered as having a complete response (CR) after CT were considered as having partial response (PR) after PI-PET and 53% (30/57) patients considered as having a PR after CT were considered as a CR after PI-PET. With a median follow-up of 34 months, the 3-year PFS was 66% and 35%, respectively, for patients with negative and positive PI-PET (P<0.001). At multivariate analysis, PI-PET (hazard ratio 2.57, 95% confidence interval 1.52-4.34, P<0.001) was independent of conventional response, FLIPI and treatment arm. Also, the prognostic role of PI-PET was maintained within each FLIPI risk group. CONCLUSIONS: In FL patients, PI-PET substantially modifies response assessment and is strongly predictive for the risk of progression. PET should be considered in further updates of response criteria.

2013 - A case of skeletal and bone marrow metastases from breast cancer treated with eribulin mesylate. [Articolo su rivista]
Pashaj, Etleva; Cortesi, L.; Proietto, Manuela; Bonacorsi, G.; Liardo, ELIANA VALENTINA; Federico, Massimo
abstract

Abstract AIM: We report our experience with eribulin mesylate in a pancytopenic heavily pretreated patient with multiple bone metastases and bone marrow infiltration from breast cancer. METHODS: Eribulin mesylate was given at 1.4 mg/m(2) on day 1 and 8 every 3 weeks for a total of 11 courses. RESULTS: After seven cycles, evaluation with a bone marrow biopsy showed a large decrease of neoplastic involvement with substitution of osteolitic lesions for the osteoaddensant type. No unexpected acute toxicity was observed. CONCLUSION: To our knowledge, this represents the first report of bone marrow metastases from breast cancer treated with eribulin mesylate that obtained an improvement of hematopoietic values with an acceptable profile of tolerability and good compliance for the subject.

2013 - [About 1,400 new cancer diagnosis in Italian children (0-14 years) are attended every year (7,000 in 5 years)] [Articolo su rivista]
Crocetti, Emanuele; Rondelli, Roberto; Dal Maso, Luigino; Autelitano, M; Bizzoco, S; Vercelli, M; Borciani, E; Buzzoni, C; Candela, G; Cocchioni, M; Cremone, L; Crocetti, E; Crosignani, P; Cusimano, R; Dei Tos, A; Falcini, F; Federico, Massimo; Ferretti, S; Fusco, M; Gennaro, V; Giacomin, A; Gola, G; La Rosa, F; Madeddu, A; Magoni, M; Mangone, L; Maspero, S; Mazzoleni, G; Melcarne, A; Merletti, F; Michiara, M; Minerba, S; Pannozzo, F; Piffer, S; PONZ DE LEON, Maurizio; Quarta, F; Ricci, P; Russo, A; Sampietro, G; Sciacca, S; Sechi, O; Serraino, D; Sutera Sardo, A; Tisano, F; Traina, A; Tumino, R; Usala, M; Vitale, F; Vitarelli, S; Zanetti, R.
abstract

Not applicable

2013 - Acceptability and adherence in a chemoprevention trial among women at increased risk for breast cancer attending the Modena Familial Breast and Ovarian Cancer Center [Articolo su rivista]
Razzaboni, Elisabetta; Toss, Angela; Cortesi, Laura; Marchi, I.; Sebastiani, Federica; DE MATTEIS, Elisabetta; Federico, Massimo
abstract

Chemoprevention for women at risk for breast cancer has been shown to be effective, but in actual practice, women's uptake of chemoprevention has been poor. We explored factors that influence acceptability, adherence, and dropout in the International Breast (Prevention) Intervention Study during our first 3 years of activity at the Modena Familial Breast and Ovarian Cancer Center. We evaluated socio-demographic characteristics, health status, adherence, and side effect intensity. Semi-structured interviews analyzed reasons for accepting/refusing/stopping the trial. A total of 471 postmenopausal women were invited to participate, of which 319 declined to participate (68%), 137 accepted to participate (29%), and 15 participants did not make a final decision (3%). Breast cancer-related worries and trust in our preventive and surveillance programs were the most frequent reasons for accepting. Side effect-related worry was the most frequent reason for refusing. General practitioners' and family members' opinions played an important role in the decision-making process. Adherence significantly decreased after a 12-month follow-up, but it remained unchanged after 24- and 36-month follow-ups. Mild/moderate side effects reported by women did not change after 12 months of treatment. Forty percent of women withdrew from the study due to complaints of side effects. We concluded that chemoprevention trials are difficult medical experiments and that the process of deciding about whether or not to participate is based mainly on beliefs and values. This study has important clinical implications. During counselling with prospective participants, it is important to emphasize the potential benefits and to promote an informed choice. How participants make decisions, their belief systems, and their perception of risk are all factors that should be investigated in future research.

2013 - BEACOPP or no BEACOPP [Articolo su rivista]
Federico, Massimo; Bellei, Monica; Cheson, B. D.
abstract

no abstract available

2013 - Chromosome 2p gain in monoclonal B-cell lymphocytosis and in early stage chronic lymphocytic leukemia. [Articolo su rivista]
Fabris, S; Mosca, L; Cutrona, G; Lionetti, M; Agnelli, L; Ciceri, G; Barbieri, M; Maura, F; Matis, S; Colombo, M; Gentile, M; Recchia, Ag; Anna Pesce, E; Di Raimondo, F; Musolino, C; Gobbi, M; Di Renzo, N; Mauro, Fr; Brugiatelli, M; Ilariucci, F; Lipari, Mg; Angrilli, F; Consoli, U; Fragasso, A; Molica, S; Festini, G; Vincelli, I; Cortelezzi, A; Federico, Massimo; Morabito, F; Ferrarini, M; Neri, A.
abstract

Recent studies have described chromosome 2p gain as a recurrent lesion in chronic lymphocytic leukemia (CLL). We investigated the 2p gain and its relationship with common prognostic biomarkers in a prospective series of 69 clinical monoclonal B-cell lymphocytosis (cMBL) and 218 early stage (Binet A) CLL patients. The 2p gain was detected by FISH in 17 patients (6%, 16 CLL, and 1 cMBL) and further characterized by single nucleotide polymorphism-array. Overall, unfavorable cytogenetic deletions, i.e., del(11)(q23) and del(17)(p13) (P = 0.002), were significantly more frequent in 2p gain cases, as well as unmutated status of IGHV (P &lt; 1 × 10(-4) ) and CD38 (P &lt; 1 × 10(-4) ) and ZAP-70 positive expression (P = 0.003). Furthermore, 2p gain patients had significantly higher utilization of stereotyped B-cell receptors compared with 2p negative patients (P = 0.009), and the incidence of stereotyped subset #1 in 2p gain patients was significantly higher than that found in the remaining CLLs (P = 0.031). Transcriptional profiling analysis identified several genes significantly upregulated in 2p gain CLLs, most of which mapped to 2p. Among these, NCOA1 and ROCK2 are known for their involvement in tumor progression in several human cancers, whereas among those located in different chromosomes, CAV1 at 7q31.1 has been recently identified to play a critical role in CLL progression. Thus, 2p gain can be present since the early stages of the disease, particularly in those cases characterized by other poor prognosis markers. The finding of genes upregulated in the cells with 2p gain provides new insights to define the pathogenic role of this lesion. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.

2013 - Clinicopathologic characteristics of angioimmunoblastics T-cell lymphoma (AITL): analysis of 243 cases from the International Peripheral T-cell Lymphoma Project. [Articolo su rivista]
Federico, Massimo; Rudiger, T.; Bellei, Monica; Nathwani, B. N.; Luminari, Stefano; Coiffier, B.; Harris, N. L.; Jaffe, E.; Pileri, S.; Savane, K. J.; Weisenburger, D. D.; Armitage, J. O.; Mounier, N.; Vose, J. M.
abstract

PURPOSE The International Peripheral T-Cell Lymphoma Project was undertaken to better understand the subtypes of T-cell and natural killer (NK) -cell lymphomas. PATIENTS AND METHODSAngioimmunoblastic T-cell lymphoma (AITL) was diagnosed according to the 2001 WHO criteria by a central review process consisting of panels of expert hematopathologists. Clinical, pathologic, immunophenotyping, treatment, and survival data were correlated. RESULTS: age ≥ 60 years, stages III to IV disease, lactic dehydrogenase (LDH) &gt; normal, extranodal sites (ENSs) &gt; one, and performance status (PS) ≥ 2; the Prognostic Index for Peripheral T-Cell Lymphoma, comprising: age ≥ 60 years, PS ≥ 2, LDH &gt; normal, and bone marrow involvement; and the alternative Prognostic Index for AITL (PIAI), comprising: age &gt; 60 years, PS ≥ 2, ENSs &gt; one, B symptoms, and platelet count &lt; 150 × 10(9)/L. The simplified PIAI had a low-risk group (zero to one factors), with 5-year survival of 44%, and a high-risk group (two to five factors), with 5-year survival of 24% (P = .0065). CONCLUSIONAITL is a rare clinicopathologic entity characterized by an aggressive course and dismal outcome with current therapies.

2013 - Consistency and inconsistency in testing biomarkers in breast cancer. A GRELL study in cut-off variability in the Romance language [Articolo su rivista]
Crocetti, E.; Caldarella, A.; Ferretti, S.; Ardanaz, E.; Arveux, P.; Bara, S.; Barrios, M. J.; Bordoni, A.; Buzzoni, C.; Candela, G.; Colombani, F.; Delafosse, P.; Federico, Massimo; Francart, J.; Giacomin, A.; Grosclaude, P.; Guizard, A. V.; Izarzugaza, I.; Konzelmann, I.; La Rosa, F.; Lapotre, B.; Leone, N.; Ligierk, ; Mangone, L.; Marcos Gragera, R.; Martinez, R.; Michelena, M. J.; Michiara, A.; Miranda, A.; Moliniè, F.; Mugarza Gomez, C.; Paci, E.; Piffer, S.; Puig Vives, M.; Sacchettini, C.; Sanchez, M. J.; Traina, A.; Tretarre, B.; Tumno, R.; Van Vaerenbergh, E.; Velten, M.; Woronoff, A. S.
abstract

PURPOSE: Biological markers are crucial factors in order to differentiate female breast cancers and to determine the right therapy. This study aims at evaluating whether testing for biomarkers for female breast cancer has similar frequency and characteristics across and within countries. METHODS: Population-based cancer registries of the Association for cancer registration and epidemiology in Romance language countries (GRELL) were asked to complete a questionnaire on biomarkers testing. The data collected referred to invasive female breast cancer cases diagnosed between 2004 and 2009. The investigation focused on 1) the overexpression and amplification of the human epidermal growth factor receptor 2 oncogene (HER2); 2) the expression of oestrogen (ER) and progesterone (PgR) receptors; and 3) the proliferation index (PI). Weighted percentages, the heterogeneity among and within countries, and the correlation between responses and calendar years were evaluated. The study was based on 19,644 breast cancers. RESULTS: Overall, 85.9% of the cases were tested for HER2, 91.8% for both ER and PgR, and 74.1% for proliferative markers. For HER2 and ER-PgR, the frequency of testing increased from 2004 to 2009. Testing varied among countries (HER2 from 82.0% to 95.9%, ER-PgR from 89.3% to 98.9%, PI from 10% to 92%) and also within the same country (e.g. HER2 in Italy from 51% to 99%) as well as within single cancer registries. The most relevant differences were in the scores for positive/negative/not clearly defined HER2 (e.g. HER2 was defined positive if IHC 3+ in 21/33 registries), and in the cut-off of positive cells for ER/PgR (from >0% to >30%) and PI positivity (from >0% to >20%). CONCLUSIONS: Biological markers are widely tested in the Romance language countries; however, the parameters defining their positivity may vary, raising concerns about homogeneity in breast cancer classification and treatment.

2013 - ESMO guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) [Articolo su rivista]
Ghielmini, M.; Vitolo, U.; Kimby, E.; Montoto, S.; Walewski, J.; Pfreundschuh, M.; Federico, Massimo; Hoskin, P.; McNamara, C.; Caligaris Cappio, F.; Stilgenbauer, .; Marcus, R.; Trmeny, M.; Dreger, P.; Montserrat, E.; Dreyling, M.
abstract

To complete the existing treatment guidelines for all tumor types, ESMO organizes consensus conferences to better clarify open issues in each disease. In this setting, a consensus conference on the management of lymphoma was held on 18 June 2011 in Lugano, immediately after the end of the 11th International Conference on Malignant Lymphoma. The consensus conference convened ∼45 experts from all around Europe and selected six lymphoma entities to be addressed; for each of them three to five open questions were to be discussed by the experts. For each question, a recommendation should be given by the panel, supported by the strength of the recommendation based on the level of evidence. This consensus report focuses on the three most common lymphoproliferative malignancies: diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia. A second report will concentrate on mantle cell lymphoma, marginal zone lymphoma and T-cell lymphomas.

2013 - Estimates of cancer burden in Emilia-Romagna [Articolo su rivista]
Falcini, F.; Mancini, S.; Ravaioli, A.; Vattiato, R.; Bucchi, L.; Ferretti, S.; Dichiara, M.; Federico, Massimo; PONZ DE LEON, Maurizio; Mangone, L.; Rossi, S.; Foschi, R.
abstract

AIMS AND BACKGROUND: This paper aims to provide a comprehensive overview of mid-term epidemiological trends for the major cancer sites in the Emilia-Romagna region of northern Italy (population 4,400,000). METHODS: The MIAMOD method, a back-calculation approach to estimate and project the incidence of chronic diseases from mortality and patient survival, was used for the estimation of incidence and prevalence by calendar year (from 1970 to 2015) and age (from 0 to 99). Survival estimates were taken from cancer registries of northeastern Italy. RESULTS: The estimated incidence of stomach cancer decreased by approximately 75% for both sexes. Trends in incidence of colorectal cancer differed between males and females. For females, the rate increased moderately until the year 2000 with a slow decrease thereafter, whereas the male colorectal cancer incidence showed a regular increase until 2010 followed by a substantial leveling off. Among males the lung cancer incidence and mortality rates showed a steep increase until the late 1980s and a rapid decrease thereafter. Among females, the trends were increasing over the entire study period. The estimated incidence of female breast cancer rose sharply between 1970 and 2001, but from that year onwards a slightly decreasing trend was observed. Mortality peaked in 1988 and has fallen since. The incidence of prostate cancer showed a 3-fold increase. After 2005, the rate is expected to stabilize. Among females, the estimated prevalence increased for breast cancer (52,700 cases expected in 2015), colorectal cancer, lung cancer and melanoma, while decreasing for stomach cancer and cervical cancer. Among males, the estimates showed an upward trend for prostate cancer (32,100 cases expected in 2015) and colorectal cancer, and a leveling off for lung cancer after 2010. CONCLUSION: The estimates were fairly consistent with previous data from several epidemiological sources. The MIAMOD method provided a picture of the impressive increase in the prevalence of breast cancer and prostate cancer over the 45-year period studied.

2013 - Estimates of cancer burden in Italy [Articolo su rivista]
Rossi, Silvia; Crocetti, Emanuele; Capocaccia, Riccardo; Gatta, Gemma; Buzzoni, C; Giacomin, A; Zanetti, R; Bisanti, L; Tessandori, R; Crosignani, P; Vercelli, M; Mazzoleni, G; Piffer, S; Zambon, P; Serraino, D; Ferretti, S; Michiara, M; Federico, Massimo; PONZ DE LEON, Maurizio; Mangone, L; Falcini, F; Crocetti, E; La Rosa, F; Vitarelli, S; Pannozzo, F; Fusco, M; Donato, A; Traina, A; Tumino, R; Madeddu, A; Contrino, Ml; Budroni, M.
abstract

This paper presents updated estimates of the incidence, prevalence and mortality of stomach, colorectal, lung, breast, uterine cervix and prostate cancer and skin melanoma in the Italian population. In particular, point estimates for 2012 and time trends from 1970 to 2015 will be provided.

2013 - External validation on a prospective basis of a nomogram for predicting the time to first treatment in patients with chronic lymphocytic leukemia [Articolo su rivista]
Molica, S.; Giannarelli, D.; Gentile, M.; Cutrona, G.; Di Renzo, N.; Di Raimondo, F.; Neri, A.; Federico, Massimo; Ferrarini, M.; Morabito, F.
abstract

BACKGROUND: A nomogram that incorporates traditional and newer prognostic factors to identify patients with chronic lymphocytic leukemia (CLL) who are at high risk of receiving therapy was developed by investigators at The University of Texas M. D. Anderson Cancer Center (MDACC). Because the model required validation before its extensive use could be recommended, the authors sought to externally validate the nomogram in an independent, community-based cohort of patients with CLL. METHODS: In total, 328 previously untreated patients with newly diagnosed, asymptomatic, Binet stage A CLL from different primary hematology centers who were registered on a prospective basis during 2006 to 2010 on an observational database of the Italian Lymphoma Study Group were considered suitable for external validation of the model. RESULTS: A total point score was calculated for each patient using a formula proposed by MDACC investigators, and the median score was 19.9 (range, 0-69.5). Furthermore, when the score was evaluated as continuous variable (ie, by measuring the risk of each point increase), the total point score was associated with the time to first treatment (hazard ratio [HR], 1.04; 95% confidence interval [CI], 1.02-1.05; P &lt; .0001). Receiver operating characteristic analysis identified a point score of 25 (area under curve; 0.64; sensitivity, 61.5; specificity, 72.1; P &lt; .0001) as the best threshold capable of separating patients who needed therapy from patients who did not (HR, 3.27; 95% CI, 2,07-5.18; P &lt; .0001). The prognostic index category also remained a predictor of the time to first treatment when the analysis was limited to patients with Rai stage 0 disease (HR, 4.05; 95% CI, 2.25-7.52; P &lt; .0001). Finally, a goodness-of-fit test demonstrated that the nomogram model had a significantly good fit at 2 years (correlation coefficient [r2] = 0.966; P = .002). CONCLUSIONS: The current results confirmed the ability of a newly developed prognostic index to predict the time to first treatment among previously untreated patients with CLL who had early disease and extended the utility of the model to those with Rai stage 0 disease. In addition, the actual and predicted time to first treatment outcomes revealed good agreement, suggesting that, externally, the results provided by the model are well calibrated. Cancer 2013. © 2012 American Cancer Society.

2013 - Follicular lymphoma [Capitolo/Saggio]
Luminari, S.; Dondi, A.; Biasoli, I. B.; Federico, M.
abstract

2013 - Impact of diabetes on overal and cancer-specific mortality in colorectal cancer patients [Articolo su rivista]
Bella, F.; Minicozzi, P.; Giacomin, A.; Crocetti, E.; Federico, Massimo; PONZ DE LEON, Maurizio; Fusco, M.; Tumino, R.; Mangone, L.; Giuliani, O.; Budroni, M.; Sant, M.
abstract

PURPOSE: Diabetes is associated with increased risk of developing colorectal cancer (CRC), but its effect on overall and cancer-specific mortality in CRC patients has been little investigated. The aim of this study was to assess the influence of diabetes on overall and cancer-specific mortality in Italian CRC patients. METHODS: Cases of adult (≥15 years) CRC, diagnosed in 2003-2005, most followed-up to the end of 2008, were randomly selected from the Italian Cancer Registries database. Diabetic status, sex, age, tumor stage, subsite, treatment, morphology, and grade were obtained by consultation of patient clinical records. Poisson multivariable regression models, adjusted for potential confounding variables, were used to estimate hazard ratios (HRs) for all-cause and CRC-specific mortality, according to diabetic status. RESULTS: A total of 1,039 CRC cases with known fasting glucose or diabetic status, archived in 7 cancer registries, was analyzed. Compared to non-diabetics, diabetics (specific diagnosis or glucose ≥126 mg/dl) were older and less likely to receive adjuvant therapy. Diabetics were at higher risk of all-cause death [HR 1.41; 95 % confidence interval (CI) 1.18-1.70] and CRC death (HR 1.36; 95 % CI 1.11-1.67), with no differences by sex or subsite. CONCLUSIONS: Diabetes was significantly associated with increased overall and CRC-specific mortality. Our findings indicate that diabetes is a negative prognostic factor for CRC and suggest that in patients with CRC, diabetes prevention and treatments that stabilize the condition and control its complications might reduce mortality. Further studies are required to ascertain the mechanisms linking diabetes to greater mortality in CRC patients.

2013 - Italian cancer figures, report 2013: Multiple tumours [Articolo su rivista]
Adamo, Ms; Alessi, D; Aletta, P; Amodio, R; Andreone, S; Angelin, T; Anghinoni, E; Annulli, Ml; Antonini, S; Artioli, Me; Autelitano, M; Balducci, C; Balottari, P; Baracco, M; Battisti, W; Bella, F; Bellatalla, C; Belluardo, C; Benatti, Piero; Benedetto, G; Benfatto, L; Bernazza, E; Bianconi, F; Biavati, P; Bidoli, E; Birri, S; Bizzoco, S; Bonelli, L; Bonini, A; Borciani, E; Bovo, E; Bozzani, F; Bozzeda, A; Braghiroli, B; Brucculeri, Ma; Brunori, V; Bucalo, G; Bucchi, L; Bugliarello, E; Bulatko, A; Busco, S; Busso, P; Buzzoni, C; Calabretta, L; Caldarella, A; Candela, G; Canu, L; Cappelletti, M; Caprara, L; Carboni, D; Carletti, N; Caroli, S; Carone, S; Cascio, Ma; Cascone, G; Casella, C; Castaing, M; Cecconami, L; Celesia, Mv; Cena, T; Cercato, Mc; Cesaraccio, R; Chiesa, R; Cirilli, C; Civaschi, A; Cocchioni, M; Codazzi, T; Cogno, R; Colamartini, A; Colanino Ziino, A; Cometti, I; Contiero, P; Contrino, Ml; Corbinelli, A; Cordaro, C; Corti, M; Costa, A; Costarelli, D; Cremone, L; Crocetti, E; Curatella, S; Cusimano, R; D'Alò, D; D'Angelo, S; Dal Cappello, T; Dal Cin, A; Dal Maso, L; Dall'Acqua, M; Dalsasso, F; Davini, C; De Dottori, M; De Maria, V; De Santis, E; De Valiere, E; Dei Tos, Ap; Demurtas, G; Devigli, E; Di Felice, E; di Grazia, L; Di Gregorio, C; Di Prima, A; Distefano, R; Doa, N; Domati, F; Fabiano, S; Facchinelli, G; Falcini, F; Falk, M; Fanetti, Ac; Fattoruso, S; Federico, Massimo; Ferrari, L; Ferretti, S; Fidelbo, M; Filipazzi, L; Fiore, Ar; Fiori, G; Foca, F; Forgiarini, O; Frasca, G; Frassoldi, E; Frizza, J; Fusco, M; Fusco, M; Gada, D; Garrone, E; Gasparotti, C; Gatti, L; Gaudiano, C; Gennaro, V; Gentilini, M; Gerevini, C; Ghilardi, S; Ghisleni, S; Giacomin, A; Giavazzi, L; Gilardi, F; Giorgetti, S; Giubelli, C; Giuliani, O; Giurdanella, Mc; Gola, G; Goldoni, Ca; Golizia, Mg; Grandi, L; Greco, A; Guarda, L; Guttadauro, A; Guzzinati, S; Iachetta, F; Iannelli, A; Ieni, A; Intrieri, T; Kaleci, S; La Rosa, F; Lando, C; Lavecchia, Am; Lazzarato, F; Leone, A; Leone, R; Lonati, F; Lottero, B; Lucchi, S; Luminari, Stefano; Macci, L; Macerata, V; Madeddu, A; Maffei, S; Maghini, A; Magnani, C; Magnani, G; Magoni, M; Mameli, G; Mancini, S; Mancuso, P; Mangone, L; Manneschi, G; Mannino, R; Mannino, S; Marani, E; Mariani, F; Martorana, C; Marzola, L; Maspero, S; Maule, M; Mazzei, A; Mazzoleni, G; Mazzucco, G; Melcarne, A; Merletti, F; Michiara, M; Migliari, E; Minerba, S; Minicuzzi, A; Mizzi, M; Monetti, D; Morana, G; Moroni, E; Mosso, Ml; Muni, A; Mura, F; Natali, M; Nemcova, L; Nicita, C; Ocello, C; Paci, E; Pala, F; Palumbo, M; Panico, M; Pannozzo, F; Pascucci, C; Pastore, G; Patriarca, S; Pedroni, Monica; Pellegri, C; Perrotta, C; Pesce, P; Petrinelli, Am; Petrucci, C; Pezzarossi, A; Piffer, S; Pintori, N; Pirani, M; Pirino, D; Pironi, V; PONZ DE LEON, Maurizio; Prandi, R; Prazzoli, R; Preto, L; Puleio, M; Puppo, A; Quaglia, A; Quarta, F; Quattrocchi, M; Raho, Am; Ramazzotti, V; Rashid, I; Ravaioli, A; Ravazzolo, B; Ravegnani, M; Reggiani Bonetti, L; Ribaudo, M; Rinaldi, E; Ricci, P; Rizzello, R; Rollo, Pc; Roncucci, Luca; Rosano, A; Rossi, F; Rossi, G; Rossi, M; Rossini, S; Rosso, S; Rudisi, G; Ruggeri, Mg; Russo, Ag; Russo, M; Sacchettini, C; Sacco, G; Sacerdote, C; Salvatore, S; Salvi, O; Sampietro, G; Sandrini, M; Santucci, C; Scheibel, M; Schiacchitano, S; Sciacca, S; Sciacchitano, C; Scuderi, T; Sechi, O; Seghini, P; Senatore, G; Serafini, G; Serraino, D; Sgargi, P; Sigona, A; Sini, Gm; Sobrato, I; Soddu, M; Solimene, C; Spano, F; Spata, E; Sperduti, I; Staiti, R; Stocco, C; Stracci, F; Sunseri, R; Sardo, As; Tagliabue, G; Tamburo, L; Tamburrino, S; Tanzarella, M; Terracini, B; Tessandori, R; Tisano, F; Tittarelli, A; Tognazzo, S; Torrisi, A; Torrisi, A; Traina, A; Trapani, C; Tschugguel, B; Tumino, R; Usala, M; Vacirca, S; Valerio, O; Valla, K; Varvarà, M; Vasquez, E; Vassante, B; Vattiato, R; Vercelli, M; Vercellino, Pc; Vicentini, M; Villa, M; Vitale, F; Vital
abstract

OBJECTIVES: This collaborative study, based on data collected by the network of Italian association of cancer registries (AIRTUM), provides updated estimates on the incidence risk of multiple primary cancer (MP). The objective is to highlight and quantify the bidirectional associations between different oncological diseases. The quantification of the excess or decreased risk of further cancers in cancer patients, in comparison with the general population, may contribute to understand the aetiology of cancer and to address clinical follow-up. MATERIAL AND METHODS: Data herein presented were provided by AIRTUM population-based cancer registries, which cover nowadays 48% of the Italian population. This monograph utilizes the AIRTUM database (December 2012), considering all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to ICD-O-3. Non-melanoma skin cancer cases, cases based on death certificate only, cases based on autopsy only, and cases with follow-up time equal to zero were excluded. To define multiple primaries, IARC-IACR rules were adopted (http://www.iacr.com.fr/MPrules_july2004.pdf). Data were subjected to standard quality control procedures (described in the AIRTUM data management protocol) and specific quality control checks defined for the present study. A cohort of cancer patients was followed over time from first cancer diagnosis until the date of second cancer diagnosis, death, or the end of follow-up, to evaluate whether the number of observed second cancer cases was greater than expected. Person years at risk (PY) were computed by first cancer site, geographic area (North, Centre, South and Islands), attained age, and attained calendar-year group. All second cancers diagnosed in the cohort's patients were included in the observed numbers of cases. The expected number of cancer cases was computed multiplying the accumulated PY by the expected rates, calculated from the AIRTUM database stratified by cancer site, geographic area, age, and calendar-year group. The Standardized Incidence Ratio (SIR) was calculated as the ratio of observed to expected cancer cases. The Excess Absolute Risk (EAR) beyond the expected amount were calculated subtracting the expected number of subsequent cancers from the observed number of cancer cases; the difference was then divided by the PY and the number of cancer cases in excess (or deficit) was expressed per 1,000 PY. Confidence intervals were stated at 95%. The two months (60 days) after first cancer diagnosis were defined as "synchronicity period", and in the main analysis observed and expected cases during this period were excluded. It was estimated the excess risk in the period after first diagnosis (≥ 0 months), excluding the synchronicity period (≥ 2 months), and during the following periods: 2-11, 12-59, 60-119 and 120 months after diagnosis. First-cancer-site-and-gender-specific sheets are presented, reporting both SIRs and EARs. RESULTS: For 5,979,338 person-years a cohort of 1,635,060 cancer patients (880,361 males and 754,699 females) diagnosed between 1976 and 2010 was followed. The mean follow-up length was 14 years. Overall, 85,399 metachronous (latency ≥2 months) cancers were observed, while 77,813 were expected during the study period: SIR: 1.10 (95%CI 1.09-1.10), EAR: 1.32 x 1,000 person-years (95%CI 1.19 - 1.46). The SIR was 1.08 (95%CI 1.08-1.09) for men (54,518 observed and 50,260 expected) and 1.12 (95%CI 1.11-1.13) for women (30,881/27,553), and the EAR 1.61 (95%CI 1.37-1.84) and 1.08 x 1,000 person-years (95%CI 0.93-1.24), respectively.Moreover, during the first two months after first cancer diagnosis (synchronous period) 14,807 cancers were observed while 3,536 were expected (SIR: 4.16; 95%CI 4.09-4.22); the SIR was 4.08 (95%CI 4.00-4.16) for men and 4.32 (95%CI 4.20-4.45) for women.The mean age of patients at first cancer diagnosis was 67.0 years among males and

2013 - [Lung cancer incidence in young women (20-49 years) reached incidence in young men] [Articolo su rivista]
Maso, Dal; Luigino, ; Autelitano, M; Bizzoco, S; Vercelli, M; Borciani, E; Buzzoni, C; Candela, G; Cocchioni, M; Cremone, L; Crocetti, E; Crosignani, P; Cusimano, R; Dei Tos, A; Falcini, F; Federico, Massimo; Ferretti, S; Fusco, M; Gennaro, V; Giacomin, A; Gola, G; La Rosa, F; Madeddu, A; Magoni, M; Mangone, L; Maspero, S; Mazzoleni, G; Melcarne, A; Merletti, F; Michiara, M; Minerba, S; Pannozzo, F; Piffer, S; PONZ DE LEON, Maurizio; Quarta, F; Ricci, P; Russo, A; Sampietro, G; Sciacca, S; Sechi, O; Serraino, D; Sutera Sardo, A; Tisano, F; Traina, A; Tumino, R; Usala, M; Vitale, F; Vitarelli, S; Zanetti, R.
abstract

not applicable

2013 - Lymph node evaluation in stage IIA colorectal cancer and its impact on patient prognosis: A population-based study [Articolo su rivista]
Iachetta, Francesco; REGGIANI BONETTI, Luca; Marcheselli, Luigi; DI GREGORIO, Carmela; Cirilli, C.; Messinese, S.; Cervo, Gian Luca; Postiglione, Raffaella; DI EMIDIO, Katia; Pedroni, Monica; Longinotti, E.; Federico, Massimo; PONZ DE LEON, Maurizio
abstract

Background. The analysis of regional lymph nodes is particularly relevant in patients with stage II colorectal cancer, in whom the role of adjuvant chemotherapy remains unclear. The aim of this study was to assess the relationship between number of examined lymph nodes and survival in patients with stage IIA (pT3N0M0) colorectal cancer, and to determine the optimal number of lymph nodes that should be examined. Methods. The study group included all the surgically-treated colorectal cancer patients in stage IIA (n = 657) who were identified through the population-based Cancer Registry of the Province of Modena (Northern Italy), during the period 2002-2006. Results. The median number of harvested lymph nodes was 19 (range 1-68). Considering, as a reference point, patients with 12 or less lymph nodes, subjects with n ≥ 20 lymph nodes examined showed, in univariate analysis, a significantly higher cancer specific (p = 0.01) and relapse-free survival (p = 0.003). The results were confirmed by multivariate analysis (Cox model). Conclusion. The result suggests that colorectal cancer patients in stage IIA with n ≥ 20 lymph nodes examined exhibit better survival when compared with subjects in whom fewer lymph nodes were examined. The number of 20 lymph nodes is the essential requirement for an oncologic resection of the large bowel.

2013 - Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas: results of a phase III diagnostic accuracy study [Articolo su rivista]
Piccaluga, P. P.; Fuligni, F.; De Leo, A.; Bertuzzi, C.; Rossi, M.; Bacci, F.; Sabattini, E.; Agostinelli, C.; Gazzola, A.; Laginestra, M. A.; Mannu, C.; Sapienza, M. R.; Hartmann, S.; Hansmann, M. L.; Piva, R.; Iqbal, J.; Chan, J. C.; Weisenburger, D.; Vose, J. M.; Bellei, Monica; Federico, Massimo; Inghirami, G.; Zinzani, P. L.; Pileri, S. A.
abstract

PURPOSE: The differential diagnosis among the commonest peripheral T-cell lymphomas (PTCLs; ie, PTCL not otherwise specified [NOS], angioimmunoblastic T-cell lymphoma [AITL], and anaplastic large-cell lymphoma [ALCL]) is difficult, with the morphologic and phenotypic features largely overlapping. We performed a phase III diagnostic accuracy study to test the ability of gene expression profiles (GEPs; index test) to identify PTCL subtype. METHODS: We studied 244 PTCLs, including 158 PTCLs NOS, 63 AITLs, and 23 ALK-negative ALCLs. The GEP-based classification method was established on a support vector machine algorithm, and the reference standard was an expert pathologic diagnosis according to WHO classification. RESULTS: First, we identified molecular signatures (molecular classifier [MC]) discriminating either AITL and ALK-negative ALCL from PTCL NOS in a training set. Of note, the MC was developed in formalin-fixed paraffin-embedded (FFPE) samples and validated in both FFPE and frozen tissues. Second, we found that the overall accuracy of the MC was remarkable: 98% to 77% for AITL and 98% to 93% for ALK-negative ALCL in test and validation sets of patient cases, respectively. Furthermore, we found that the MC significantly improved the prognostic stratification of patients with PTCL. Particularly, it enhanced the distinction of ALK-negative ALCL from PTCL NOS, especially from some CD30+ PTCL NOS with uncertain morphology. Finally, MC discriminated some T-follicular helper (Tfh) PTCL NOS from AITL, providing further evidence that a group of PTCLs NOS shares a Tfh derivation with but is distinct from AITL. CONCLUSION: Our findings support the usage of an MC as additional tool in the diagnostic workup of nodal PTCL.

2013 - Monocytosis has adverse prognostic significance and impacts survival in patients with T-cell lymphomas [Articolo su rivista]
Bari, Alessia; Tadmor, T.; Sacchi, Stefano; Marcheselli, L.; Liardo, ELIANA VALENTINA; Pozzi, Samantha; Luminari, Stefano; Baldini, L.; Marmiroli, Sandra; Federico, Massimo; Polliack, A.
abstract

In this retrospective study we evaluated the prognostic impact of peripheral blood monocytosis in patients with T-cell non Hodgkin lymphomas with "aggressive-typically nodal presentation". In this dataset monocytes >0.8×10(9)/L had a strong and statistically significant negative impact on overall survival (OS). In univariate analysis several parameters, including age >60 years, advanced stage, bone marrow involvement, ECOG PS >1, high LDH level, monocytes >0.8×10(9)/L, hemoglobin<120g/L, albumin<35g/L) had a negative influence on outcome, but in multivariate analysis, monocytosis alone had a stronger association with poor OS.

2013 - Ovarian cancer: can proteomics give new insights for therapy and diagnosis? [Articolo su rivista]
Toss, Angela; DE MATTEIS, Elisabetta; Rossi, Elena; Casa, L. D.; Iannone, Anna; Federico, Massimo; Cortesi, Laura
abstract

The study of the ovarian proteomic profile represents a new frontier in ovarian cancer research, since this approach is able to enlighten the wide variety of post-translational events (such as glycosylation and phosphorylation). Due to the possibility of analyzing thousands of proteins, which could be simultaneously altered, comparative proteomics represent a promising model of possible biomarker discovery for ovarian cancer detection and monitoring. Moreover, defining signaling pathways in ovarian cancer cells through proteomic analysis offers the opportunity to design novel drugs and to optimize the use of molecularly targeted agents against crucial and biologically active pathways. Proteomic techniques provide more information about different histological types of ovarian cancer, cell growth and progression, genes related to tumor microenvironment and specific molecular targets predictive of response to chemotherapy than sequencing or microarrays. Estimates of specificity with proteomics are less consistent, but suggest a new role for combinations of biomarkers in early ovarian cancer diagnosis, such as the OVA1 test. Finally, the definition of the proteomic profiles in ovarian cancer would be accurate and effective in identifying which pathways are differentially altered, defining the most effective therapeutic regimen and eventually improving health outcomes.

2013 - Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program [Articolo su rivista]
Ladetto, Marco; Lobetti-Bodoni, Chiara; Mantoan, Barbara; Ceccarelli, Manuela; Boccomini, Carola; Genuardi, Elisa; Chiappella, Annalisa; Baldini, Luca; Rossi, Giuseppe; Pulsoni, Alessandro; Francesco Di Raimondo, ; Rigacci, Luigi; Pinto, Antonello; Galimberti, Sara; Bari, Alessia; Rota-Scalabrini, Delia; Ferrari, Angela; Zaja, Francesco; Gallamini, Andrea; Specchia, Giorgina; Musto, Pellegrino; Francesca Gaia Rossi, ; Gamba, Enrica; Andrea Evangelista and Umberto Vitolo for the Fondazione Italiana Linfomi, ; Collaborators: Lobetti-Bodoni, C; Mantoan, B; Genuardi, E; Boccadoro, M; Ladetto, M; Ciccone, G; Evangelista, A; Ceccarelli, M; Boccomini, C; Chiappella, A; Botto, B; Orsucci, L; Vitolo, U; Goldaniga, M; Rossi, Fg; Baldini, L; Bottelli, C; Tucci, Angelo Carmelo; Rossi, G; Pulsoni, A; De Angelis, F; RUSSO ERMOLLI, Elda; Martelli, M; Foà, R; Di Raimondo, F; Chiarenza, Antonino; Rigacci, L; Puccini, B; Bosi, A; Pinto, Alessandra; Petrini, Marino; Galimberti, S; Bari, A; Sacchi, S; Federico, M; Rota-Scalabrini, D; Aglietta, M; Ferrari, A; Alvarez De Celis, I; Merli, F; Zaja, F; Fanin, R; Castellino, C; Gallamini, A; Parvis, G; Saglio, G; Perrone, T; Specchia, G; Musto, P; Gamba, E; Corradini, P; Pogliani, Em; Liberati, Am; Leone, G; Patti, C; Fioritoni, G; Rusconi, C; Morra, E; Tonso, A; Cabras, G; Angelucci, E; Rossi, A; Rambaldi, A; Cortelazzo, S; Morandi, S; Lanza, F; Pizzolo, G; Amadori, S; Zinzani, Pl; Stelitano, C; Nobile, F
abstract

We assessed the prognostic value of minimal residual disease (MRD) within the ML17638 phase 3 trial from the Fondazione Italiana Linfomi, investigating the role of rituximab maintenance in elderly follicular lymphoma (FL) patients after a brief first-line chemoimmunotherapy. MRD for the bcl-2/IgH translocation was determined on bonemarrowcells in a centralized laboratory belonging to the Euro-MRD consortium, using qualitative and quantitative polymerase chain reactions (PCRs). Of 234 enrolled patients, 227 (97%) were screened at diagnosis. A molecular marker (MM) was found in 51%. Patients with an MM were monitored at 8 subsequent times. Of the 675 expected follow-up samples, 83% were analyzed. Conversion to PCR negativity predicted better progression-free survival (PFS) at all post-treatment times (eg, end of therapy: 3-year PFS, 72% vs 39%; P < .007). MRD was predictive in both maintenance (83% vs 60%; P < .007) and observation (71% vs 50%; P < .001) groups. PCR positivity at the end of induction was an independent adverse predictor (hazard ratio, 3.1; 95% confidence interval, 1.36-7.07). MRD is a powerful independent outcome predictor in FL patients who receive rituximab-intensive programs, suggesting a need to investigate its value for decision-making. This trial was registered at www.clinicaltrial.gov as #NCT01144364. © 2013 by The American Society of Hematology.

2013 - Prognostic role of gender in diffuse large B-cell lymphoma treated with rituximab containing regimens: a Fondazione Italiana Linfomi/Grupo de Estudos em Moléstias Onco-Hematológicas retrospective study [Articolo su rivista]
Carella, Angelo M; de Souza, Carmino A; Luminari, Stefano; Marcheselli, Luigi; Chiappella, Annalisa; di Rocco, Alice; Cesaretti, Marina; Rossi, Andrea; Rigacci, Luigi; Gaidano, Gianluca; Merli, Francesco; Spina, Michele; Stelitano, Caterina; Hohaus, Stefan; Barbui, Anna; Puccini, Benedetta; Miranda, Eliana C; Guida, Annalisa; Federico, Massimo
abstract

Male gender was recently reported as an adverse prognostic factor in patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). We conducted a retrospective study of adult patients with DLBCL initially treated with rituximab containing regimens between 2001 and 2007. Patients were identified from the clinical archives of 43 Italian and Brazilian institutions. The principal endpoint was overall survival (OS). One thousand seven hundred and ninety-three patients were fully eligible for the study. Thirty-eight percent, 27%, 22% and 12% of patients had an International Prognostic Index (IPI) score of 0-1, 2, 3 and 4-5, respectively; 53% were males. After a median follow-up of 36 months (1-106), the 5-year OS was 76% (95% confidence interval 74-78%). In univariate analysis, male gender was an adverse prognostic factor with a hazard ratio of 1.52. In multivariate analysis, when adjusted by IPI, again gender maintained its prognostic relevance, showing an independent additive effect. In conclusion, in patients with DLBCL treated with rituximab containing regimens, gender may increase the predictive power of the IPI. Based on these results, given possible differences in blood clearance of rituximab between males and females, the benefit of higher doses of rituximab in males should be explored.

2013 - R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lmphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Dondi, Alessandra; Tucci, Alessandra; Vitolo, Umberto; Rigacci, Luigi; Di Raimondo, Francesco; Carella, Angelo Michele; Pulsoni, Alessandro; Merli, Francesco; Arcaini, Luca; Angrilli, Francesco; Stelitano, Caterina; Gaidano, Gianluca; Dell'Olio, Matteo; Marcheselli, Luigi; Franco, Vito; Galimberti, Sara; Sacchi, Stefano; Brugiatelli, Maura
abstract

PURPOSE Although rituximab (R) is commonly used for patients with advanced follicular lymphoma (FL) requiring treatment, the optimal associated chemotherapy regimen has yet to be clarified. PATIENTS AND METHODS We conducted an open-label, multicenter, randomized trial among adult patients with previously untreated stages II to IV FL to compare efficacy of eight doses of R associated with eight cycles of cyclophosphamide, vincristine, and prednisone (CVP) or six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or six cycles of fludarabine and mitoxantrone (FM). The principal end point of the study was time to treatment failure (TTF). Results There were 534 patients enrolled onto the study. Overall response rates were 88%, 93%, and 91% for R-CVP, R-CHOP, and R-FM, respectively (P=.247). After a median follow-up of 34 months, 3-year TTFs were 46%, 62%, and 59% for the respective treatment groups (R-CHOP v R-CVP, P=.003; R-FM v R-CVP, P=.006; R-FM v R-CHOP, P=.763). Three-year progression-free survival (PFS) rates were 52%, 68%, and 63% (overall P=.011), respectively, and 3-year overall survival was 95% for the whole series. R-FM resulted in higher rates of grade 3 to 4 neutropenia (64%) compared with R-CVP (28%) and R-CHOP (50%; P&lt; .001). Overall, 23 second malignancies were registered during follow-up: four in R-CVP, five in R-CHOP, and 14 in R-FM. CONCLUSION In this study, R-CHOP and R-FM were superior to R-CVP in terms of 3-year TTF and PFS. In addition, R-CHOP had a better risk-benefit ratio compared with R-FM.

2013 - Relative and disease-free survival for breast cancer in relation to subtype: a population-based study [Articolo su rivista]
Minicozzi, P.; Bella, F.; Toss, Angela; Giacomn, A.; Fusco, M.; Zarcone, M.; Tumino, R.; Falcini, F.; Cesaraccio, R.; Candela, G.; La Rosa, F.; Federico, Massimo; Sant, M.
abstract

PURPOSE: No population-based study has investigated breast cancer (BC) subtypes defined by including Ki67. The aim of this study was to evaluate the relative proportions of immunohistochemical subtypes and differences in relative and disease-free survival between subtypes, in relation to patient and other cancer characteristics in Italian BC patient. METHODS: Information on estrogen, progesterone, human epidermal growth factor (HER2), Ki67, and relapses was obtained for 3,381 cases, sampled randomly and anonymously from cases diagnosed in 2003-2005 in nine Italian cancer registries. Relative excess risks (RERs) of death and risks of relapse 5 years after diagnosis were estimated. RESULTS: Luminal A cancers were 42 % of the total, luminal B 27 %, luminal-HER2 14 %, triple-negative 11 %, and HER2-enriched 7 %. For non-metastatic (3,302) cases, 4 and 7 % developed locoregional and distant metastases, respectively. RERs of death and risks of relapse were significantly greater for all cancer subtypes than luminal A, particularly for triple-negative and HER2-enriched cancers, which were more frequent in women <40 years. CONCLUSIONS: Our population-based findings confirm that subtype is an independent prognostic factor for BC. Triple-negative and HER2-enriched subtypes would benefit from the development and wide application, respectively, of targeted treatments, which would also improve survival for younger patients.

2013 - Replay to R.L.Olin et al. [Articolo su rivista]
Federico, Massimo; Dondi, Alessandra
abstract

not available

2013 - Risk factors for impaired gonadal function in female Hodgkin lymphoma survivors: final analysis of a retrospective multicenter joint study from Italian and Brazilian Institutions. [Articolo su rivista]
Falorio, S; Biasoli, I; Luminari, Stefano; Quintana, G; Musso, M; Dell'Olio, M; Specchia, Mr; di Renzo, N; Cesaretti, Marina; Buda, G; Vallisa, D; Mannina, D; Andriani, A; Chiattone, Cs; Delamain, Mt; de Souza, Ca; Spector, N; Angrilli, F; Federico, Massimo
abstract

Hodgkin lymphoma (HL) is one of the most common types of cancer in the young and one of the most curable forms of cancer. Therefore, there has been an increasing interest in the study of long-term morbidities. The aims of the present study were to evaluate the prevalence and risk factors for impaired gonadal function in a retrospective cohort of 238 HL female survivors from Italy and Brazil and to analyse the role of oral contraceptives (OC) and GnRH-analogues. Besides data collection from HL databases, a specific questionnaire was administered to collect data on gonadal function. The median age at diagnosis was 25 years and the median follow-up was 7 years. Overall, 25% of the patients developed impaired gonadal function. Older age at diagnosis, front-line therapies containing alkylating agents and more than one treatment were independent risk factors, whereas the use of OC or GnRH-a reduced independently the risk of impaired gonadal function. The fertility rate among fertile survivors was low when compared with the general population. We confirmed that older age, type of front-line chemotherapy and a higher number of therapies are associated with gonadal function impairment in terms of infertility and premature menopause in female HL survivors. Also, the use of GnRH-a or OC was independently identified as a protective factor. Further prospective studies are needed to better understand the barriers to parenthood in HL survivors.

2013 - Role of radiotherapy in patients with early-stage diffuse large B-cell lymphoma of Waldeyer's ring in remission after anthracycline-containing chemotherapy [Articolo su rivista]
Mian, Michael; Ferreri, Andrés J. M; Rossi, Andrea; Conconi, Annarita; Tsang, Richard; Gospodarowicz, Mary K; Oldani, Elena; Federico, Massimo; Luminari, Stefano; Pogliani, Enrico M; Rossini, Fausto; Cabrera, Maria E; Martelli, Maurizio; Gutierrez Garcia, Gonzalo; Busetto, Mario; Cavalli, Franco; Zucca, Emanuele; Rambaldi, Alessandro; Cortelazzo, Sergio
abstract

Consolidation radiotherapy (cRT) in patients with stage I/II diffuse large B-cell lymphoma of the Waldeyer's ring (WR-DLBCL) in complete remission (CR) after induction chemotherapy (CHT) is often associated with relevant acute and chronic toxicity, and its impact on survival remains to be defined. A total of 184 patients in CR after anthracycline-based chemotherapy were retrospectively analyzed: 62 underwent CHT alone (CHT group), while 122 (66%) patients were referred to cRT (CHT + RT group). After a median follow-up of 54 months, 36 patients (20%) experienced relapse: 19% in the CHT group and 20% in the CHT + RT group. At the time of analysis 47 (76%) CHT patients and 97 (80%) CHT + RT patients were alive. Five-year overall survival (OS), disease-free survival (DFS) and lymphoma-specific survival (LSS) were 80%, 74% and 86%, respectively. Five-year OS was significantly prolonged in the CHT + RT group, while DFS and LSS were similar between groups. This discrepancy was attributed to a high percentage of deaths due to unrelated causes in CHT patients. cRT does not prolong LSS in patients with early-stage WR-DLBCL in CR after anthracycline-containing chemotherapy. An international confirmatory trial is warranted.

2013 - Screening patterns within organized programs and survival of italian women with invasive cervical cancer [Articolo su rivista]
Zucchetto, A.; Ronco, G.; Giorgi Rossi, P.; Zappa, M.; Ferretti, S.; Franzo, A.; Falcini, F.; Visioli, C. B.; Zanetti, R.; Biavati, P.; La Rosa, F.; Baracco, S.; Federico, Massimo; Campari, C.; De Togni, A.; Piffer, S.; Pannozzo, F.; Fusco, M.; Michiara, M.; Castaing, M.; Seghini, P.; Tisano, F.; Serraino, D.
abstract

OBJECTIVES: To evaluate screening patterns within organized cervical screening programs (OCSPs) and survival of women with invasive cervical cancer (ICC). METHODS: A population-based study was conducted in Italian areas covered by cancer registries and OCSPs. The study included all women aged 25-65years diagnosed with ICC between 1995 and 2008, and their screening histories within OCSPs were retrieved. Hazard ratios (HR) of death and 95% confidence intervals (CI) were computed according to screening pattern, using Cox models adjusted for age, ICC stage, and major confounders. RESULTS: Among 3268 women with ICC, 20% were never-invited to OCSP, 36% were never-compliant with OCSP's invitation, 33% were compliant and had a screen-detected ICC within OCSP (i.e., after a positive cytology), and 11% were compliant but had a non-screen-detected ICC. Screen-detected ICCs were more frequently micro-invasive (42%) compared to non-screen-detected ones (14%). Compared to women with screen-detected ICC, the adjusted HRs of death were 1.9 (95% CI 1.5-2.4) for those never-invited, 2.0 (95% CI 1.6-2.5) for never-compliant, and 1.7 (95% CI 1.3-2.4) for compliant women having non-screen-detected ICC. CONCLUSION: Prolonged survival, beyond down-staging, of women with ICC detected within OCSPs in Italy, further calls for improvements of OCSPs' invitational coverage and participation.

2013 - Survival of multiple myeloma patients in the era of novel therapies confirms the improvement in patients younger than 75 years: a population-based analysis [Articolo su rivista]
Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Liardo, ELIANA VALENTINA; Marcheselli, Raffaella; Luminari, Stefano; Quaresima, Micol; Cirilli, C.; Ferri, Paola; Federico, Massimo; Sacchi, Stefano
abstract

Novel treatments for multiple myeloma (MM) have shown promising results in clinical trials, but the advantage in unselected patients is still unclear. In order to evaluate whether novel therapies impact survival of MM patients, we performed a population-based analysis on data collected by the Modena Cancer Registry from 1989 to 2009. The analysis evaluated 1206 newly diagnosed MM patients collected in the years 1988-96 (conventional therapy), 1997-05 (high dose melphalan and autologous transplant), and 2006-09 (novel agents era). Both relative survival (RS) and overall survival (OS) improved over the years, but not equally in the three groups. For patients aged <65 years, RS improved in 1997-05 and 2006-09 compared with previous years and a trend to improvement was observed from 1997-05 to 2006-09. For patients aged 65-74 years, RS improved significantly in 2006-09 compared with 1988-96 and 1997-05. No amelioration was observed for patients 75+ years old. OS confirmed RS. In conclusion, the survival of MM patients aged <65 and, in particular, 65-74 years, has improved over time, especially after 2006. This observation provides circumstantial evidence that novel therapies might impact patient survival. Despite the limits of this study, these data refer to an unselected population, giving a picture of every day clinical practice.

2013 - The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi [Articolo su rivista]
Luminari, Stefano; Biasoli, I.; Arcaini, L.; Versari, A.; Rusconi, C.; Merli, F.; Spina, M.; Ferreri, A. J.; Zinzani, P. L.; Gallamini, A.; Mastronardi, S.; Boccomini, C.; Gaidano, G.; D'Arco, A. M.; Di Raimondo, F.; Carella, A. M.; Santoro, A.; Musto, P.; Federico, Massimo
abstract

BACKGROUND: The role of [(18)F] fluorodeoxyglucose (FDG)-positron emission tomography (PET) in follicular lymphoma (FL) staging is not yet determined. PATIENTS AND METHODS: The aim of the present study was to investigate the role of PET in the initial staging of FL patients enrolled in the FOLL05-phase-III trial that compared first-line regimens (R-CVP, R-CHOP and R-FM). Patients should have undergone conventional staging and have available PET baseline to be included. RESULTS: A total of 142 patients were analysed. PET identified a higher number of nodal areas in 32% (46 of 142) of patients and more extranodal (EN) sites than computed tomography (CT) scan. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score increased in 18% (26 of 142) and decreased in 6% (9 of 142) of patients. Overall, the impact of PET on modifying the stage was highest in patients with limited stage. Actually, 62% (15 of 24) of cases with limited disease were upstaged with PET. CONCLUSIONS: The inclusion of PET among staging procedures makes the evaluation of patients with FL more accurate and has the potential to modify therapy decision and prognosis in a moderate proportion of patients. Further prospective clinical trials on FL should incorporate PET at different moments, and the therapeutic criteria to start therapy should be re-visited in the views of this new tool.

2013 - The utility of two prognostic models for predicting time to forst treatment in early chronic lymphocytic leukemia patients: results of a comparative analysis [Articolo su rivista]
Molica, S.; Giannarelli, D.; Gentile, M.; Cutrona, G.; Di Renzo, N.; Di Raimondo, F.; Neri, A.; Federico, Massimo; Ferrarini, M.; Morabito, F.
abstract

The use of both traditional and novel prognostic parameters combined in a statistical model for predicting patient clinical outcome has been recently proposed by both MD Anderson Cancer Center (MDACC) and German chronic lymphocytic leukemia (CLL) group. Using time to first treatment (TTFT) as end-point, we performed a comparative external validation of MDACC score versus a modified version of German score, which excluded thymidine kinase measurement, in a prospective, multicenter, community-based cohort consisting of 328 patients who had asymptomatic, early stage CLL. With both models a significant correlation between higher score and shorter TTFT could be found. As a matter of fact, patients with total point score ≥25 according to MDACC model (HR, 3.27; 95% CI, 2.07-5.18; P<0.0001) or ≥2 according to modified German model (HR, 2.02; 95% CI, 1.29-3.16; P=0.002) were more likely to receive therapy. Both models provided similar results in terms of sensitivity (MDACC score, 61.5%; modified German score, 57.7%; P=0.79), whereas specificity was significantly higher for MDACC score (72.1% versus 63%; P=0.02). The prognostic utility of either MDACC or modified German score was assessed by time-dependent Receiver Operating Characteristic (ROC) analysis. Results of this comparative analysis showed that after the 2nd year area under curve (AUC) for TTFT was higher than 0.60 for both models and kept unmodified this trend over the time. Results of this study suggest that in CLL both MDACC and modified German score group should be considered the benchmarking of comparison for any novel prognostic proposal having as endpoint TTFT in CLL and including both traditional and newer prognostic parameters.

2013 - Total body computed tomography scan in the initial work-up of binet stage a chronic lymphocytic leukemia patients: results of the prospective, multicenter o-cll1-gisl study [Articolo su rivista]
Gentile, M.; Cutrona, G.; Fabris, S.; Pesce, Emanuela Anna; Baldini, L.; Di Raimondo, F.; Musolino, C.; Ditonno, P.; Di Renzo, N.; Molica, S.; Brugiatelli, M.; Ilariucci, F.; Zupo, S.; Matis, S.; Maura, F.; Vigna, E.; Angrilli, F.; Recchia, A. G.; Quarta, G.; Iannitto, E.; Fragasso, A.; Musto, P.; Spriano, M.; Vincelli, I.; Vallisa, D.; Cortelezzi, A.; Mauro, F. R.; Foà, R.; Federico, Massimo; Neri, A.; Ferrarini, M.; Morabito, F.
abstract

Total body computed tomography (TB-CT) scan is not mandatory in the diagnostic/staging algorithm of chronic lymphocytic leukemia (CLL). The aim of this study was to determine the value and prognostic significance of TB-CT scan in early stage CLL patients. Baseline TB-CT scan was performed in 240 Binet stage A CLL patients (179 Rai low- and 61 Rai intermediate-risk) included in a prospective multicenter observational study (clinicaltrial.gov ID:NCT00917549). The cohort included 69 clinical monoclonal B lymphocytosis (cMBLs). Patients were restaged considering only radiological data. Following TB-CT scans, 20% of cases reclassified as radiologic Binet (r-Binet) stage B. r-Binet B patients showed a higher incidence of unfavorable cytogenetic abnormalities (P = 0.027), as well as a shorter PFS (P = 0.001). At multivariate analysis, r-Binet stage [HR = 2.48; P = 0.004] and IGHV mutational status [HR = 3.01; P = 0.002] retained an independent predictive value for PFS. Among 179 Rai low-risk cases, 100 were redefined as r-Rai intermediate-risk based upon TB-CT scan data, showing a higher rate of cases with higher ZAP-70 (P = 0.033) and CD38 expression (P = 0.029) and β2-microglobulin levels (P &lt; 0.0001), as well as a shorter PFS than those with r-Rai low-risk (P = 0.008). r-Rai stage [HR = 2.78; P = 0.046] and IGHV mutational status [HR = 4.25; P = 0.009] retained a significant predictive value for PFS at multivariate analysis. Forty-two percent of cMBL patients were reclassified as r-small lymphocytic lymphomas (r-SLLs) by TB-CT scan. TB-CT scan appears to provide relevant information in early stage CLL related to the potential and the timing of patients to progress towards the more advanced disease stages.

2013 - Tumor size, node status, grading, HER2 and estrogen receptor status still retain a strong value in patients with operable breast cancer diagnosed in recent years. [Articolo su rivista]
Cortesi, Laura; Marcheselli, Luigi; Guarneri, Valentina; Cirilli, Claudia; Braghiroli, Barbara; Toss, Angela; Sant, Milena; Ficarra, Guido; Conte, Pier Franco; Federico, Massimo
abstract

Breast cancer prognosis has improved greatly in recent years. Consequently, a thorough search for sensitive prognostic factors, able to help clinicians offer appropriate therapy, has become a priority in this area. In this study, we considered all new cases of invasive breast cancer diagnosed in the Province of Modena, Italy, between 1997 and 2007, registered by the Modena Cancer Registry. The principal endpoint of this study was relapse-free survival (RFS). A set of 11 clinic and pathological parameters was investigated. After a median follow-up of 73 months, 494 relapses were recorded. Tumor size, node status, grading, HER2 and estrogen receptor status were retained as independent factors in a multivariate analysis. Using these variables, a prognostic model was devised to identify three groups at different risk. In the training sample, the 5-year RFS rates resulted 96.0%, 82.9% and 63.7% in patients at low, intermediate and high risk, respectively (p < 0.0001). In the validation sample, the 5-year RFS was 96.2%, 85.4% and 66.9%, respectively. To conclude our study demonstrates that a very simple prognostic index based on easily available clinical data may represent a useful tool for the identification of patients at different risk of relapse and may be a notable device to predict who truly benefits from medical treatment.

2012 - An increased number of individuals with clinically recognized monoclonal B-cell lymphocytosis characterizes a recent database of chronic lymphocytic leukemia Rai stage 0. [Articolo su rivista]
Molica, S.; Gentile, .; Mauro, F. R.; Brugiatelli, M.; Federico, Massimo; Sperduti, I.; Neri, A.; Ferrarini, M.; Foà, R.; Morabito, F.
abstract

No abstract available

2012 - Collective evidence supports neutrality of BRCA1 V1687I, a novel sequence variant in the conserved THV motif of the first BRCT repeat [Articolo su rivista]
Cortesi, Laura; Nicolo, Arcangela De; Medici, Veronica; Marino, Marco; Turchetti, Daniela; Pradella, Laura Maria; Rossi, Giulio; Parisini, Emilio; Federico, Massimo
abstract

Unambiguous classification of BRCA1 and BRCA2 variants of uncertain significance (VUS) is a challenging task that vexes health care providers and has profound implications for patients and their family members. Numerous VUS have been described to date, which await assessment of their functional, hence clinical, impact. As a result of a routine BRCA1/BRCA2 mutational screening, we identified a previously unreported BRCA1 sequence alteration [c.5178G>A (V1687I)] in a patient diagnosed with early onset triple negative breast cancer. The sequence alteration falls in the invariant THV motif of the BRCT domain. To investigate its significance, we applied an integrated approach that, in addition to genetic and histopathological data, included in silico analyses, comparative structural modeling and verification of BRCT-mediated interactions. In line with web-based algorithms that predicted the benign nature of BRCA1 V1687I, the three-dimensional model of the BRCA1 V1687I BRCT domain did not reveal any major structural changes relative to its wild-type counterpart, thus suggesting that BRCA1 V1687I has a negligible impact on both the local architecture and the overall stability of the protein. Consistently, the BRCA1 V1687I protein was properly expressed and localized to the nucleus, and it was still capable of binding three BRCT-interacting, DNA damage response, and repair partner proteins, namely BRIP1/FANCJ, CtIP, and Abraxas. Our collected evidence suggests that, although occurring in a highly conserved region, the BRCA1 V1687I variant is likely a benign sequence alteration.

2012 - Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly “fit” patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi [Articolo su rivista]
Merli, F.; Luminari, Stefano; Rossi, G.; Mammi, Caterina; Marcheselli, Luigi; Tucci, A.; Ilariucci, F.; Chiappella, A.; Musso, M.; Di Rocco, A.; Stelitano, C.; Alvarez, I.; Baldini, L.; Mazza, P.; Salvi, F.; Arcari, A.; Fragasso, A.; Gobbi, P. G.; Liberati, A. M.; Federico, Massimo
abstract

We conducted a prospective study to compare epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab (R-miniCEOP) to cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (R-CHOP) for the treatment of “fit” elderly patients with diffuse large B-cell lymphoma (DLBCL). Patients over the age of 65 with stage II-IV DLBCL were screened with a comprehensive geriatric assessment. Patients were randomized to receive 6 courses of R-miniCEOP (114) or R-CHOP (110). Overall, the rate of complete remission was 70% (P=0.466). After a median follow-up of 42 months, 5-year EFS rates were 46% and 48% for R-miniCEOP and R-CHOP, respectively (P = 0.538). Patients older than 72 years and with low risk disease had a better outcome when treated with R-miniCEOP (P=0.011). Overall R-CHOP and R-miniCEOP are similarly effective for elderly “fit” patients with DLBCL. The less intense R-miniCEOP may be an acceptable option for the treatment of relatively older patients with low-risk disease.

2012 - Differences in stage and treatment of breast cancer across Italy point ot inequalities in access to and availability of proper care. [Articolo su rivista]
Minicozzi, P.; Cirilli, C.; Federico, Massimo; Capocaccia, R.; Budroni, M.; Candela, P.; Falcini, F.; Fusco, M.; Giacomin, A.; La Rosa, F.; Traina, A.; Tumino, R.; Sant, M.
abstract

Population-based cancer registry studies of patterns of care can help elucidate reasons for differences in breast cancer survival across Italy documented by previous studies. The aims of the present study were to investigate across-country variation in stage at presentation and standard care for breast cancer cases diagnosed in Italy in the early 2000s. METHODS: Samples of adult (≥ 15 years) women with breast cancer diagnosed in 2003-2005 were randomly selected in 9 Italian cancer registries. Logistic regression models were used to estimate the odds of receiving breast-conserving surgery plus radiotherapy (BCS + RT) in each cancer registry, age group, and disease stage category compared with the entire sample (reference); the z test was used to evaluate differences in proportions of stage at diagnosis, employment of chemotherapy in node-positive (N+) disease, and use of endocrine treatment in estrogen-receptor positive (ER+) and negative (ER-) tumors across Italy. RESULTS: Stage at diagnosis was earlier in northern/central registries than in southern areas. Compared with the reference, the odds of receiving BCS + RT was significantly lower in Trapani, Sassari and Naples (southern Italy) after adjusting for age and stage at diagnosis. Among N+ patients, 73% received adjuvant chemotherapy (range, 51% [Biella, northern Italy] to 87% [Ragusa, southern Italy]). Eighty percent of ER+ cancers (range, 50% [Biella, northern Italy] to 97% [Ragusa, southern Italy]) and 18% of ER- cancers (range, 6% [Modena, northern Italy] to 28% [Umbria, central Italy]) were treated with hormonal therapy. CONCLUSIONS: Disparities in stage distributions and conservative surgery in breast cancer persist across Italy. On a positive note, we found lower variations in the use of systemic treatment between Italian regions

2012 - Fertility in female survivors of hodgkin's lymphoma. [Articolo su rivista]
Biasoli, I.; Falorio, S.; Luminari, Stefano; Spector, N.; Federico, Massimo
abstract

Currently, Hodgkin's lymphoma is one of the most curable types of cancer. Patients are often young and so the long-term morbidities of treatment have become of increasing concern. Among these, infertility is one of the most challenging consequences for patients in reproductive age. Premature ovarian failure in premenopausal women is a serious long-term sequel of the toxicity of chemotherapy. The main consequence of this syndrome is infertility, but women also present other symptoms related to estrogen deprivation. Different rates of impaired gonadal function are reported, depending on the patient's age, stage of disease, dose and intensity of chemotherapy and the use of radiation therapy. The most established strategy in female infertility is cryopreservation of embryos after in vitro fertilization. Additionally, the use of oral contraceptives or gonadotropin-releasing hormone analogs (GnRH-a) during treatment is under study. This review will provide a general overview of the main studies conducted to evaluate the infertility rate among female Hodgkin's lymphoma survivors and risk factors associated to treatment, different end-pointg definitions for evaluating fertility and also a brief description of the available strategies for fertility preservation.

2012 - Follicular Lymphoma - treatment and prognostic factors. [Articolo su rivista]
Luminari, Stefano; Bellei, Monica; Biasoli, I.; Federico, Massimo
abstract

Follicular lymphoma is the second most frequent non-Hodgkin lymphoma accounting for about 10-20% of all lymphomas in western countries. The median age at diagnosis is 60 years old. The clinical presentation is usually characterized by asymptomatic peripheral adenopathy in cervical, axillary, inguinal and femoral regions. Treatment options for patients with naive or recurrent follicular lymphoma are still controversial, ranging from a "watch and wait" policy to hematopoietic stem cell transplantation. More recently, the availability of rituximab has substantially changed follicular lymphoma therapeutic approaches to such an extent that R-Chemo is now the standard induction first-line treatment. This review provides a general overview of the state of the art in the management of follicular lymphoma and also, a brief description regarding the the current prognostic tools available for treatment decisions.

2012 - Incidence of stomach cancer is decreasing faster in the Centre-North of Italy [Articolo su rivista]
Castaing, M; Bella, F; Buzzoni, C; Buzzoni, C; Bisanti, L; Sechi, O; Candela, G; Crosignani, P; De Lisi, V; Donato, A; Mangoni, M; Falcini, F; Federico, Massimo; Fusco, M; Gennaro, V; Giacomin, A; La Rosa, F; Madeddu, A; Contrino, Ml; Mangone, L; Mazzoleni, G; Pannozzo, F; Zanetti, R; Cocchioni, M; Piffer, S; Pisani, P; PONZ DE LEON, Maurizio; Ricci, P; Serraino, D; Sutera, A; Tessandori, R; Traina, A; Tumino, R; Usala, M; Vercelli, M; Vitarelli, S; Zambon, P; Crocetti, E; Crocetti, E; Ferretti, S; Gola, G; Sciacca, S.
abstract

not applicable

2012 - MRI before initial surgery outside of clinical trials: the real world! [Articolo su rivista]
Cortesi, Laura; DE MATTEIS, Elisabetta; Cirilli, C.; Filieri, E.; Pecchi, Annarita; Battista, R.; Canossi, B.; Torricelli, Pietro; Federico, Massimo
abstract

Abstract not available

2012 - MRI in high risk women: benefits and problems [Articolo su rivista]
Cortesi, Laura; Pecchi, Annarita; DE MATTEIS, Elisabetta; Filieri, E.; Battista, R.; Canossi, B.; Torricelli, Pietro; Federico, Massimo
abstract

Abstract not available

2012 - Outcome evaluation in pre-trastuzumab era between different breast cancer phenotypes: a population-based study on italian women [Articolo su rivista]
Cortesi, Laura; DE MATTEIS, Elisabetta; Cirilli, C.; Marchselli, L.; Proietto, Manuela; Federico, Massimo
abstract

AIMS AND BACKGROUND: Based on estrogen receptor (ER), progesterone receptor (PgR) and Her2/neu (HER2) expression, four breast cancer subtypes have been distinguished: luminal A (ER and/or PgR/HER2-, Ki67 <14%), luminal B (ER and/or PgR/HER2-, Ki67 ≥14% or ER and/or PgR/HER2), triple-negative (ER-/PgR-/HER2-), and HER2 (ER-/PgR-/HER2). Our aim was to evaluate the prognosis of these phenotypes in the pre-trastuzumab era in a large cohort of Italian women. METHODS AND STUDY DESIGN: We studied 2347 breast cancer patients, in stage I-II, registered by the Modena Cancer Registry from 1999 to 2006 in the Modena province, Italy. Overall survival, disease-free survival and second non-mammary tumors were evaluated. RESULTS: A total of 1868 luminal A (79.6%), 195 luminal B (8.3%), 205 triple-negative (8.7%) and 79 HER2 (3.4%) patients were identified. A better prognosis was observed for luminal A than for luminal B, HER2 and triple-negative subtypes (5-year overall survival, 91% vs 89% vs 87% vs 86%, respectively, P <0.001). Disease-free survival for pT1a and pT1b tumors was worse in HER2 (82%) than in triple-negative (90%), luminal B (95%) and luminal A (97%) (P = 0.013). Finally, luminal B patients had a significantly higher rate of second non-mammary tumors than the other groups. CONCLUSIONS: In the pre-trastuzumab era, luminal A patients showed a better 5-year overall survival than luminal B, HER2 and triple-negative patients, but in terms of disease-free survival, HER2 subtype represented an unfavorable group over time, whereas the triple-negative group had an increased risk of relapse in the first 42 months and then decreased. Among each prognostic factor, ER <10%, Ki67 >14% and HER2 overexpression are considered as risk factors, but only HER2 positivity seems to preserve the role over time

2012 - Prognosis and treatment of micrometastatic breast cancer sentinel lymph node: a population-based study. [Articolo su rivista]
Cortesi, L.; Proietto, Manuela; Cirilli, C.; Tazzioli, Giovanni; Andreotti, Alessia; Federico, Massimo
abstract

BACKGROUND AND OBJECTIVES: Major concern of sentinel lymph node (SLN) biopsy (SLNB) regards the prognosis of micrometastasis (Nmic) in SLN. The purpose of this study is to determine the adequate surgical treatment and prognosis of Nmic in a population-based series of breast cancer patients.METHODS: All non-metastatic breast cancer patients registered by the Modena Cancer Registry (MCR), from January 2000 to December 2008, were evaluated for SLNB. Information on patients' characteristics, treatment and follow-up was collected.RESULTS: Among 2,078 patients treated with SLNB, 28.5% (590) showed a positive SLN, subdivided in N0i+ 6.3% (31), Nmic 28.8% (176), N1 64.1% (378), and N2 0.8% (5). Of 176 Nmic, 80% (142) received an axillary lymph node dissection (ALND). Only three patients had ≥4 SLN involved. No axillary recurrence occurred in Nmic patients. The overall and disease-free survival rates were N0 99.2% and 97.7%, N0i+ 100% and 100%, Nmic 96% and 93.2%, N+ (N1 + N2) 96.1% and 92.4%, respectively (N0 vs. Nmic P < 0.001).CONCLUSIONS: This study suggests that patients with Nmic have a similar prognosis to N+ (N1 + N2) patients, and a low risk of local recurrence, questioning the necessity of ALND for Nmic SLN. J. Surg. Oncol © 2012 Wiley Periodicals, Inc

2012 - Prophylactic Surgery to Reduce the Risk of Developing Breast Cancer: Issues and Clinical Implications [Articolo su rivista]
Razzaboni, Elisabetta; Tazzioli, Giovanni; Andreotti, Alessia; Elisabetta De, Matteis; Laura, Cortesi; Federico, Massimo
abstract

Women with BRCA1 or BRCA2 mutations are at increased risk of developing breast and ovarian cancer. Options to manage this risk are regular surveillance, chemoprevention, and risk reduction surgery which includes, risk reduction mastectomy (bilateral or contralateral) and risk reduction salpingo-oophorectomy. Risk-reduction surgery (RRS) has been proven to be efficacy in the reduction of breast and ovarian cancer up to 90% but are irreversible procedure and psychological and physical implication could be challenging for women. Authors provide an overview of the current literature regarding efficacy of RRS, acceptability and psychological implication. Decisions about RRS are complex owing to the multiple associated risks and benefits. Specific and multidisciplinary approach is needed. Many factors, mostly psychological, influenced the decision. Research on psychological impact of these procedure are controversial. The majority of these studies reported that women who choose surgery have diminished anxiety about cancer risk, and experience few psychological difficulties, but physical complication and change in body image, sexual life are often reported. In conclusion, women need to be counselled about the decision to undergo RRS Potential negative effects of should be discussed thoroughly with each woman considering this procedure. Careful psychological follow up after the surgery should be scheduled.

2012 - Regional inequalities in cancer care persist in Italy and can influence survival. [Articolo su rivista]
Sant, M.; Mincozzi, P.; Allemani, C.; Cirilli, C.; Federico, Massimo; Capocaccia, R.; Budroni, M.; Candela, P.; Crocetti, E.; Falcini, F.; Ferretti, S.; Fusco, M.; Giacomin, A.; La Rosa, F.; Mangone, L.; Natali, M.; PONZ DE LEON, Maurizio; Traina, A.; Tumino, R.; Zambon, P.
abstract

BACKGROUND: Population-based cancer registry studies of care patterns can help elucidate reasons for the marked geographic variation in cancer survival across Italy. The article provides a snapshot of the care delivered to cancer patients in Italy. METHODS: Random samples of adult patients with skin melanoma, breast, colon and non-small cell lung cancers diagnosed in 2003-2005 were selected from 14 Italian cancer registries. Logistic models estimated odds of receiving standard care (conservative surgery plus radiotherapy for early breast cancer; surgery plus chemotherapy for Dukes C colon cancer; surgery for lung cancer; sentinel node biopsy for >1mm melanoma, vs. other treatment) in each registry compared to the entire sample (reference). RESULTS: Stage at diagnosis for breast, colon and melanoma was earlier in north/central than southern registries. Odds of receiving standard care were lower than reference in Sassari (0.68, 95%CI 0.51-0.90) and Napoli (0.48, 95%CI 0.35-0.67) for breast cancer; did not differ across registries for Dukes C colon cancer; were higher in Romagna (3.77, 95%CI 1.67-8.50) and lower in Biella (0.38, 95%CI 0.18-0.82) for lung cancer; and were higher in Reggio Emilia (2.37, 95%CI 1.12-5.02) and lower in Ragusa (0.27, 95%CI 0.14-0.54) for melanoma. CONCLUSIONS: Notwithstanding limitations due to variations in the availability of clinical information and differences in stage distribution between north/central and southern registries, our study shows that important disparities in cancer care persist across Italy. Thus the public health priority of reducing cancer survival disparities will not be achieved in the immediate future.

2012 - Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. [Articolo su rivista]
Joensuu, H; Vehtari, A; Riihimäki, J; Nishida, T; Steigen, Se; Brabec, P; Plank, L; Nilsson, B; Cirilli, C; Braconi, C; Bordoni, A; Magnusson, Mk; Linke, Z; Sufliarsky, J; Federico, Massimo; Jonasson, Jg; Dei Tos, Ap; Rutkowski, P.
abstract

BACKGROUND: The risk of recurrence of gastrointestinal stromal tumour (GIST) after surgery needs to be estimated when considering adjuvant systemic therapy. We assessed prognostic factors of patients with operable GIST, to compare widely used risk-stratification schemes and to develop a new method for risk estimation.METHODS: Population-based cohorts of patients diagnosed with operable GIST, who were not given adjuvant therapy, were identified from the literature. Data from ten series and 2560 patients were pooled. Risk of tumour recurrence was stratified using the National Institute of Health (NIH) consensus criteria, the modified consensus criteria, and the Armed Forces Institute of Pathology (AFIP) criteria. Prognostic factors were examined using proportional hazards and non-linear models. The results were validated in an independent centre-based cohort consisting of 920 patients with GIST.FINDINGS: Estimated 15-year recurrence-free survival (RFS) after surgery was 59·9% (95% CI 56·2-63·6); few recurrences occurred after the first 10 years of follow-up. Large tumour size, high mitosis count, non-gastric location, presence of rupture, and male sex were independent adverse prognostic factors. In receiver operating characteristics curve analysis of 10-year RFS, the NIH consensus criteria, modified consensus criteria, and AFIP criteria resulted in an area under the curve (AUC) of 0·79 (95% CI 0·76-0·81), 0·78 (0·75-0·80), and 0·82 (0·80-0·85), respectively. The modified consensus criteria identified a single high-risk group. Since tumour size and mitosis count had a non-linear association with the risk of GIST recurrence, novel prognostic contour maps were generated using non-linear modelling of tumour size and mitosis count, and taking into account tumour site and rupture. The non-linear model accurately predicted the risk of recurrence (AUC 0·88, 0·86-0·90).INTERPRETATION: The risk-stratification schemes assessed identify patients who are likely to be cured by surgery alone. Although the modified NIH classification is the best criteria to identify a single high-risk group for consideration of adjuvant therapy, the prognostic contour maps resulting from non-linear modelling are appropriate for estimation of individualised outcomes.FUNDING: Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds.Copyright © 2012 Elsevier Ltd. All rights reserved.

2012 - Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo Italiano Studio Linfomi. [Articolo su rivista]
Merli, F; Luminari, Stefano; Ilariucci, F; Petrini, M; Visco, C; Ambrosetti, A; Stelitano, C; Caracciolo, F; Di Renzo, N; Angrilli, F; Carella, Am; Capodanno, I; Barbolini, E; Galimberti, S; Federico, Massimo
abstract

This study investigated the clinical activity and toxicity of R-HCVAD-AM [rituximab plus HyperCVAD (R-HCVAD) alternating with high-dose cytarabine and methotrexate (AM)] in patients with newly diagnosed Mantle Cell Lymphoma (MCL). Patients aged ≤70years with confirmed MCL received four alternating cycles each of R-HCVAD and AM. Patients who obtained a partial response proceeded to autologous stem cell transplant. Sixty-three patients were enrolled and 60 were fully eligible. Median age was 57years (22-66); 60%, 33% and 7% were classified at low (L)-, intermediate (I)- or high (H)-risk, respectively, according to the MCL International Prognostic Index (MIPI). Only 22 patients (37%) completed the four cycles and three patients died during therapy. Overall response and complete response rates were 83% and 72% respectively. After a median follow-up of 46months (range 1-72) the estimated 5-year overall survival (OS) and progression-free survival rates were 73% [95% confidence interval (CI) 59-83%], and 61% (95%CI 45-73%) respectively. MIPI maintained the prognostic value with an estimated 5-year OS of 89%, 80% and 24% for L, I, and H groups respectively (P<0·001). This multicentre study confirms that R-HCVAD-AM is an active regimen for the initial treatment of patients with MCL, but is associated with significant toxicity.

2012 - Role of Glutathione-S-Transferase (GST) polymorphisms in patients with advanced Hodgkin Lymphoma: results from the HD2000 GISL Trial [Articolo su rivista]
Morabito, F.; Hohaus, S.; Mammi, Caterina; Marcheselli, Luigi; Gentile, M.; Merli, F.; Montanini, Antonella; Stelitano, C.; La Sala, A.; Scalone, R.; Voso, M. T.; Luminari, Stefano; Iannitto, E.; Gobbi, P. G.; Federico, Massimo
abstract

Abstract Polymorphisms of the Glutathione-S Transferase (GST) family may influence the prognosis in lymphoma patients. We aimed to validate the impact of GSTT1 and GSTM1 deletions and of the GSTP1Ile105Val polymorphism on outcome and toxicity in 140 patients with advanced Hodgkin's lymphoma enrolled in the prospective multicenter HD2000-GISL trial, comparing ABVD, BEACOPP and CEC regimens. Carriers of the GSTP1Ile105Val polymorphism had a higher rate of grade 3-4 anemia following treatment. Overall, our study failed to validate GST genotyping as prognostic factor for progression-free survival (PFS). Only the small cohort of patients with an international prognostic score (IPS) >3 and undeleted GSTT1 and/or GSTM1, treated with ABVD had worse progression-free survival (PFS) (GSTT1+ vs GSTT1-: HR 5.02, 95% C.I., 1.16-21.8, P=0.031, GSTM1+/GSTT1+ vs GSTM1-and/or GSTT1-: HR 4.61, 95% C.I. 1.28-16.6, P=0.019, respectively). No differences were observed for patients treated with intensified regimens, as BEACOPP and CEC. In conclusion, the prognostic role of GST polymorphism, if at all, is limited to a small subgroup of patients treated with standard ABVD regimen.

2012 - Survival for all cancers is increasing, especially in men, but only thanks to PSA. [Articolo su rivista]
Coviello, E; Rashid, I; Buzzoni, C; Fusco, M; Buzzoni, C; Bisanti, L; Sechi, O; Candela, G; Crosignani, P; De Lisi, V; Donato, A; Mangoni, M; Falcini, F; Federico, Massimo; Fusco, M; Gennaro, V; Giacomin, A; La Rosa, F; Madeddu, A; Contrino, Ml; Mangone, L; Mazzoleni, G; Pannozzo, F; Zanetti, R; Cocchioni, M; Piffer, S; Pisani, P; PONZ DE LEON, Maurizio; Ricci, P; Serraino, D; Sutera, A; Tessandori, R; Traina, A; Tumino, R; Usala, M; Vercelli, M; Vitarelli, S; Zambon, P; Crocetti, E; Crocetti, E; Ferretti, S; Gola, G; Sciacca, S.
abstract

not applicable

2012 - T-cell lymphoma in South America and Europe. [Articolo su rivista]
Bellei, Monica; Chiattone, C. S.; Luminari, Stefano; Pesce, Emanuela Anna; Cabrera, M. E.; de Souza, A. C.; Gabùs, R.; Zoppegno, L.; Milone, J.; Pavlovsky, A.; Connors, J. M.; Foss, F. M.; Horwitz, S. M.; Liang, R.; Montolo, S.; Pileri, S. A.; Polliak, A.; Vose, J. M.; Zinzani, P. L.; Zucca, E.; Federico, Massimo
abstract

Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cell, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneos. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year oversall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.

2012 - Tumor burden in Hodgkin's lymphoma can be reliably estimated from a few staging parameters. [Articolo su rivista]
Gobbi, P. G.; Bergonzi, M.; Bassi, E.; Merli, F.; Coriani, C.; Stelitano, C.; Iannitto, E.; Federico, Massimo
abstract

The relative tumor burden (rTB), the tumor burden normalized to body surface area, is of prime clinical and prognostic value in Hodgkin's lymphoma. However, its measurement is rather complicated and a bedside computation cannot be proposed. We investigated the possibility of estimating, instead of measuring, rTB from elementary parameters of the initial staging. The rTB of 507 patients, treated with therapeutic protocols of the Gruppo Italiano Studio Linfomi according to their staging characteristics, was measured through their pre-therapy computed tomographies. The relationships between rTB and staging characteristics were analyzed with simple and multiple regressions both in a training sample (254 patients) for a selection of predictive parameters, and in a test sample (253 patients) for validation of the results. The number of involved sites, bulky mass and the IPI score were the variables best related to rTB. The resulting final equation {estimated rTB = -4.3 + 8.3 x IPI2 + 22.7 x [no. of involved sites (+3 if a bulky mass is present)]} provided the maximal approximation to the measured rTB (R2 =0.671). The validity of the equation was confirmed on the test sample and the predictive superiority of the estimated rTB over IPI was still evident in terms of failure-free survival in both groups of patients. The estimated rTB is accurate enough to retain most of the prognostic advantage of the measured rTB over the IPI score. It can be easily calculated, allows a valid approximation of the measured rTB, and can be proposed as a useful tool for clinical research and practice.

2012 - Tumour burden predicts treatment resistance in patients with early unfavourable or advanced stage Hodgkin lymphoma treated with ABVD and radiotherapy. [Articolo su rivista]
Gobbi, Pg; Bassi, E; Bergonzi, M; Merli, F; Coriani, C; Iannitto, E; Luminari, Stefano; Polimeno, G; Federico, Massimo
abstract

The purpose of the work was to investigate the factors predicting early resistance to treatment in Hodgkin lymphoma. Many staging parameters, including relative tumour burden (rTB), were analysed in 246 patients with Hodgkin lymphoma in relation to early failure, that is, less than complete remission (i.e. partial response, null response or progression) or occurrence of early relapse, as clinical expressions of resistance to treatment. Patients with early unfavourable disease were 129 and were treated with four to six cycles of ABVD + involved field radiotherapy; 117 patients with advanced stage disease received six cycles of ABVD + optional irradiation to no more than two sites. The rTB was volumetrically measured through the evaluation of staging computed tomography for all the lesions except bone marrow involvement, which was quantified by calculation. The relationship with early resistance was analysed with logistic regressions. The rTB demonstrated to be the best predictor of early failure in both patient subsets, being superior to the multiparameter International Prognostic Score. The rTB showed a significant exponential relationship with the relative risk of early failure, and with inclusion of the extranodal involvement into the model, a single equation became adequate to predict resistance in both early unfavourable and advanced stage patients. The conclusions are that the rTB is the best pretreatment factor related to the risk of resistance to combined ABVD + radiotherapy and that this relationship can be mathematically expressed in an easy way. A simplified assessment of rTB is highly desirable.

2012 - Watchful waiting in low-tumorburden follicular lymphoma in the Rituximab era. Results of a F2 observational [Articolo su rivista]
Solal Céligny, P.; Bellei, Monica; Marcheselli, Luigi; Pesce, Emanuela Anna; Pileri, S.; Mclaughlin, P.; Luminari, Stefano; Pro, B.; Montolo, S.; Ferreri, A. J. M.; Deconinck, E.; Milpied, N.; Gordon, L. I.; Federico, Massimo
abstract

PURPOSEPatients with follicular lymphoma (FL) registered in the F2-study and initially managed without treatment were analyzed to describe the presentation and outcome of a watch and wait (W&amp;W) strategy in the rituximab era, to identify parameters for initiating treatment, and to evaluate whether initial W&amp;W could have deleterious effects on treatment efficacy after progression or relapse. PATIENTS AND METHODSBetween 2003 and 2005, 120 patients selected from the 1,093 treatment-naive patients with FL in the F2-study cohort were initially managed expectantly (W&amp;W), and 107 patients were assessed. Most of these patients (80%) had disseminated disease with a low tumor burden according to Groupe d'Etudes des Lymphomes Folliculaires criteria.ResultsAfter a median follow-up of 64 months, treatment was initiated in 54 patients (50%), with a median delay of 55 months for the entire cohort. In a univariate analysis, involvement of more than four nodal areas (hazard ratio [HR], 2.26) and serum albumin less than 3.5 g/dL (HR, 3.51) were predictive of a shorter time to lymphoma treatment initiation. In a multivariate analysis, only involvement of more than four nodal areas remained significant (HR, 2.32). The 4-year freedom from treatment failure (FFTF) rate of W&amp;W patients (79%; 95% CI, 69% to 85%) was not inferior to that of a subgroup of 242 patients from the F2-study cohort with good prognosis characteristics who were initially treated with a rituximab-based regimen (69%; 95% CI, 61% to 76%; P = .103). CONCLUSIONIn the rituximab era, patients with FL in a selected prognostically favorable group can still be managed with W&amp;W. W&amp;W does not seem to have detrimental effects on FFTF and overall survival rates after treatment.

2012 - What has happened to VBM (vinblastine, bleomycin and methotrexate) chemotherapy for early-stage Hodgkin lymphoma? [Articolo su rivista]
Gobbi, P. G.; Federico, Massimo
abstract

The VBM (vinblastine, bleomycin, methotrexate) chemotherapy combined with involved-field radiotherapy in early-stage Hodgkin lymphoma has not become popular in spite of its excellent results. Nine small trials with this combined therapy were carried out and described in eleven reports. VBM+ radiotherapy offered complete remission rates of 94-100%, with 5-year progression-free survival of 75-95% (elderly patients included). Considerable pulmonary toxicity was recorded in the first trials, but was fully controlled in the later studies through slight modifications of the schedule. The pulmonary toxicity was found related to mediastinal radiotherapy, bleomycin dose and administration of chemotherapy after radiotherapy; it is mitigated by low doses of prednisone. The very good results, the abated side effects on the lungs, the low extrapulmonary toxicity, and the anthracycline-free formulation make this combination therapy worth considering for early-stage Hodgkin lymphoma, particularly in the case of mediastinal involvement or in elderly patients.

2011 - Anthracyclines: a cornerstone in the management of non-Hodgkin's lymphoma. [Articolo su rivista]
Luminari, Stefano; Montanini, Antonella; Federico, Massimo
abstract

Since anthracyclines were introduced in the treatment of non-Hodgkin's lymphoma in the late 1960s, they have been acknowledged as a cornerstone in the management of the disease and, in particular, of aggressive lymphomas. The high efficacy of anthracycline-containing regimens must, however, be balanced against the drug-related toxicity, which mainly affects the cardiovascular system and represents a major concern for clinicians, especially in the treatment of elderly patients. Patients' outcomes could be further improved, particularly for those at high risk of cardiotoxicity, by substituting liposomal doxorubicin for conventional doxorubicin. This approach has already been tested and shown to be effective in several cancers, especially in different subsets of patients with diffuse large B-cell lymphoma. The use of liposomal doxorubicin in combination regimens for other conditions, such as follicular lymphoma and splenic marginal zone lymphoma, is also under investigation, and early results are promising.

2011 - Case studies of elderly patients with non-Hodgkin's lymphoma. [Articolo su rivista]
Luminari, Stefano; Federico, Massimo
abstract

No abstract available

2011 - Chemorasistance as a function of the pretherapy tumor burden and the chemotherapy regimen administered: differences observed with 2 current chemotherapy regimens for advanced Hodgkin Lymphoma [Articolo su rivista]
Gobbi, P. G.; Valentino, F.; Bassi, E.; Coriani, C.; Merli, F.; Bonfante, V.; Marchianò, A.; Gallamini, A.; Bolis, S.; Stelitano, C.; Levis, A.; Federico, Massimo; Angrilli, F.; Di Giulio, G.; Corazza, G. R.
abstract

BACKGROUND: The mature results from trials comparing ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) and BEACOPP (bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, Oncovin [vincristine], procarbazine, prednisone) chemotherapies in advanced Hodgkin lymphoma will be available in some years. An early comparison of their curative potential can however be obtained from an assessment of initial tumor burden and chemoresistance.PATIENTS AND METHODS: Less than a complete remission after treatment and relapse occurring within 12 months thereafter were assumed to be clinical expressions of chemoresistance. The tumor burden was calculated from the measurements of all the lesions documented by staging computed tomography (CT) and was normalized to body surface area to give the relative tumor burden (rTB). Using logistic regression analysis, the relationship between initial rTB, chemoresistance, and chemotherapy regimen administered was retrospectively studied in 222 patients selected from those enrolled in 2 similar randomized trials.RESULTS: The median rTB volumes were 157.9 cm(3)/m(2) in the 115 patients treated with ABVD vs. 154.6 cm(3)/m(2) in the 107 patients treated with BEACOPP, and the distribution of the volumes was identical in the 2 groups. The rTB was confirmed as the best predictor of early treatment failures (22 less than complete responses plus 21 early relapses). For the same rTB, the risk of chemoresistance to BEACOPP was about half that of the chemoresistance to ABVD or, for a given risk of chemoresistance, BEACOPP cured patients with an rTB 89.1 cm(3)/m(2) greater than that cured by ABVD (ie, more than 50% of the median tumor load of patients with advanced-stage disease).CONCLUSION: This account of rTB allows an early comparative evaluation of the curative ability of different chemotherapy regimens.

2011 - CLIPI: a new prognostic index for indolent cutaneos B cell lymphoma proposed by the International Extranodal Lymphoma Study Group (IELSG 11) [Articolo su rivista]
Mian, M.; Marcheselli, Luigi; Luminari, Stefano; Federico, Massimo; Cantonetti, M.; Sarris, A. H.; Rossi, A.; Rambaldi, A.; Frontani, M.; Devizzi, L.; Gianni, A. M.; Busetto, M.; Berti, E.; Martinelli, G.; Tsang, R. W.; Ferreri, A. J. M.; Pinotti, G.; Pogliani, E.; Zucca, E.; Cortelazzo, S.
abstract

Indolent primary cutaneous B cell lymphomas (PCBCL) generally have a good prognosis, but they often relapse leading in some cases to extracutaneous disease and therefore, to poor survival. We developed a prognostic model to improve the therapeutic approach to these lymphomas. Two hundred and seventeen patients with diagnosis of indolent PCBCL stage IE or IIE were assessed retrospectively. The prognostic model was built to fit a Cox proportional hazard model using all the covariates affecting progression-free survival (PFS) at p < 0.1 in the univariate analysis, and the final model was selected based on the Bayes Information Criteria. Elevated serum lactate dehydrogenase, morphology of the lesion (nodule vs. other), and >2 lesions were independent predictors for PFS. To each prognostic factor was assigned a value of 1. Patients were then stratified to three risk groups: score 0 (28%), low risk; score 1 (55%), intermediate risk; score 2 and 3 (17%), high risk with a 5-year PFS of 91%, 64%, and 48%, respectively (p < 0.001). The CLIPI is an easily applicable prognostic index and represents a promising tool for risk-adapted treatment strategies. However, it needs to be addressed in prospective clinical studies.

2011 - Enteropathy-associated T-cell lymphoma: clinical and histological findings from the International Peripheral T-cell Lymphoma Project [Articolo su rivista]
Delabie, J.; Holte, H.; Vose, J. M.; Ullrich, F.; Jaffe, E. S.; Savage, K. J.; Connors, J. M.; Rimsza, L.; Harris, N. L.; Muller Hermelink, K.; Rudiger, T.; Coiffier, B.; Gascoyne, R. D.; Berger, F.; Tobinai, K.; Au, W. Y.; Liang, R.; Montserrat, E.; Hochberg, E. P.; Pileri, S.; Federico, Massimo; Nathwani, B.; Armitage, J. O.; Weisenburger, D. D.
abstract

Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.

2011 - High response rate and improvement of long-term survival with combined treatment modalities in patients with poor-risk primary thyroid diffuse large B-cell lymphoma: an International Extranodal Lymphoma Study Group and Intergruppo Italiano Linfomi Study [Articolo su rivista]
Mian, M.; Gaidano, G.; Conconi, A.; Tsang, R.; Gospodarowicz, M. K.; Rambaldi, A.; Rossi, A.; Oldani, E.; Federico, Massimo; Luminari, Stefano; Bellei, Monica; Pogliani, E. M.; Rossini, F.; Cabrera, M. E.; Martelli, M.; Lopez Guillermo, A.; Busetto, M.; Cavalli, F.; Zucca, E.; Cortelazzo, S.
abstract

The impact of different treatment modalities and prognostic factors on the clinical course of primary thyroid diffuse large B-cell lymphoma (PTDLBCL) is still the subject of research. This study was conducted to clarify these clinical aspects of this disorder. The clinical parameters of 48 patients with PTDLBCL at time of diagnosis were comparable to those of previous studies. Patients underwent either radiotherapy (RT)  ±  surgery (SX), chemotherapy (CHT) alone or in combination with local treatments (RT or SX), or SX followed by CHT and RT. A 90% complete remission (CR) rate was observed among patients who underwent combined treatment modalities (CTM), compared to 76% among the others. The 5-year progression-free survival differed significantly between both groups (p = 0.028). Poor performance status and advanced age correlated with decreased survival. PTDLBCL is a curable disease prevalent in elderly patients. Combined treatment modalities were able to induce an elevated rate of CR, improving long-term survival in younger patients. However, the outcome in elderly patients still remains unsatisfactory.

2011 - I tumori in Italia. Rapporto 2011: La sopravvivenza dei pazienti oncologici in Italia [Articolo su rivista]
Fusco M, AIRTUM Working G. r. o. u. p.; Buzzoni, C; Coviello, E; Rashid, I; Bianconi, F; Cuccaro, F; Castaing, M; De Angelis, R; Giacomin, A; Guzzinati, S; Mosso, Ml; Pisani, P; Quaglia, A; Randi, G; Ramazzotti, V; Russo, A; Senatore, G; Stracci, F; Traina, A; Vercelli, M; Zarcone, M; Ferretti, S; Mazzoleni, G; Bellú, F; Tschugguel, B; De Valiere, E; Facchinelli, G; Falk, M; Dal Cappello, T; Vercellino, Pc; Andreone, S; Busato, A; Marzola, L; Migliari, E; Carletti, N; Nenci, I; Crocetti, E; Caldarella, A; Corbinelli, A; Giusti, F; Intrieri, T; Manneschi, G; Nemcova, L; Romeo, G; Sacchettini, C; Zappa, M; Paci, E; Serraino, D; Angelin, T; Bidoli, E; Dal Maso, L; de Dottori, M; De Paoli, A; De Santis, E; Forgiarini, O; Lise, M; Zucchetto, A; Zanier, L; Orengo, Ma; Casella, C; Marani, E; Puppo, A; Celesia, Mv; Cogno, R; Manenti, S; Garrone, E; Pannozzo, F; Busco, S; Cercato, Mc; Battisti, W; Sperduti, I; Macci, L; Bugliarello, E; Bernazza, E; Tamburo, L; Rossi, M; Curatella, S; De Francesco, C; Tamburrino, S; Bisanti, L; Autelitano, M; Ghilardi, S; Leone, R; Filipazzi, L; Bonini, A; Giubelli, C; Federico, Massimo; Artioli, Me; Valla, K; Braghiroli, B; Cirilli, C; Luminari, Stefano; Pirani, M; Ferrari, L; Bellatalla, C; Fusco, M; Panico, M; Perrotta, C; Vassante, B; Vitale, Mf; Michiara, M; Bozzani, F; Sgargi, P; Tumino, R; La Rosa, Mg; Cascone, G; Frasca, G; Giurdanella, Mc; Martorana, C; Morana, G; Nicita, C; Rollo, Pc; Ruggeri, Mg; Sigona, A; Spata, E; Vacirca, S; Mangone, L; Di Felice, E; Pezzarossi, A; Caroli, S; Pellegri, C; Vicentini, M; Storchi, C; Cavuto, S; Costa, J; Falcini, F; Colamartini, A; Bucchi, L; Balducci, C; Ravegnani, M; Vitali, B; Cordaro, C; Caprara, L; Giuliani, O; Giorgetti, S; Salvatore, S; Palumbo, M; Vattiato, R; Ravaioli, A; Foca, F; Rinaldi, E; Mancini, S; Tonelli, C; Amadori, M; Cremone, L; Iannelli, A; Zevola, A; Budroni, M; Cesaraccio, R; Pirino, D; Carboni, D; Fiori, G; Soddu, M; Mameli, G; Mura, F; Contrino, Ml; Madeddu, A; Tisano, F; Sciacca, S; Muni, A; Mizzi, M; Russo, M; Sacco, G; Aletta, P; Colanino Ziino, A; Tessandori, R; Fanetti, Ac; Maspero, S; Annulli, Ml; Moroni, E; Sanoja Gonzalez, Me; Zanetti, R; Rosso, S; Patriarca, S; Prandi, R; Sobrato, I; Gilardi, F; Busso, P; Piffer, S; Gentilini, Ma; Battisti, L; Rizzello, R; Cappelletti, M; Moser, M; La Rosa, F; D'Alò, D; Scheibel, M; Costarelli, D; Spano, F; Rossini, S; Santucci, C; Petrinelli, Am; Solimene, C; Brunori, V; Crosignani, P; Tagliabue, G; Contiero, P; Preto, L; Tittarelli, A; Maghini, A; Codazzi, T; Frassoldi, E; Gada, D; Costa, E; di Grazia, L; Zambon, P; Baracco, M; Bovo, E; Dal Cin, A; Fiore, Ar; Greco, A; Monetti, D; Rosano, A; Stocco, C; Tognazzo, S; Donato, F; Limina, Rm; Adorni, A; Andreis, P; Zani, G; Piovani, F; Salvi, O; Puleio, M; Vitarelli, S; Antonini, S; Candela, G; Pappalardo, G; Scuderi, T; Lottero, B; Ribaudo, M; Ricci, P; Guarda, L; Gatti, L; Bozzeda, A; Dall'Acqua, M; Pironi, V; Sutera Sardo, A; Mazzei, A; Sirianni, N; Lavecchia, Am; Mancuso, P; Usala, M; Pala, F; Sini, Gm; Pintori, N; Canu, L; Demurtas, G; Doa, N; PONZ DE LEON, Maurizio; Domati, Federica; Rossi, Giuseppina; Goldoni, Ca; Rossi, F; De Gaetani, C; Benatti, Piero; Roncucci, Luca; Di Gregorio, C; Pedroni, Monica; Pezzi, A; Maffei, Stefania; Mariani, Francesco; Borsi, E; Carruba, G; Cusimano, R; Amodio, R; Dolcemascolo, C; Staiti, R; Pastore, G; Magnani, C; Terracini, B; Cena, T; Alessi, D; Baussano, I; Merletti, F; Maule, M; Macerata, V; Cocchioni, M; Pascucci, C; Gennaro, V; Lazzarotto, A; Benfatto, L; Mazzucco, G; Montanaro, F.
abstract

INTRODUCTION: population-based survival analyses are fundamental to assess the impact of public health interventions and new therapies in cancer control. This monograph updates previous reports on cancer patient survival in Italy up to the year 2007. MATERIAL AND METHODS: we extracted from the Network of Italian Cancer Registries (AIRTUM) database over 1,490,000 records of tumours diagnosed during 1990-2007 and followed up to the end of 2008, including all multiple tumours. We used the Ederer II method to estimate relative survival (RS) for 29 different types of neoplasm. Five-year relative survival rates were analysed by gender and macroarea. Trends in 5-, 10- and 15-year RS were studied by gender over six 3-year diagnostic periods, from 1990 to 2007. Conditional 5-year RS was also computed by gender and macroarea. Hybrid approaches were applied to exploit the recent survival experiences of cases diagnosed up to 2007. Adjustment for age was performed using EUROCARE weights. Additional sections describe cancer patient survival in childhood and in elderly patients and provide a comparison of cancer patient survival rates in Italy with those of other countries. RESULTS: Standardized 5-year RS for all tumours but skin in 52% for men and 61% for women. Patient survival has improved for almost all types of cancer: from 1990 to 2007 5-year RS has increased by 15% for all cancers but skin; the exceptions are some cancers with poor prognosis, where patient survival has remained basically unchanged. In males, RS was usually lower than in females, but trend analysis shows that the gap is narrowing. We also report persisting lower RS in southern Italy: 5-year RS in the South is usually from 4% to 10% lower than in the North and Centre. CONCLUSION: this study provides valuable information for all stakeholders in cancer control, both in Italy and elsewhere. Increasing survival reflects improvements in various areas of cancer control. On the other hand, delayed diagnosis and suboptimal management are consistent with the reported differences in survival within the country.

2011 - Italian cancer figures: North and South are getting closer [Articolo su rivista]
Buzzoni, C; Bisanti, L; Budroni, M; Candela, G; Crosignani, P; De Lisi, V; Donato, A; Donato, F; Falcini, F; Federico, Massimo; Fusco, M; Gennaro, V; Giacomin, A; La Rosa, F; Madeddu, A; Contrino, Ml; Mangone, L; Mazzoleni, G; Pannozzo, F; Pascucci, C; Cocchioni, M; Piffer, S; Pisani, P; PONZ DE LEON, Maurizio; Ricci, P; Serraino, D; Sutera, A; Tessandori, R; Traina, A; Tumino, R; Usala, M; Vercelli, M; Vitarelli, S; Zambon, P; Zanetti, R; Crocetti, E; Ferretti, S.
abstract

Not appplicable

2011 - Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin's lymphoma: a study from the Intergruppo Italiano Linfom [Articolo su rivista]
Chisesi, T.; Bellei, Monica; Luminari, Stefano; Montanini, Antonella; Marcheselli, Luigi; Levis, A.; Gobbi, P. G.; Vitolo, U.; Stelitano, C.; Pavone, V.; Merli, F.; Liberati, A. M.; Baldini, L.; Bordonaro, R.; Pesce, Emanuela Anna; Federico, Massimo
abstract

PURPOSEThe Intergruppo Italiano Linfomi HD9601 trial compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus doxorubicin, vinblastine, mechloretamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V [StV]) versus the combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) with epidoxorubicin, bleomycin, vinblastine (EBV), lomustine, doxorubicin, and vindesine (CAD) (MOPP/EBV/CAD [MEC]) for the initial treatment of advanced-stage Hodgkin's lymphoma to select which regimen would best support a reduced radiotherapy program (limited to two or fewer sites of either previous bulky or partially remitting disease). Superiority of ABVD and MEC to StV was demonstrated. We report analysis of long-term outcome and toxicity. PATIENTS AND METHODSPatients with stage IIB, III, or IV were randomly assigned among six cycles of ABVD, three cycles of StV, and six cycles of MEC; radiotherapy was administered in 76, 71, and 50 patients in the three arms, respectively.ResultsCurrently, the median follow-up is 86 months; in the prolonged observation period, eight additional failures, including two relapses, both in the StV arm, and six additional deaths in complete response were recorded. The 10-year overall survival rates were 87%, 80%, and 78% for ABVD, MEC, and StV, respectively (P = .4). The 10-year failure-free survival was 75%, 74%, and 49% in the ABVD, MEC, and StV arms, respectively (P < .001). The 10-year disease-free survival of patients treated or not with radiotherapy (RT) showed no difference for ABVD or MEC (85% v 80% and 93% v 68%), and a statistically significant difference for StV (76% v 33%; P = .004). No significant long-term toxicity was recorded. CONCLUSIONThe long-term analysis confirmed ABVD and MEC superiority to StV. The use of RT after StV was established as mandatory. ABVD is still to be considered as the standard treatment with a good balance between efficacy and toxicity.

2011 - Multicenter surveillance of women at high genetic breast cancer risk using mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (the high breast cancer risk italian 1 study): final results. [Articolo su rivista]
Sardanelli, F.; Podo, F.; Santoro, F.; Manoukian, S.; Bergonzi, S.; Trecate, G.; Vergnaghi, D.; Federico, Massimo; Cortesi, L.; Corcione, S.; Morassut, S.; Di Maggio, C.; Cilotti, A.; Martincich, L.; Calabrese, M.; Zuiani, C.; Preda, L.; Bonanni, B.; Carbonaro, L. A.; Contegiacomo, A.; Panizza, P.; Di Cesare, E.; Savarese, A.; Crecco, M.; Turchetti, D.; Tonutti, M.; Belli, P.; Maschio, A. D.
abstract

Objectives: To prospectively compare clinical breast examination, mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging (MRI) in a multicenter surveillance of high-risk women.Materials and Methods: We enrolled asymptomatic women aged ≥25: BRCA mutation carriers; first-degree relatives of BRCA mutation carriers, and women with strong family history of breast/ovarian cancer, including those with previous personal breast cancer.Results: A total of 18 centers enrolled 501 women and performed 1592 rounds (3.2 rounds/woman). Forty-nine screen-detected and 3 interval cancers were diagnosed: 44 invasive, 8 ductal carcinoma in situ; only 4 pT2 stage; 32 G3 grade. Of 39 patients explored for nodal status, 28 (72%) were negative. Incidence per year-woman resulted 3.3% overall, 2.1% <50, and 5.4% ≥50 years (P < 0.001), 4.3% in women with previous personal breast cancer and 2.5% in those without (P = 0.045). MRI was more sensitive (91%) than clinical breast examination (18%), mammography (50%), ultrasonography (52%), or mammography plus ultrasonography (63%) (P < 0.001). Specificity ranged 96% to 99%, positive predictive value 53% to 71%, positive likelihood ratio 24 to 52 (P not significant). MRI showed significantly better negative predictive value (99.6) and negative likelihood ratio (0.09) than those of the other modalities. At receiver operating characteristic analysis, the area under the curve of MRI (0.97) was significantly higher than that of mammography (0.83) or ultrasonography (0.82) and not significantly increased when MRI was combined with mammography and/or ultrasonography. Of 52 cancers, 16 (31%) were diagnosed only by MRI, 8 of 21 (38%) in women <50, and 8 of 31 (26%) in women ≥50 years of age.Conclusion: MRI largely outperformed mammography, ultrasonography, and their combination for screening high-risk women below and over 50.

2011 - Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project [Articolo su rivista]
Weisenburger, D. D.; Savage, K. J.; Harris, N. L.; Gascoyne, R. D.; Jaffe, E. S.; Maclennan, K. A.; Rudiger, T.; Pileri, S.; Nakamura, S.; Nathwani, B.; Campo, E.; Berger, F.; Coiffier, B.; Kim, W. S.; Holte, H.; Federico, Massimo; Au, W. Y.; Tobinai, K.; Armitage, J. O.; Vose, J. M.
abstract

The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (≥ 10 cm), thrombocytopenia (< 150 × 109/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies.

2011 - [Population ageing effect on number of cancer cases: Italian cancer registries data]. [Articolo su rivista]
Buzzoni, C; Bisanti, L; Budroni, M; Candela, G; Crosignani, P; De Lisi, V; Donato, A; Donato, F; Falcini, F; Federico, Massimo; Fusco, M; Gennaro, V; Giacomin, A; La Rosa, F; Madeddu, A; Contrino, Ml; Mangone, L; Mazzoleni, G; Pannozzo, F; Pascucci, C; Cocchioni, M; Piffer, S; Pisani, P; PONZ DE LEON, Maurizio; Ricci, P; Serraino, D; Sutera, A; Tessandori, R; Traina, A; Tumino, R; Usala, M; Vercelli, M; Vitarelli, S; Zambon, P; Zanetti, R; Crocetti, E; Paci, E; Ferretti, S.
abstract

OBJECTIVE: To describe causes of cancer incidence increase. We identified and quantified a population ageing factor, a factor due to incidence trend of cancer sites with early-diagnosis interventions and a remainder factor (concerning all other cancer sites). METHODS: We calculated incidence rates for two calendar period (1993-95 and 2003-05).We used data from Cancer Registries with at least one incidence year available for each period (jointly for males and female). We compared crude and age-adjusted rates by the direct method for prostate cancer, breast cancer, colorectal cancer, melanoma of the skin cancer, thyroid cancer, group of other cancer sites and for all cancer sites (but non-melanoma skin cancer). RESULTS: Since 1993-95 to 2003-05 all cancer crude incidence rates have been increasing 17.9% (from 555.4 cases for 100,000 inhabitants/years to 654.8). If population age structure had remained the same, rates would have increased only 6.6% (from 555.4 to 592.0): almost 2/3 of observed increasing are due to population ageing. The remainder part of the increasing is due to incidence trend of cancer sites with early-diagnosis interventions (that anticipates the diagnosis). CONCLUSIONS: This study helps to quantify the incidence increase due to population ageing and the raise due to trend of cancer sites with early-diagnosis interventions.

2011 - Protein expression patterns associated with advanced stage ovarian cancer [Articolo su rivista]
Cortesi, L.; Rossi, Elena; DELLA CASA, Lara; Barchetti, Andrea; Nicoli, A.; Piana, S.; Abrate, M.; LA SALA, Giovanni Battista; Federico, Massimo; Iannone, Anna
abstract

This is a comparative proteomic study on biopsies from patients with ovarian cancer to identify potential diagnostic/prognostic biomarkers in both healthy and tumor tissue, interstitial fluid (normal interstitial fluid and tumoral interstitial fluid and peritoneal effusion. Protein expression/identification was evaluated by 2-DE and MS analysis: six proteins showed differential expression in tumoral interstitial fluid and tumor tissue compared to normal interstitial fluid and healthy tissue: five were found to be downregulated and identified as galectin 3, glutathione S-transferase A-2, retinol binding protein 1, phosphatidylethanolamine-binding protein and annexin 5, while the calgranulin, was significantly upregulated in all pathological samples, including the ascitic fluid. Validation of S100A8 overexpression in carcinoma tissue was obtained by immunohistochemistry. To our knowledge, this is the first study to report an over-expression of calgranulin by 2-DE associated with MS/MS analysis on surgical biopsy. The reduced expression of galectin 3 and retinol binding protein 1 in cystic fluid and serum of patients with early stage disease is confirmed in this study. The results highlight alterations in proteins that control cell-cycle progression and apoptosis, as well as factors that modulate the activity of signal transduction pathways. Moreover, this study suggests that calgranulin expression may be used as a diagnostic and/or prognostic biomarker.

2011 - Relevance of stereotyped B-cell receptors in the context of the molecular, cytogenetic and clinical features of chronic lymphocytic leukemia. [Articolo su rivista]
Maura, F.; Cutrona, G.; Fabris, S.; Colombo, M.; Tuana, G.; Agnelli, L.; Matis, S.; Lionetti, M.; Gentile, M.; Recchia, A. G.; Di Raimondo, F.; Musolino, C.; Ilariucci, F.; Di Renzo, N.; Pesce, Emanuela Anna; Molica, S.; Federico, Massimo; Cortelezzi, A.; Morabito, F.; Ferrarini, M.; Neri, A.
abstract

Highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3), are expressed in a recurrent fraction of patients affected by chronic lymphocytic leukemia (CLL). We investigated the IGHV status of 1131 productive IG rearrangements from a panel of 1126 CLL patients from a multicenter Italian study group, and correlated the presence and class of HCDR3 stereotyped subsets with the major cytogenetic alterations evaluated by FISH, molecular prognostic factors, and the time to first treatment (TTFT) of patients with early stage disease (Binet A). Stereotyped HCDR3 sequences were found in 357 cases (31.7%), 231 of which (64.7%) were unmutated. In addition to the previously described subsets, 31 new putative stereotypes subsets were identified. Significant associations between different stereotyped HCDR3 sequences and molecular prognostic factors, such as CD38 and ZAP-70 expression, IGHV mutational status and genomic abnormalities were found. In particular, deletion of 17p13 was significantly represented in stereotype subset #1. Notably, subset #1 was significantly correlated with a substantially reduced TTFT compared to other CLL groups showing unmutated IGHV, ZAP-70 or CD38 positivity and unfavorable cytogenetic lesions including del(17)(p13). Moreover, subset #2 was strongly associated with deletion of 13q14, subsets #8 and #10 with trisomy 12, whereas subset #4 was characterized by the prevalent absence of the common cytogenetic abnormalities. Our data from a large and representative panel of CLL patients indicate that particular stereotyped HCDR3 sequences are associated with specific cytogenetic lesions and a distinct clinical outcome.

2011 - Risk for second malignancies in non-Hodgkin's lymphoma survivors: a meta-analysis [Articolo su rivista]
Pirani, Monica; Marcheselli, Raffaella; Marcheselli, Luigi; Bari, Alessia; Federico, Massimo; Sacchi, Stefano
abstract

BACKGROUND: Late side-effects are becoming an important issue in non-Hodgkin's lymphoma (NHL) survivors. We intended to estimate pooled relative risk (RR) of secondary malignant neoplasms (SMNs), to evaluate site-associated RR and the impact of different treatments. Design: We carried out an electronic search of Medline and EMBASE seeking articles investigating the risk of SMNs and reporting RR measures. The studies were evaluated for heterogeneity before meta-analysis and for publication bias. Pooled RRs were estimated using fixed- and random-effects models.RESULTS: A total of 23 studies met the inclusion criteria. Pooled RRs of SMNs overall and for solid tumors were 1.88 and 1.32, respectively. We found an excess of risk for several specific cancer sites. Radiotherapy alone did not increase the risk for SMNs, while chemotherapy and combined treatments augmented the RR. Regression analyses revealed a positive significant association for all SMNs with total body irradiation, and for solid SMNs with younger age. No publication bias was observed.CONCLUSIONS: Our results indicate that NHL patients experience a higher risk for SMNs than the general population and that various treatments have different impact on RR. More information will be necessary to evaluate possible interactions with genetic susceptibility and environmental exposure.

2011 - Single-dose Palonosetron for prevention of chemotherapy-induced nausea and vomiting in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy containig steroids: results of a phase II study from the Gruppo Italiano per lo Studio dei Linfomi (GISL). [Articolo su rivista]
Di Renzo, N.; Montanini, Antonella; Mannina, D.; Dondi, Alessandra; Muci, S.; Mancuso, S.; De Polis, M. R.; Plati, C.; Stelitano, C.; Patti, C.; Olivieri, A.; Liardo, E.; Buda, G.; Cantaffa, R.; Federico, Massimo
abstract

PURPOSE: The control of nausea and vomiting induced by chemotherapy is paramount for overall treatment success in cancer patients. Antiemetic therapy during chemotherapy in lymphoma patients generally consists of anti-serotoninergic drugs and dexamethasone. The aim of this trial was to evaluate the efficacy of a single dose of palonosetron, a second-generation serotonin type 3 (5-HT(3)) receptor antagonist, in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy (MEC) containing steroids.METHODS: Patients received a single intravenous bolus of palonosetron (0.25 mg) before administration of chemotherapy. Complete response (CR) defined as no vomiting and no rescue therapy during overall phase (0-120 h) was the primary endpoint. Complete control (CC) defined as CR and only mild nausea was a secondary endpoint.RESULTS: Eighty-six evaluable patients entered in the study. A CR was observed in 74 patients (86.0%) during the overall phase; the CR during the acute (0-24 h) and delayed (24-120 h) phases was 90.7% and 88.4%, respectively. CC was 89.5% during the acute and 84.9% during the delayed phase; the overall CC was 82.6%.CONCLUSIONS: This was the first trial, which demonstrated the efficacy of a single dose of palonosetron in control CINV in patients with aggressive non-Hodgkin's lymphoma receiving MEC regimen containing steroids.

2011 - Use of 2-(18F)fluoro-2-deoxy-D-glucose positron emission tomography in patients with Hodgkin lymphoma in daily practice: a population-based study from Northern Italy [Articolo su rivista]
Luminari, Stefano; Cesaretti, Marina; Tomasello, Chiara; Guida, Annalisa; Bagni, Bruno; Merli, F.; Postiglione, Raffaella; Mangone, L.; Versari, A.; Re, F.; De Lisi, V.; Ruffini, L.; Ferretti, S.; Cuneo, A.; Federico, Massimo
abstract

We conducted a population-based study to assess how positron emission tomography (PET) is currently used in patients with Hodgkin lymphoma (HL). Four cancer registries from northern Italy were used to identify patients with HL diagnosed from 2006 to 2008. Computed tomography (CT) and PET scans were collected before treatment start (B), at the end (F), and during treatment (I). One hundred and thirty-six patients were identified as the study population. B-PET, I-PET, and F-PET were performed in 82%, 65%, and 85% of patients, respectively. Overall, I-PET was coded as positive in 16% of cases. F-PET was positive in 13% of cases. The I-PET result was a prognostic factor for failure-free survival (FFS) (hazard ratio [HR] 5.33); the F-PET result was the only prognostic factor for overall survival (OS) (HR 14.2). This population-based study confirms the prognostic role of I-PET for FFS also in daily practice; the results of F-PET can be used to predict OS.

2010 - Analysis of Stereotyped IGHV Distribution In a Series of 1133 Chronic Lymphocytic Leukemia Patients: The Experience of a Multicenter Italian Study Group [Abstract in Rivista]
F., Maura; G., Cutrona; M., Gentile; S., Matis; M., Colombo; L., Agnelli; G., Tuana; R., Massara; F., Loiacono; S., Pedemonte; D., Reverberi; E. A., Pesce; M., Lionetti; S., Fabris; A. G., Recchia; F., Di Raimondo; C., Musolino; M., Gobbi; N., Di Renzo; F. R., Mauro; R., Cantaffa; M., Brugiatelli; F., Merli; S., Zupo; Caterina, Mammi; L., Baldini; F., Angrilli; G., Quintana; U., Consoli; G., Bertoldero; E., Iannitto; P., Di Tonno; A., Fragasso; Stefano, Molica; P., Musto; M. C., Cox; G., Festini; V., Callea; Sacchi, Stefano; G., Lambertenghi Deliliers; R., Foà; Federico, Massimo; A., Cortelezzi; F., Morabito; M., Ferrarini; A., Neri
abstract

Chronic lymphocytic leukemia (CLL) is characterized by an extremely variable clinical course. Mutational status of the immunoglobulin heavy-chain variable (IGHV) region defines two disease subsets with different prognosis. A fraction of CLL cases carries highly homologous B-cell receptors (BCR), i.e. characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3). We performed sequence analysis to characterize IGHV regions in a panel of 1133 CLL patients investigated by a multicenter Italian study group. A total of 1148 rearrangements were identified; the analysis of stereotyped subsets was performed based on previously reported criteria (Messmer et al, J Exp Med 2004; Stamatopuolos et al, Blood 2007). Specifically, we compared all our sequences with those found in three different publicly available data sets (Stamatopoulos et al, Blood 2007; Murray et al, Blood 2008 and Rossi et al, 2009 Clin Cancer Res). In addition, a pairwise alignment within all sequences was performed in order to discover novel potential subsets (HCDR3 identity > 60%). Based on the 2% cut-off used to discriminate between Mutated (M) and Unmutated (UM) cases, 777 sequences (67.59%) were classified as M, while 371 sequences (32.3%) as UM. The most represented IGHV genes within mutated cases were IGHV4-34 (104/118) and IGHV3-23 (85/96), whereas IGHV1-69 (97/112) was the most frequently used in the UM group. Interestingly, the IGHV3-21 gene, reported to be frequently expressed in CLL patients from Northern Europe, was present in only a small fraction of cases (24; 2.07%), confirming a previous finding reported by Ghia et al (Blood 2005) in a smaller panel. In our series, stereotyped HCDR3 sequences were found in 407/1148 (35.45%) patients, 177 of whom were M and 230 were UM cases. Overall, we observed that stereotyped sequences were significantly associated with UM IGHV status (Fisher’s exact test, P<0.0001). Among the 407 stereotyped HCDR3 sequences, 345 belong to the clusters reported by Murray et al and 14 to those described by Rossi et al., 2009 Clin Cancer Res. The most frequent stereotyped subsets identified in our panel were #1 (35 cases), #7 (28 cases), #4 (24 cases), #3 and #9 (16 cases), #28 (13 cases), and #2 (12 cases), together with subsets #5, #8, #10, #12, #13, #16 and #22 (all ranging from 6 to 9 cases). Finally, we were able to identify by auto-matching analysis 48 sequences potentially specific for 23 novel putative stereotype subsets. In our series we identified 407/1148 (35.45%) stereotyped HCDR3 sequences. The percentage was higher than that reported by Stamatopoulos et al and Murray et al. This discrepancy may partially be due to the different approach used in our analysis, namely the matching to a general data set including all published stereotyped subsets instead of the auto-matching performed by those Authors. We demonstrated a significant association between IGHV status and stereotyped sequences and confirmed the finding that #1 is the most frequent subset identified so far. Finally, we were able to identify a series of 23 novel putative subsets that will require further confirmation.

2010 - Cancer incidence in people with residential exposure to a municipal waste incinerator: an ecological study in Modena (Italy), 1991-2005 [Articolo su rivista]
Federico, Massimo; Pirani, Monica; Rashid, I.; Caranci, N.; Cirilli, C.
abstract

We conducted a retrospective ecological study to assess cancer incidence during the period 1991-2005 in proximity of a municipal waste incinerator (MWI) in Modena (Italy). We identified three bands of increasing distance from the MWI, up to a radius of 5 km and used the residence as surrogate marker of the exposure. Residential history for Modena's population was reconstructed and residents were associated to the most appropriate census unit. Age-standardized incidence ratios (ASR) and standardized incidence ratios (SIR) were estimated for all cancers and selected sites. Variations in cancer incidence were investigated using space and space-time scan statistic. Deprivation index was taken into account as potential confounding factor. During the 15-year study period, 16,443 new cases of cancer were diagnosed among residents in Modena. The space-time clustering test identified three significant clusters but their shapes were not associable to the MWI exposition. The purely spatial analysis not showed statistically significant clusters. The SIR computed for all cancers and selected sites did not show any excess of risk in the area closest to the plant. Higher SIR for leukaemia was found in the second band from MWI (2-3.5 km) for females (SIR, age and DI adjusted: 1.35, 95%CI: 1.01-1.79) and for both sexes (SIR, age and DI adjusted: 1.28, 95%CI: 1.03-1.57), but not a spatial trend was observed, thus excluding a possible link with MWI. In conclusion, bearing in mind the intrinsic limits of the study, the results suggest that there is no detectable increase of cancer risk for people living in proximity to the Modena MWI.

2010 - Cancer profile in Eastern Libya: incidence and mortality in the year 2004. [Articolo su rivista]
El Mistiri, M.; Pirani, Monica; El Sahli, N.; El Mangoush, M.; Attia, A.; Shembesh, R.; Habel, S.; El Homry, F.; Hamad, S.; Federico, Massimo
abstract

No abstract available

2010 - Clinical categories identified by a new prognostic index reflect biological characteristics of patients in early chronic lymphocytic leukemia: The Gruppo Italiano Studio Linfomi (GISL) experience. [Articolo su rivista]
Molica, S; Di Raimondo, F; Cutrona, G; Fabris, S; Mauro, F; Brugiatelli, M; Baldini, L; Musto, P; Sacchi, Stefano; Cortelezzi, A; Foà, R; Neri, A; Federico, Massimo; Ferrarini, M; Morabito, F.
abstract

No abstract available

2010 - Concordance between four European centre of PET reporting criteria designed for use in multicentre trials in Hodgkin lymphoma. [Articolo su rivista]
Barrington, S. F.; Qian, W.; Somer, E. J.; Franceschetto, Antonella; Bagni, Bruno; Brun, E.; Almquist, H.; Loft, A.; Hojgaard, L.; Federico, Massimo; Gallamini, A.; Smith, P.; Johnson, P.; O'Doherty, M. J.
abstract

PURPOSE: To determine if PET reporting criteria for the Response Adapted Treatment in Hodgkin Lymphoma (RATHL) trial could enable satisfactory agreement to be reached between 'core' laboratories operating in different countries.METHODS: Four centres reported scans from 50 patients with stage II-IV HL, acquired before and after two cycles of Adriamycin/bleomycin/vinblastine/dacarbazine. A five-point scale was used to score response scans using 'normal' mediastinum and liver as reference levels. Centres read scans independently of each other. The level of agreement between centres was determined assuming (1) that uptake in sites involved at diagnosis that was higher than liver uptake represented disease (conservative reading), and (2) that uptake in sites involved at diagnosis that was higher than mediastinal uptake represented disease (sensitive reading).RESULTS: There was agreement that the response scan was 'positive' or 'negative' for lymphoma in 44 patients with a conservative reading and in 41 patients with a sensitive reading. Kappa was 0.85 (95% CI 0.74-0.96) for conservative reading and 0.79 (95% CI 0.67-0.90) for sensitive reading. Agreement was reached in 46 and 44 patients after discussion for the conservative and sensitive readings, respectively.CONCLUSION: The criteria developed for reporting in the RATHL trial are sufficiently robust to be used in a multicentre setting.

2010 - Decreasing incidence of gastric MALT lymphomas in the era of anti-Helicobacter pilori interventions: results from a population-based study on extranodal marginal zone lymphomas [Articolo su rivista]
Luminari, Stefano; Cesaretti, Marina; Marcheselli, Luigi; Rashid, I.; Madrigali, Stefano; Maiorana, Antonino; Federico, Massimo
abstract

BACKGROUND: Few studies have been carried out to date that have addressed the epidemiology of extranodal marginal zone lymphomas (EN-MZLs). PATIENTS AND METHODS: We carried out a population-based study to investigate incidence rates (IRs) and time trends of EN-MZL diagnosed in the province of Modena (Italy) from 1997 to 2007. RESULTS: One hundred and sixty-five cases were identified from the Modena Cancer Registry that corresponded to an age-standardized IR of 2.3 cases per 100 000. A bimodal distribution of age was shown with the group of young patients mostly represented by males with cutaneous lymphoma. No time trends were observed for the IR; the incidence of gastric mucosa-associated lymphoid tissue (g-MALT) lymphomas (N = 51) markedly declined during the study period, dropping from 1.4 in 1997 to 0.2 in 2002 and then remaining stable until 2007; the calculated annual percent change for g-MALT was -17.0% (95% confidence interval -26.6% to -6.2%). We also observed a significant decrease in the rate of g-MALT associated with Helicobacter pylori (HP) infection from 61% to 17% of patients diagnosed before and after 2002 (P = 0.007; P for trend = 0.016). CONCLUSION: This population-based study provides new insights into recent changes in the epidemiology of EN-MZL, mainly represented by the sharp reduced incidence of HP-positive g-MALT lymphomas.

2010 - Differentiation on Biological Basis of Monoclonal B-Cell Lymphocytosis (MBL) From Chronic Lymphocytic Leukemia (CLL): Results of a Prospective GISL (Gruppo Italiano Studio Linfomi) Trial [Abstract in Rivista]
Molica, ; S., Fabris; G., Cutrona; S., Matis; E. A., Pesce; F., Maura; G. Ciceri F., Di Raimondo; C., Musolino; M., Gobbi; N., Di Renzo; F., Romana Mauro; R., Cantaffa; M., Brugiatelli; F., Merli; S., Zupo; C., Mammi; L., Baldini; F., Angrilli; G., Quintana; U., Consoli; E., Iannitto; P., Di Tonno; A., Fragasso; Pellegrino, Musto; M. C., Cox; G., Festini; V., Callea; Sacchi, Stefano; A., Cortelezzi; G., Lambertenghi Deliliers; R., Foà; Federico, Massimo; A., Neri; M., Ferrarini; F., Morabito
abstract

The arbitrary cut-off of 5000/µL chronic lymphocytic leukemia (CLL)-phenotype cells in peripheral blood is generally used to separate monoclonal B-cell lymphocytosis (MBL) from CLL. However, a major concern is the biological differentiation, if any, between MBL and CLL. We tried to address the issue therefore analyzing 261 Rai stage 0 patients enrolled in a Gruppo Italiano Studio Linfomi (GISL) prospective multicentre trial designed to validate biological parameters in early CLL as well as to assess the impact on clinical outcome of an early versus delayed policy of treatment with subcutaneous alemtuzumab in the high biological risk. In this cohort, biological characteristics of 105 (40.2%) patients who would be reclassified as MBL using the 2008 CLL diagnostic criteria were compared with those of the remaining 156 patients who had more than 5000/µL CLL-phenotype cells in peripheral blood and fulfilled diagnostic criteria of CLL. Male to female ratio was similar for MBL and CLL (54/53 vs. 92/66, P=0.21) as was median age (58.18 vs 58.18, P=0.98). Median absolute number of cells with CLL phenotype in peripheral blood was 3120/µL (range,400-4959) in MBL and 9925/µL (range, 5020-110000) in CLL (P&lt;0.0001). No difference in the CD38 status (P=0.48),ZAP-70 expression (P=0.29) or cytogenetic abnormalities as detected by FISH [trisomy 12 (P=0.24); deletion 11q (P=0.68); del17p (P=0.09)] was found between patients with MBL and CLL. The only feature differentiating CLL from MBL was represented by an excess of patients with unmutated IgVH disease in the former group (CLL,69.2% vs. MBL, 30.8%: P=0.04). In addition, patients with CLL had an about 2-fold risk of having IgVH germline status in comparison to patients with MBL (OR,1.80; 95% CI, 1.02-3.13; P=0.04). Since the arbitrary cut-off of 5000/µL CLL-phenotype cells in peripheral blood failed to identify a peculiar biological profile for either MBL or CLL, we wondered whether a different B-cell threshold based on disease clinical outcome better stratified patients according to biological risk. In an independent cohort including 818 Rai stage 0 patients registered in a GIMEMA (Gruppo Italiano Malattie EMatologiche Maligne dell’Adulto) database, we demonstrated that a count of 10000/ µL B-cells is the best lymphocyte threshold to predict time to first therapy (TFT). When this cut-off was applied to the GISL series we found that the distribution of main high-risk features [CD38, P=0.83; trisomy 12,P=0.36; del11q,P=0.85; del17,P=0.37) was similar between patients with B-cell lymphocytes higher and lower than 10000/ µL. Only an excess of cases with unmutated IgVH (P=0.04) and slightly increase of ZAP-70 (P=0.06) characterized patients B-cell higher than 10000 µL. In conclusion, present data obtained from a prospective multicentre study indicate that biological characteristics of CLL are found also in MBL and there is no general predominance of good risk variables in MBL in comparison to CLL. This implies that MBL may not be considered a distinct disease but as an early stage of CLL.

2010 - Favourable ten-year overall survival in a Caucasian population with high probability of hereditary breast cancer. [Articolo su rivista]
Cortesi, L.; Masini, Cristina; Cirilli, C.; Medici, Veronica; Marchi, I.; Cavazzini, G.; Pasini, G.; Turchetti, D.; Federico, Massimo
abstract

BACKGROUND: The purpose of our study was to compare differences in the prognosis of breast cancer (BC) patients at high (H) risk or intermediate slightly (IS) increased risk based on family history and those without a family history of BC, and to evaluate whether ten-year overall survival can be considered a good indicator of BRCA1 gene mutation.METHODS: We classified 5923 breast cancer patients registered between 1988 and 2006 at the Department of Oncology and Haematology in Modena, Italy, into one of three different risk categories according to Modena criteria. One thousand eleven patients at H and IS increased risk were tested for BRCA1/2 mutations. The overall survival (OS) and disease free survival (DFS) were the study end-points.RESULTS: Eighty BRCA1 carriers were identified. A statistically significantly better prognosis was observed for patients belonging to the H risk category with respect to women in the IS and sporadic groups (82% vs.75% vs.73%, respectively; p < 0.0001). Comparing only BRCA1 carriers with BRCA-negative and sporadic BC (77% vs.77% vs.73%, respectively; p < 0.001) an advantage in OS was seen.CONCLUSIONS: Patients belonging to a population with a high probability of being BRCA1 carriers had a better prognosis than those with sporadic BC. Considering these results, women who previously had BC and had survived ten years could be selected for BRCA1 analysis among family members at high risk of hereditary BC during genetic counselling. Since only 30% of patients with a high probability of having hereditary BC have BRCA1 mutations, selecting women with a long term survival among this population could increase the rate of positive analyses, avoiding the use of expensive tests.

2010 - INCIDENCE OF CYTOGENETIC ABNORMALITIES IN NEWLY DIAGNOSED BINET STAGE A B-CLL AND RELATIONSHIP WITH PROGNOSTIC BIO-MARKERS: UPDATED RESULTS ON 319 PATIENTS INCLUDED IN THE PROSPECTIVE O-CLL1 GISL STUDY [Abstract in Rivista]
S., Fabris; G., Cutrona; M., Gentile; S., Matis; E., Pesce; F., Di Raimondo; C., Musolino; M., Gobbi; N., Di Renzo; F., Mauro; R., Cantaffa; M., Brugiatelli; F., Merli; S., Zupo; C., Mammi; L., Baldini; F., Angrilli; G., Quintana; U., Consoli; G., Bertoldero; E., Iannitto; P., Di Tonno; A., Fragasso; S., Molica; P., Musto; Mc, Cox; G., Festini; V., Callea; Sacchi, Stefano; A., Cortelezzi; G., Lambertenghi Deliliers; R., Foà; Federico, Massimo; F., Morabito; M., Ferrarini; A., Neri
abstract

Background. Biologic risk factors such as immunoglobulin variable heavy chain (IgVH) gene mutation status and CD38 and ZAP-70 expression levels, along with genomic aberrations, have been identified in B-CLL and their prognostic impact has been intensively evaluated in the disease. Aims. We investigated the incidence of the known major cytogenetic alterations (+12 and 13q14, 17p13, 11q23 deletions) in Binet A B-CLL patients included in the prospective multicenter O-CLL1 GISL trial. The study was performed by FISH in 319 out of 377 patients enrolled to date. Methods. Molecular markers characterization and FISH analyses were previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. GCC, 2008). Results. At least one abnormality was found in 209/319 (65.5%) cases. The most frequent abnormality was del(13)(q14), which was detected in 160 cases (50%) followed by +12 (42/319, 13 2%) (one case harboring 17p13 deletion), del(17)(p13) (8/319, 2.5%) and del(11)(q23) (18/319, 5.6%). 13q14 deletion was found as a sole abnormality in 142 (44.5%) patients; in the remaining cases, it was combined with +12 (3 pts) and 17p13 (4 pts) or 11q23 deletions (11 pts). The 13q deletion was found as a monoallelic deletion in 127/160 (79.3%); in the remaining 33 cases the presence of a biallelic deletion was found in >20% of interphase nuclei. No acquisition of new cytogenetic aberrations was evidenced among the 13 patients developing progressive disease (range, 6 to32 months; median, 20 months). In only one case, the proportion of nuclei with 17p13 and 13q14 deletions increased from the time of diagnosis (from 33% to 92%). Biomarkers data were available in all of the patients. CD38 percentages (mean value±sem) were 9.3±1.5, 16.2±2.0, 53.4±5.4, 23.3±1.1,47.3±13.6, 35.1±10.3 for del(13)(q14), normal karyotype, +12, del(11)(q23), del(17)(p13) and multiple alterations, respectively (P<0.0001). The percentages of IgVH mutations significantly correlated with cytogenetic alterations; namely, 5.5±0.3 for cases with del(13)(q14), 4.6±0.4 for normal karyotype, 2.6±0.5 for +12, 0.3±0.2 for del(11)(q23), 1.9±1.1 for del(17)(p13) and 1.2±0.6 for multiple alterations (P<0.0001). Similarly, a significant correlation was found for ZAP-70 expression: namely 33.5±1.8 for cases with del(13)(q14), 38.6±2.2 for normal karyotype, 47.5±3.5 for +12, 71.4±8.2 for del(11)(q22), 38.3±12.5 for del(17)(p13) and 46.0±6.1 multiple alterations (P<0.0001). Finally, cytogenetic abnormalities were clustered in 3 risk groups [i.e. low del(13)(q14) and normal; intermediate (+12); and high risk del(11)(q23) and del(17)(p13)] and correlated with a scoring system in which patients were stratified in 4 different groups according to the absence (group 0) or presence of 1 (group 1), 2 (group 2) or 3 (group 3) biomarkers (Morabito et al., BJH, 2009,). Notably, 154/162 cases scoring 0, gathered in the low FISH group, whereas 16/20 high FISH risk cases clustered in scoring 2-3 (P<0.0001). Conclusions. Our data indicate that cytogenetic abnormalities predicting unfavorable prognosis show a relatively low incidence in newly diagnosed Binet stage A B-CLL patients and are significantly associated with negative prognostic biomarkers predictive of disease progression. Furthermore, preliminary results in a limited number of cases indicate that the acquisition of new abnormalities seem to be an infrequent event during disease progression.

2010 - Incidence of hematologic malignancies in Europe by morphologic subtype: Results of the HAEMACARE project [Articolo su rivista]
Sant, M.; Allemani, C.; Tereanu, C.; De Angelis, R.; Capocaccia, R.; Visser, O.; Marcos Gragera, R.; Maynadié, M.; Simonetti, A.; Lutz, J. M.; Berrino, F.; Hackl, M.; Holub, J.; Maynadie, M.; Holleczek, B.; Tryggvadottir, L.; Comber, H.; Bellù, F.; Giacomin, A.; Ferretti, S.; Crocetti, E.; Serraino, D.; Vercelli, M.; Federico, Massimo; Fusco, M.; Michiara, M.; Tumino, R.; Mangone, L.; Falcini, F.; Iannelli, A.; Budroni, M.; Zanetti, R.; Piffer, S.; La Rosa, F.; Zambon, P.; Sowe, S.; England, K.; Langmark, F.; Rachtan, J.; Mezyk, R.; Zwierko, M.; Ondrusova, M.; Primic Žakelj, M.; Khan, S.; Jundt, G.; Usel, M.; Ess, S. M.; Bordoni, A.; Otter, R.; Coebergh, J. W.; Siesling, S.; Greenberg, D.; Easey, N.; Roche, M.; Lawrence, G.; Gavin, A.; Brewster, D. H.; Steward, J.
abstract

Changing definitions and classifications of hematologic malignancies (HMs) complicate incidence comparisons. HAEMACARE classified HMs into groupings consistent with the latest World Health Organization classification and useful for epidemiologic and public health purposes. We present crude, age-specific and age-standardized incidence rates for European HMs according to these groupings, estimated from 66 371 lymphoid malignancies (LMs) and 21 796 myeloid malignancies (MMs) registered in 2000-2002 by 44 European cancer registries, grouped into 5 regions. Age-standardized incidence rates were 24.5 (per 100 000) for LMs and 7.55 for MMs. The commonest LMs were plasma cell neoplasms (4.62), small B-cell lymphocytic lymphoma/chronic lymphatic leukemia (3.79), diffuse B-cell lymphoma (3.13), and Hodgkin lymphoma (2.41). The commonest MMs were acute myeloid leukemia (2.96), other myeloproliferative neoplasms (1.76), and myelodysplastic syndrome (1.24). Unknown morphology LMs were commonest in Northern Europe (7.53); unknown morphology MMs were commonest in Southern Europe (0.73). Overall incidence was lowest in Eastern Europe and lower in women than in men. For most LMs, incidence was highest in Southern Europe; for MMs incidence was highest in the United Kingdom and Ireland. Differences in diagnostic and registration criteria are an important cause of incidence variation; however, different distribution of HM risk factors also contributes. The quality of population-based HM data needs further improvement.

2010 - [Italian cancer figures, report 2010: Cancer prevalence in Italy. Patients living with cancer, long-term survivors and cured patients] [Articolo su rivista]
AIRTUM Working, Group; Guzzinati, S.; Dal Maso, L.; De Angelis, R.; De Paoli, A.; Buzzoni, C.; Crocetti, E.; Bucchi, L.; Casella, C.; Cuccaro, F.; Fusco, M.; Luminari, Stefano; Madeddu, A.; Mangone, L.; Patriarca, S.; Piffer, S.; Stracci, F.; Tagliabue, G.; Tumino, R.; Zappa, M.; Capocaccia, R.; Ferretti, S.; Mazzoleni, G.; Bellú, F.; Tschugguel, B.; De Valiere, E.; Facchinelli, G.; Falk, M.; Dal Cappello, T.; Giacomin, A.; Vercellino, P. C.; Andreone, S.; Busato, A.; Marzola, L.; Migliari, E.; Carletti, N.; Nenci, I.; Caldarella, A.; Corbinelli, A.; Giusti, F.; Intrieri, T.; Manneschi, G.; Nemcova, L.; Romeo, G.; Sacchettini, C.; Paci, E.; Serraino, D.; Angelin, T.; Bidoli, E.; de Dottori, M.; De Santis, E.; Forgiarini, O.; Zucchetto, A.; Zanier, L.; Vercelli, M.; Orengo, M. A.; Marani, E.; Puppo, A.; Celesia, M. V.; Cogno, R.; Manenti, S.; Garrone, E.; Quaglia, A.; Pannozzo, F.; Busco, S.; Rashid, I.; Ramazzotti, V.; Cercato, M. C.; Battisti, W.; Sperduti, I.; Macci, L.; Bugliarello, E.; Bernazza, E.; Tamburo, L.; Rossi, M.; Curatella, S.; De Francesco, C.; Tamburrino, S.; Bisanti, L.; Autelitano, M.; Randi, G.; Ghilardi, S.; Leone, R.; Filipazzi, L.; Bonini, A.; Giubelli, C.; Federico, Massimo; Artioli, M. E.; Valla, K.; Braghiroli, B.; Cirilli, C.; Pirani, M.; Ferrari, L.; Bellatalla, C.; Fusco, M.; Panico, M.; Perrotta, C.; Vassante, B.; Traina, A.; Carruba, G.; Cusimano, R.; Amodio, R.; Dolcemascolo, C.; Staiti, R.; Zarcone, M.; Michiara, M.; Bozzani, F.; Sgargi, P.; Cilia, S.; La Rosa, M. G.; Cascone, G.; Frasca, G.; Giurdanella, M. C.; Martorana, C.; Morana, G.; Nicita, C.; Rollo, P.; Ruggeri, M. G.; Sigona, A.; Spata, E.; Vacirca, S.; Di Felice, E.; Pezzarossi, A.; Caroli, S.; Pellegri, C.; Vicentini, M.; Storchi, C.; Cavuto, S.; Costa, J.; Falcini, F.; Colamartini, A.; Balducci, C.; Ravegnani, M.; Vitali, B.; Cordaro, C.; Caprara, L.; Giuliani, O.; Giorgetti, S.; Salvatore, S.; Palumbo, M.; Vattiato, R.; Ravaioli, A.; Foca, F.; Rinaldi, E.; Donato, A.; Iannelli, A.; Senatore, G.; Zevola, A.; Budroni, M.; Cesaraccio, R.; Pirino, D.; Carboni, D.; Fiori, G.; Soddu, M.; Mameli, G.; Mura, F.; Contrino, M. L.; Tisano, F.; Sciacca, S.; Muni, A.; Mizzi, M.; Russo, M.; Tessandori, R.; Ardemagni, G.; Gianola, L.; Maspero, S.; Annulli, M. L.; Moroni, E.; Roberto, G.; Zanetti, R.; Rosso, S.; Prandi, R.; Sobrato, I.; Gilardi, F.; Busso, P.; Franchini, S.; Gentilini, M. A.; Battisti, L.; Cappelletti, M.; Moser, M.; La Rosa, F.; D'Alò, D.; Scheibel, M.; Costarelli, D.; Spano, F.; Rossini, S.; Santucci, C.; Petrinelli, A. M.; Solimene, C.; Bianconi, F.; Brunori, V.; Crosignani, P.; Contiero, P.; Preto, L.; Tittarelli, A.; Maghini, A.; Codazzi, T.; Frassoldi, E.; Gada, D.; Costa, E.; di Grazia, L.; Zambon, P.; Baracco, M.; Bovo, E.; Dal Cin, A.; Fiore, A. R.; Greco, A.; Monetti, D.; Rosano, A.; Stocco, C.; Tognazzo, S.; Donato, F.; Limina, R. M.; Adorni, A.; Andreis, P.; Zani, G.; Piovani, F.; Salvi, O.; Puleio, M.; Vitarelli, S.; Antonini, S.; Candela, G.; Pappalardo, G.; Scuderi, T.; Lottero, B.; Ribaudo, M.; Ricci, P.; Guarda, L.; Gatti, L.; Bozzeda, A.; Dall'Acqua, M.; Pironi, V.; Sutera Sardo, A.; Mazzei, A.; Sirianni, N.; Lavecchia, A. M.; Mancuso, P.; Usala, M.; Pala, F.; Sini, G. M.; Pintori, N.; Canu, L.; Demurtas, G.; Doa, N.; Pisani, P.; Pastore, G.; Magnani, C.; Terracini, B.; Cena, T.; Alessi, D.; Baussano, I.; Merletti, F.; Maule, M.; Mosso, M. L.; Nonnato, M.; Rasulo, A.; Richiardi, L.; Zuccolo, L.; Pivetta, E.; Dalmasso, P.; Macerata, V.; Ponz De Leon, Maurizio; Domati, F.; Rossi, G.; Goldoni, C. A.; Rossi, F.; De Gaetani, C.; Benatti, Piero; Roncucci, Luca; Di Gregorio, C.; Pedroni, Monica; Pezzi, A.; Maffei, S.; Mariani, F.; Borsi, E.; Cocchioni, M.; Pascucci, C.; Gennaro, V.; Lazzarotto, A.; Benfatto, L.; Mazzucco, G.; Montanaro, F.
abstract

OBJECTIVES: the aim of the present monograph is to update the estimation of the number of people living with cancer in Italy, to describe geographic variability, and estimate the number of long-term survivors, i.e., people living five years or more after a cancer diagnosis. MATERIALS AND METHODS: the study included the data of the AIRTUMdatabase. Twenty-four Cancer Registries (CRs) (covering 27% of the Italian population) collected information on the incidence and vital status of 1,275,353 cases diagnosed between 1978 and 2005. For each CR, the observed prevalence was calculated up to the maximum observable duration. To estimate the complete prevalence (all living patients, independently from time since diagnosis) and the prevalence for lengths of time exceeding the CR maximum duration of registration, the observed prevalence was corrected through a completeness index. Completeness indices, gender, age and site specific, were estimated by means of statistical regression models using cancer incidence and survival data available from CRs with more than 15 years of observation. As of 1 January 2006, the prevalence was estimated (as absolute numbers and as a proportion per 100,000 inhabitants) for 46 cancer sites, by gender, age class, years since diagnosis and geographic areas. RESULTS: as of 2006, 2,244,000 persons (4%of the Italian population) were alive with a cancer diagnosis. A relevant geographic variability emerged, with proportions between 4%-5% among CRs in the Centre and North of Italy, and proportions between 2%-3% in the South. Forty-four percent of prevalent subjects (988,000) were males and 56% (1,256,000) females. Fifty-seven percent (1,285,680 people, 2.2% of total population) of these patients was represented by long-term survivors. In patients aged 75 years or more, the proportions of prevalent cases were 19%in males and 13%in females, and 10%between 60 and 75 years of age in both genders.More than half a million Italian women were alive with a breast cancer diagnosis (42%of women with a neoplasm), followed by women with cancers of the colonrectum (12%), corpus uteri (7%), thyroid (5%), and cervix uteri (4%). In men, 22%of prevalent cases (216,716) included patients with prostate cancer, 18% with bladder cancer, and 15%with colon-rectum cancer. Percentages of long-term survivors higher than 70% were reported for cancers of the cervix uteri (82% at five years, and 55% at 15 years from diagnosis), Hodgkin lymphoma, testis, brain and central nervous system, bone and connective tissue. Many patients with these types of cancers (often occurring in young people) can be considered "cured", i.e., with a life expectancy overlapping that of the general population.The estimated proportions of prevalent cases emerging from this study in Italy were quite similar to those reported in Northern Europe, but at least 15%lower than those in the United States. CONCLUSIONS: in 2006, the number of prevalent cases nearly doubled compared to 1992. The increase over time in the proportion of elderly patients, related to population ageing, requires adequate health policies. Knowing the number of people alive many years after cancer diagnosis (either cured or long-term survivors) provides the scientific bases for the definition of health policies focusing on them. Furthermore, it promotes the conduction of studies aimed at improving the present knowledge on the quality of life of these patients during and after the active phase of treatments, in addition to studies on the long-term effects of treatments.

2010 - Long term outcome of patients with localized aggressive non-Hodgkin lymphoma treated with PROMECE-CYTABOM plus involved-field radiation therapy: a study by the Gruppo Italiano Studio Linfomi. [Articolo su rivista]
Mannina, D.; Luminari, Stefano; Dondi, Alessandra; Polimeno, G.; Baldini, L.; Stelitano, C.; Merli, F.; Del'Olio, M.; Gobbi, P. G.; Giglio, G.; Barblini, E.; Brugiatelli, M.; Federico, Massimo
abstract

We conducted a retrospective analysis on 168 adult patients with newly diagnosed, limited-stage (I and II) diffuse large B-cell lymphoma (DLBCL) treated from 1988 to 2004 with PROMECE-CYTABOM (P-C) plus involved-field radiation therapy (IF-RT). At the end of P-C, the overall response rate was 92%. Radiotherapy (RT) was delivered to 84% of cases. With a median follow-up of 95 months, overall survival (OS), relapse free survival (RFS), and failure free survival at 5 and 10 years was 84% and 77%, 81% and 75%, 71% and 67%, respectively. Age (>60 years, p = 0.002), serum albumin (<3.5 g/dL; p = 0.015), and RT (p < 0.001) were independent predictors of OS. For patients in complete remission the administration of RT didn't improve both RFS and OS. This study confirms that patients with localized aggressive lymphoma have a high chance of cure with anthracycline containing regimens. Though the regimen used to treat these patients does not contain rituximab, results are considered excellent both in terms of efficacy and safety

2010 - Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group. [Articolo su rivista]
Sardanelli, F.; Boetes, B.; Decker, T.; Federico, Massimo; Gilbert, F. J.; Helbich, T.; Heywang Kobrunner, S. H.; Kaiser, W. A.; Kerin, M. J.; Mansel, R. E.; Marotti, L.; Martincich, L.; Mauriac, L.; Meijers Heijboer, H.; Orecchia, R.; Panizza, P.; Ponti, A.; Purushotham, A. D.; Regitnig, P.; Rosselli Del Turco, M.; Thibaukt, F.; Wilson, R.
abstract

The use of breast magnetic resonance imaging (MRI) is rapidly increasing. EUSOMA organised a workshop in Milan on 20-21st October 2008 to evaluate the evidence currently available on clinical value and indications for breast MRI. Twenty-three experts from the disciplines involved in breast disease management - including epidemiologists, geneticists, oncologists, radiologists, radiation oncologists, and surgeons - discussed the evidence for the use of this technology in plenary and focused sessions. This paper presents the consensus reached by this working group. General recommendations, technical requirements, methodology, and interpretation were firstly considered. For the following ten indications, an overview of the evidence, a list of recommendations, and a number of research issues were defined: staging before treatment planning; screening of high-risk women; evaluation of response to neoadjuvant chemotherapy; patients with breast augmentation or reconstruction; occult primary breast cancer; breast cancer recurrence; nipple discharge; characterisation of equivocal findings at conventional imaging; inflammatory breast cancer; and male breast. The working group strongly suggests that all breast cancer specialists cooperate for an optimal clinical use of this emerging technology and for future research, focusing on patient outcome as primary end-point.

2010 - Nonpegylated liposomal doxorubicin (Myocet) combination (R-COMP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL): results from the phase II EURO 18 trial [Articolo su rivista]
Luminari, Stefano; Montanini, Antonella; Caballero, D.; Bologna, S.; Notter, M.; Dyer, M. J. S.; Chiappella, A.; Briones, J.; Petrini, M.; Barbato, A.; Kayitalire, L.; Federico, Massimo
abstract

BACKGROUND: To evaluate the activity and safety of nonpegylated liposomal doxorubicin (Myocet) when substituted for doxorubicin in the R-CHOP regimen (R-COMP). PATIENTS AND METHODS: Seventy-five elderly patients with diffuse large B-cell lymphoma (DLBCL) were studied. Only patients with left ventricular ejection fraction (LVEF) >/=50% were allowed. R-COMP regimen was administered every 3 weeks for three cycles, followed by additional five cycles in case of complete response (CR) or partial response. RESULTS: From November 2002 to April 2005, 75 patients were registered, of which 72 were evaluated. Median age was 72 years (range 61-83); 56% of patients had high or high-intermediate International Prognostic Index score. Median LVEF at baseline was 61%. Thirty-eight patients had history of abnormal cardiovascular conditions. The overall response rate was 71%, with a CR rate of 57%. After a median follow-up of 33 months, the 3-year overall survival, failure-free survival, and progression-free survival rates were 72%, 39%, and 69%, respectively. Neutropenia (54%) was the most frequent grade 3-4 adverse event (AE); 21% of patients experienced cardiac AEs, graded as 3-4 in 4% of the cases. CONCLUSION: R-COMP is an effective regimen for the treatment of DLBCL in elderly patients, with an acceptable tolerability profile.

2010 - Other peripheral T-cell Lymphomas [Capitolo/Saggio]
Luminari, Stefano; Federico, Massimo
abstract

2008

2010 - Phase II Fludarabine and Cyclophosphamide for the treatment of indolent cell non-follicular lymphomas: final results of the LL02 trial of the Gruppo Italiano per lo Studio dei Linfomi. [Articolo su rivista]
Ferrario, A.; Merli, F.; Luminari, Stefano; Stelitano, C.; Mannina, D.; Russo, M.; Mazza, P.; Marcheselli, Luigi; Goldaniga, M. C.; Federico, Massimo; Baldini, L.
abstract

Indolent non-follicular non-Hodgkin lymphomas (INFL) are a heterogenous subset whose treatment has been poorly investigated. In this context we have evaluated the efficacy and safety of combined fludarabine and cyclophosphamide (FC) upfront therapy. Sixty-three patients with advanced INFL were enrolled in the study. Therapy consisted in FC combination (25 and 250 mg/m(2), i.v., respectively, for three consecutive days) every 28 days for six courses. After histological review, 61 patients (36 men, median age 64 years, range 40-70 years) were evaluated (22 small lymphocytic, 11 lymphoplasmacytic, 25 marginal zone and 3 CD5-negative non-Hodgkin lymphomas not otherwise specified). Further two patients were excluded for lack of essential data; six patients were withdrawn before the third cycle because of WHO grade III and IV toxicity. At the final evaluation, the overall response rate was 83% with 40.7% of complete remission. Intention-to-treat analysis showed that at the median follow-up of 36 months, overall survival, progression-free survival and failure-free survival were respectively 78%, 60% and 46%; remission duration among the 49 patients achieving complete remission/partial remission at the end of treatment was 65% (44-78) without significant differences between the main histotypes. The most frequent grade III and IV toxic events were haematological (neutropaenia 34%, anaemia 18% and thrombocytopaenia 11%) and infectious (10%). FC is effective for advanced untreated INFL. Early deaths and haematological toxicity suggest careful patient selection and monitoring.

2009 - ABVD Compared With BEACOPP Compared With CEC for the Initial Treatment of Patients With Advanced Hodgkin's Lymphoma: Results From the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial. [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Iannitto, E; Polimeno, G; Marcheselli, Luigi; Montanini, Antonella; LA SALA, A; Merli, F; Stelitano, C; Pozzi, Samantha; Scalone, R; DI RENZO, N; Musto, P; Baldini, L; Cervetti, G; Angrilli, F; Mazza, P; Brugiatelli, M; Gobbi, Pg
abstract

PURPOSE: To compare doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) versus bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) versus cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (COPPEBVCAD; CEC) for advanced Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Three hundred seven patients with advanced HL (stage IIB, III, and IV) were randomly assigned to receive six courses of ABVD, four escalated plus two standard courses of BEACOPP, or six courses of CEC, plus a limited radiation therapy program. RESULTS: After a median follow-up of 41 months, BEACOPP resulted in a superior progression-free survival (PFS), with a significant reduction in risk of progression (hazard ratio [HR] = 0.50) compared with ABVD. No differences between BEACOPP and CEC, or CEC and ABVD were observed. The 5-year PFS was 68% (95% CI, 56% to 78%), 81% (95% CI, 70% to 89%), and 78% (95% CI, 68% to 86%), for ABVD, BEACOPP, and CEC, respectively (BEACOPP v ABVD, P = .038; CEC v ABVD and BEACOPP v CEC, P = not significant [NS]). The 5-year overall survival was 84% (95% CI, 69% to 92%), 92% (95% CI, 84% to 96%), and 91% (95% CI, 81% to 96%) for ABVD, BEACOPP, and CEC, respectively (P = NS). BEACOPP and CEC resulted in higher rates of grade 3-4 neutropenia than ABVD (P = .016); BEACOPP was associated with higher rates of severe infections than ABVD and CEC (P = .003). CONCLUSION: As adopted in this study BEACOPP is associated with a significantly improved PFS compared with ABVD, with a predictable higher acute toxicity.

2009 - Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone outside German Hodgkin Study Group: The Italian experience [Articolo su rivista]
Luminari, S.; Federico, M.; Montanini, A.; Iannitto, E.; Polimeno, G.; Gobbi, P. G.
abstract

2009 - Bone marrow stem cell damage after three different chemotherapy regimens for advanced Hodgkin's lymphoma [Articolo su rivista]
Gobbi, P. G.; Valentino, F.; Danova, M.; Morabito, F.; Rovati, B.; Mammi, Caterina; Gentile, M.; Merli, F.; Stelitano, C.; Luminari, Stefano; Quintana, G.; Iannitto, E.; Brugiatelli, M.; Federico, Massimo
abstract

The aim of this study was to evaluate the apoptotic damage to bone marrow cells caused by three chemotherapy regimens for advanced Hodgkin's lymphoma, ABVD, COPPEBVCAD and BEACOPP, which were randomly administered in the HD 2000 GISL trial. Bone marrow mononuclear cells (BMMCs) stained with anti-CD34 antibody and Annexin V, were evaluated by flow cytometry before starting chemotherapy, 30 days after completing chemotherapy and after 6 months. Results are expressed as the percentages of BMMCs positive to anti-CD34, to Annexin V or to both. Fourteen patients treated with ABVD, 11 with COPPEBVCAD and 13 with BEACOPP were evaluated before and 30 days after treatment. Late assessments were made in 6, 7 and 8 of them, respectively. No differences were found among the pretherapeutic flow cytometry findings in relation to the staging characteristics (marrow involvement included). All the regimens increased the apoptotic fraction of the whole mononuclear bone marrow cells (COPPEBVCAD did so significantly) and increased the CD34+ compartment (with significant early differences after ABVD and BEACOPP, tending to late persistence for ABVD, only). All the regimens increased the apoptotic CD34+ cells within the whole BMMC population (significantly after BEACOPP), although with a general trend to decrease in their percentage within the CD34+ compartment over time, even after the most dose-dense regimens. Based on the variations induced in the apoptotic fraction of all mononuclear and CD34+ cells, ABVD was the least toxic regimen and COPPEBVCAD the most toxic one.

2009 - Concordance between four European Centres of PET reporting criteria designed for use in multicentre trials in Hodgkin Lymphoma [Abstract in Atti di Convegno]
S. F., Barrington; W., Qian; E. J., Somer; Franceschetto, Antonella; Bagni, Bruno; E., Brun; H., Almquist; A., Loft; L., Hojgaard; Federico, Massimo; A., Gallamini; P., Smith; P., Johnson; J., Radford; M. J., O'Doherty
abstract

The criteria developed for interpretation of PET scans in the RATHL study are sufficiently robust to be used in a multicentre setting. Continued audit will be required to ensure consistency in reporting is maintained. The criteria could be adapted to change the threshold for "positivity" according to the clinical research context.

2009 - Development and application of a real-time on-line blinded independent central review of interim PET scans to determine treatment allocation in lymphoma trials [Articolo su rivista]
Meignan, M.; Itti, E.; Bardet, S.; Lumbroso, J.; Edeline, V.; Oliver, P.; Borghi, T. V.; Reman, O.; Karcher, G.; Mundler, O.; Mounier, N.; Ricci, R.; Federico, Massimo; Raemaekers, J.; Andrè, M.
abstract

This article does not have an abstract

2009 - Distribution of second primari malignancies suggest a bidirectional effect between breast and endometrial cancer. A population-based study [Articolo su rivista]
Cortesi, L.; DE MATTEIS, Elisabetta; Rashid, I.; Cirilli, C.; Proietto, Manuela; Rivasi, Francesco; Federico, Massimo
abstract

INTRODUCTION: The aim of this study was to investigate the incidence of second primary tumors in patients with breast cancer (BC), with particular regard to bidirectional risk for endometrial cancer (EC). METHODS: A total of 7512 and 343 patients with first and second primary BC, respectively, were referenced to the expected number of cases calculated using the standardized incidence ratio (SIR) over the same period, to evaluate the observed and expected ratio between the groups. Data on tamoxifen use were also considered. RESULTS: A total of 499 women with primary BC developed a second tumor. The total SIR, that is, the ratio between observed second primary cancer among patients with BC and the expected primary cancers in the general population, was significantly higher (SIR = 1.23; 95% confidence interval, 1.12-1.34; P = 0.007), particularly for melanoma (2.25), EC (2.15), ovarian cancer (1.74), hematologic malignancies (1.36), and bilateral BC (1.25). A greater risk of BC after thyroid (2.22) and EC (1.62) was also observed. Furthermore, the risk of developing EC was higher in patients treated with tamoxifen (SIR = 2.50 vs 1.34). CONCLUSIONS: Bidirectional risk of endometrial cancer was not exclusively related to tamoxifen use.

2009 - Elongation factor 1 alpha interacts with phospho-Akt in breast cancer cells and regulates their proliferation, survival and motility [Articolo su rivista]
Pecorari, Luisa; Marin, O.; Silvestri, C.; Candini, Olivia; Rossi, Elena; Guerzoni, Clara; Cattelani, Sara; Mariani, S. A.; Corradini, Francesca; Ferrari, Giovanna; Cortesi, L.; Bussolari, Rita; Raschellà, G.; Federico, Massimo; Calabretta, Bruno
abstract

BACKGROUND: Akt/PKB is a serine/threonine kinase that has attracted much attention because of its central role in regulating cell proliferation, survival, motility and angiogenesis. Activation of Akt in breast cancer portends aggressive tumour behaviour, resistance to hormone-, chemo-, and radiotherapy-induced apoptosis and it is correlated with decreased overall survival. Recent studies have identified novel tumor-specific substrates of Akt that may provide new diagnostic and prognostic markers and serve as therapeutic targets. This study was undertaken to identify pAkt-interacting proteins and to assess their biological roles in breast cancer cells. RESULTS: We confirmed that one of the pAkt interacting proteins is the Elongation Factor EF1alpha. EF1alpha contains a putative Akt phosphorylation site, but is not phosphorylated by pAkt1 or pAkt2, suggesting that it may function as a modulator of pAkt activity. Indeed, downregulation of EF1alpha expression by siRNAs led to markedly decreased expression of pAkt1 and to less extent of pAkt2 and was associated with reduced proliferation, survival and invasion of HCC1937 cells. Proliferation and survival was further reduced by combining EF1alpha siRNAs with specific pAkt inhibitors whereas EF1alpha downregulation slightly attenuated the decreased invasion induced by Akt inhibitors. CONCLUSION: We show here that EF1alpha is a pAkt-interacting protein which regulates pAkt levels. Since EF1alpha is often overexpressed in breast cancer, the consequences of EF1alpha increased levels for proliferation, survival and invasion will likely depend on the relative concentration of Akt1 and Akt2.

2009 - External Validation On Biological Basis of New Prognostic Index in Early Asymptomatic Chronic Lymphocytic Leukemia (CLL) Patients: The Gruppo Italiano Studio Linfomi (GISL) Experience [Abstract in Rivista]
S., Molica; S., Fabris; G., Cutrona; M., Gentile; E. A., Pesce; F., Di Raimondo; C., Musolino; M., Gobbi; N., Di Renzo; F., Mauro; R., Cantaffa; M., Brugiatelli; F., Merli; S., Zupo; C., Mammi; L., Baldini; F., Angrilli; G., Quintana; U., Consoli; G., Bertoldero; E., Iannitto; P., Di Tonno; A., Fragasso; P., Musto; M. C., Cox; G., Festini; V., Callea; Sacchi, Stefano; A., Cortelezzi; G., Lambertenghi; R., Foà; A., Neri; Federico, Massimo; M., Ferrarini; F., Morabito
abstract

prognostic index based on widely available clinical and laboratory features was recently proposed to predict survival in patients with previously untreated patients with chronic lymphocytic leukemia (CLL) by MD Anderson investigators. However, whether proposed clinical risk categories may surrogate new biological variables of prognostic relevance (i.e., mutational status of the IgVH gene regions, ZAP-70 or CD-38 expression, cytogenetic abnormalities) is unclear thus far.In a series of 160 asymptomatic Binet stage A patients enrolled in a Gruppo Italiano Studio Linfomi (GISL) multicentre trial designed to validate prospectively biological parameters in early CLL as well as to assess the impact on clinical outcome of an early versus delayed policy of treatment with subcutaneous alemtuzumab in the high biological risk, we evaluated whether clinical categories derived from newly proposed prognostic index reflected biological risk. Since the original prognostic index was derived from a database including cases with more advanced disease we used an optimal cutoff search to determine how to best split Binet stage A patients in different prognostic groups. To this purpose an independent patient cohort consisting of 310 Binet stage A patients included in a GIMEMA (Gruppo Italiano Malattie EMatologiche Maligne dell’Adulto) database was used. According to recursive partitioning (RPART) model, a classification tree was built that identified two subsets of patients who scored respectively: 0-3 (low risk) and 4-7 (high risk). Therefore, by prognostic index, 48.7% and 51.2% of 160 asymptomatic stage A patients, respectively, met criteria of low risk and high risk disease.In our prospective series high- risk score was more frequently associated with both unmutated IgVH status (P=0.009) and higher CD38-expression (P=0.002); in contrast only a trend towards an increased ZAP-70 expression could be found (P=0.06). As far as cytogenetic abnormalities are concerned, we observed that 11q deletion occurred more frequently among patients belonging to high-risk score (P=0.005), while cases with 13q deletion or trisomy 12 were homogeneously distributed among low- and high-risk patient category(P=0.151 and P=0.452, respectively). We did not consider suitable for correlation analysis 17p deletion since observed only in 2 out of 160 Binet stage A patients. In conclusion, our results demonstrate in a prospective cohort of patients with early CLL that clinical categories of a revised score index may surrogate biological parameters of prognostic relevance. The observation reinforces the revised IWCLL guidelines recommendations to assess the risk of CLL patients on clinical basis and to deserve biological studies to patients eligible for clinical trials.

2009 - Follicular Lymphoma International Prognostic Index 2: a new prognostic index for follicular lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project [Articolo su rivista]
Federico, Massimo; Bellei, Monica; Marcheselli, Luigi; Luminari, Stefano; Lopez Guillermo, A.; Vitolo, U.; Pro, B.; Pileri, S.; Pulsoni, A.; Soubeyran, P.; Cortelazzo, S.; Martinelli, G.; Martelli, M.; Rigacci, L.; Arcaini, L.; Di Raimondo, F.; Merli, F.; Sabattini, E.; McLaughlin, P.; Solal Céligny, P.
abstract

PURPOSE: The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point. PATIENTS AND METHODS: Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed. RESULTS: After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. beta2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001). CONCLUSION: Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.

2009 - High-dose therapy and autologous stem cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy: long-term results. [Articolo su rivista]
Carella, Am; Bellei, Monica; Brice, P; Gisselbrecht, C; Visani, G; Colombat, P; Fabbiano, F; Donelli, A; Luminari, Stefano; Feugier, P; Browett, P; Hagberg, H; Federico, Massimo
abstract

no abstract available

2009 - I tumori in provincia di Modena anni 1988-2006 [Monografia/Trattato scientifico]
Rashid, I.; Artioli, M. E.; Braghiroli, B.; Cirilli, C.; Pirani, Monica; Valla, K.; Federico, Massimo
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

2009 - I tumori nelle provincie di Parma, Reggio Emilia, Modena [Monografia/Trattato scientifico]
De Lisi, V.; Bozzani, F.; Michiara, M.; Sgargi, P.; Mangone, L.; Caroli, S.; Di Felice, E.; Pellegri, C.; Pezzarossi, A.; Storchi, C.; Vicentini, M.; Federico, Massimo; Artioli, M. E.; Braghiroli, B.; Cirilli, C.; Luminari, Stefano; Marcheselli, Luigi; Orsini, Mirko; Pirani, Monica; Valla, K.
abstract

Volume contenente i dati di incidenza, mortalità e sopravvivenza dei tumori nelle provincie di Parma, Reggio Emilia e Modena nell'anno 2007.

2009 - Identification of protein clusters predictive of response to chemotherapy in breast cancer patients [Articolo su rivista]
L., Cortesi; Barchetti, Andrea; DE MATTEIS, Elisabetta; Rossi, Elena; DELLA CASA, Lara; Marcheselli, Luigi; Tazzioli, Giovanni; M. G., Lazzaretti; G., Ficarra; Federico, Massimo; Iannone, Anna
abstract

An attempt for the identification of potential biomarkers predictive of response to chemotherapy (CHT) in breast cancer patients has been performed by the use of two-dimensional electrophoresis and mass spectrometry analysis. Since growth and progression of tumor cells depend also on stromal factors in the microenvironment, we choose to investigate the proteins secreted in Tumor Interstitial Fluid (TIF) and in Normal Interstitial Fluids (NIF). One-hundred and twenty-two proteins have been analyzed and a comparison was also made between the proteomic profile of responders versus nonresponders to CHT. At baseline, proteins isolated in TIF and NIF of all the 28 patients show significant differences in expression. Two clusters of proteins, differentially expressed in TIF with respect to NIF were found. Most significant is the decreased expression in TIF of CRYAB. In the protein metabolism group, also FIBB was found decreased. Some proteins involved in energy pathways were overexpressed (PGAM-1, ALDO A, PGK1, G3Pcn), while some other were down-regulated (CAH2, G3Pdx, PRDX6, TPIS). The same trend was observed for signal transduction proteins, with 14-3-3-Z overexpressed, and ANXA2 and PEBP 1 down-regulated. Moreover, an analysis has been conducted comparing protein expression in interstitial fluids of responders and nonresponders, irrespective of TIF or NIF source. This analysis lead us to identify two clusters of proteins with a modified expression, which might be predictive of response to CHT. In responders, an increase in expression of LDHA, G3Pdx, PGK1sx (energy pathways), VIME (cell growth and maintenance) and 14-3-3-Z (signal transduction), coupled with a decreased expression of TPIS, CAH 2, G3Psx, PGK 1dx (energy pathways), TBB5 (cell growth and maintenance), LDHB and FIBB (protein metabolism), was found. We observed that CHT modifies the expression of these cluster proteins since, after treatment, their expression in TIF of responder is generally decreased. Patients not responding to CHT show an unchanged expression pattern in TIF, with the exception of protein 14-3-3-Z, which is overexpressed, and a decreased expression in NIF of several cluster proteins. In conclusion, the identification of protein clusters associated with response to CHT might be important for predicting the efficacy of a specific antineoplastic drug and for the development of less empiric strategies in choosing the therapy to be prescribed to the single patient

2009 - Incidence of Cytogenetic Abnormalities in Newly Diagnosed Binet Stage A B-CLL and Relationship with Prognostic Biomarkers: Preliminary Results On 305 Patients Included in the Prospective O-CLL1 GISL Study [Articolo su rivista]
S., Fabris; G., Cutrona; M., Gentile; S., M; E. A., Pesce; F., Di Raimondo; C., Musolino; M., Gobbi; N., Di Renzo; F., Mauro; R., Cantaffa; M., Brugiatelli; F., Merli; S., Zupo; C., Mammi; L., Baldini; F., Angrilli; G., Quintana; U., Consoli; G., Bertoldero; E., Iannitto; P., Di Tonno; A., Fragasso; S., Molica; P., Musto; M. C., Cox; G., Festini; V., Callea; Sacchi, Stefano; A., Cortelezzi; G., Lambertenghi Deliliers; R., Foà; Federico, Massimo; M., Ferrarini; F., Morabito; A., Neri
abstract

Background. The clinical heterogeneity of chronic lymphocytic leukemia (CLL) requires parameters to stratify patients into prognostic subgroups to adapt treatment ranging from ‘watch and wait’ to allogeneic stem cell transplantation. To this end, several parameters such as lymphocyte doubling time, β-2 microglobulin, CD38 and ZAP-70 expression, immunoglobulin variable heavy chain (IgVH) mutation status and genetic abnormalities, as assessed by fluorescence in situ hybridization (FISH), have been integrated in clinical practice. Aims. In the present study, we investigated by FISH the incidence of the known major cytogenetic alterations (+12 and 13q14, 17p13, 11q23 deletions) in a series of Binet A B-CLL patients included in the prospective O-CLL1 GISL study started in April 2007. Methods. Molecular markers characterization and FISH analyses were performed as previously reported (Cutrona et al. Haematologica, 2008; Fabris et al. GCC, 2008). A cut-off value of 2% was used to distinguish mutated and unmutated patients. CD38 and ZAP-70 were determined by flow-cytometry and a 30% cut-off was used to distinguish between positive or negative cases. Results. Up to date, 326 patients have been enrolled in the trial and FISH data concerning trisomy 12 and 13q14, 17p13, 11q23 deletions were available in 305 patients. At least one abnormality was found in 197 (64%) cases. The most frequent was del(13)(q14) (150/305, 49%), followed by +12 (40/303, 13%) (in one and three cases accompanied by 17p13 and 13q14 deletions, respectively), del(17)(p13) (7/305, 2%) and del(11)(q23) (17/305, 5%). 13q14 deletion was found as a sole abnormality in 134 patients; in the remaining cases, it was combined with +12 (3 pts) and 17p13 (3 pts) or 11q23 (10 pts) deletions. Among patients with 13q14 deletions, 99 were monoallelic, 12 biallelic and 39 showed a combination of the two patterns. Biomarkers data were available in all of the patients: 95/305 (31%) cases had unmutated IgVH genes; ZAP-70 and CD38 were positive in 117/305 (38%) and 72/305 (23%) cases, respectively. Concerning the distribution of cytogenetic aberrations, the unmutated IgVH group included 29/150 (19%) 13q14 deleted cases, 23/40 (57%) cases with trisomy 12 and 4/7 (57%) and 16/17 (94%) with 17p13 and 11q23 deletions, respectively. ZAP-70-positive groups included 43/150 (28%) 13q14 deleted cases, 26/40 (65%) cases showing trisomy 12 and 5/7 (71%) and 12/17 (70%) with 17p13 and 11q23 deletions, respectively. Finally, CD38-positive cases included 18/150 (12%) 13q14 deleted cases, 26/40 (65%) cases carrying trisomy 12 and 5/7 (71%) and 7/17 (41%) with 17p13 and 11q23 deletions, respectively. The percentages of IgVH mutations significantly correlated with cytogenetic alterations; namely, 5.8±0.3 for cases with del(13)(q14), 4.6±0.4 for normal karyotype, 2.6±0.5 in +12, 0.3±0.2 in del(11)(q23), and 1.7±0.9 in del(17)(p13) cases (p for trend &lt;0.0001). A significant correlation was also found for ZAP-70 expression: namely 32±1.8 for cases with del(13)(q14), 38.6±2.2 for normal karyotype, 47.6±3.7 for +12, 55.8±7.0 for del(11)(q22) and 42.4±11.7 for del(17)(p13) (p&lt;0.0001). Similarly, CD38 percentages were (mean value ± sem) 9.3±1.7, 16.9±2.1, 52.9±5.7, 26.8±6.2, 37.0±12.7 for del(13)(q14), normal karyotype, +12, del(11)(q23) and del(17)(p13) alterations, respectively (p for trend &lt;0.0001). Finally, cytogenetic abnormalities were clustered in 3 risk groups [i.e. low del(13)(q14) and normal; intermediate (+12); and high risk del(11)(q23) and del(17)(p13)] and significantly correlated (p&lt;0.0001) with a scoring system in which cases were stratified in 4 different groups according to the absence (group 0) or presence of 1 (group 1), 2 (group 2) or 3 (group 3) biomarkers (Morabito et al., BJH, 2009, voce). Interestingly, 147/154 cases scoring 0, gathered in the low FISH group, whereas 17/22 high FISH risk cases clustered in scoring 2-3. Conclus

2009 - INCLUSION OF TOTAL BODY CT SCAN IN THE INITIAL WORK-UP OF CLL PATIENTS WITH EARLY-STAGE ON CLINICAL GROUNDS: PRELIMINARY RESULTS OF A PROSPECTIVE, MULTICENTER O-CLL1-GISL STUDY [Abstract in Rivista]
M., Gentile; G., Cutrona; S., Fabris; E., Pesce; F., Di Raimondo; N., Di Renzo; F. R., Mauro; R., Cantaffa; M., Brugiatelli; F., Merli; L., Baldini; G., Quintana; E., Iannitto; P., Di Tonno; A., Fragasso; S., Molica; V., Callea; Sacchi, Stefano; Federico, Massimo; A., Neri; M., Ferrarini; F., Morabito
abstract

Background. The clinical staging systems proposed by Rai and Binet represent the backbone for assessing prognosis in patients with Chronic Lymphocytic Leukemia (CLL). However, staging systems are not devoid of some limitations, among the most significant of which is the lack of recognition of early-stage patients who will progress. Unlike the guidelines for assessing the response to therapy for most other types of non-Hodgkin’s lymphomas, the widely-used NCI-WG guidelines for patients with CLL do not incorporate use of computed tomography (CT) scans in the algorithm. However, two recent retrospective study challenged this notion. highlighting the importance of prospective validation of CT scans before routine inclusion in CLL work up. Aims. In the present study, we investigated whether total body CT scan allowed to individuate among Binet stage A CLL patients, included in the prospective multicenter O-CLL01 GISL study, cases in more advanced stage and whether this subgroup showed a different expression of clinical and biological prognostic markers. Patients. Up to date, 275 patients have been enrolled in the trial started in April 2007 and total body CT scan were available in 87 patients. Fifty-two patients (60%) were male and the median age was 61 years (range, 33 to 71 years). All patients are in Binet stage A, while 83 patients were at low risk (0-I stages) and 4 at intermediate risk (II stage) by Rai classification. LDH was elevated in 11.5% of cases and B2-microglobulin in 24%. Twenty-eight patients (33%) were IgVH unmutated, 31 patients (36%) had a high ZAP-70 expression, 17 patients (20%) were CD38 positive (>30%). Fluorescence in situ hybridization (FISH) data are available in 61/87 cases; the most frequent abnormality was del(13)(q14) (29 pts 33%), followed by trisomy 12 (5 pts, 6%), del(17p13) (4 pts 5%) and del(11q22.3) (2 pts 2%), 21 cases (24%) were normal. Cytogenetic abnormalities were clustered in 3 risk groups [i.e. low (del(13q14) and normal), intermediate (trisomy 12) and high risk (del(11q22) and del(17p13)] as suggested by others. Results. Considering total body CT scan, 22 out of 83 analyzed (25%) patients were converted into Binet stage B. Notably, 64% were male, LDH was elevated in 18% of cases and B2-microglobulin in 18%, 41% were IgVH unmutated, 27% had a high ZAP-70 expression, 27% were CD38 positive, 4,5% showed a high-risk FISH. Both main clinical characteristics and biological prognostic markers failed to correlate with a more advanced stage. In fact, no statistically different distribution of gender, age, LDH and b2-microglobulin, such as IgVH mutational status, CD38 and ZAP-70 expression and cytogenetic abnormalities were observed between Binet A cases and Binet B. According the Rai classification 14/83 (17%) low risk patients became at intermediate risk with the integration of total body CT scan. Also this subset of patients did not show a statistically different expression of all prognostic markers, but a higher rate of cases with elevated B2-microglobulin (p=0.003), than patients at low risk. Finally, total body CT scan allowed to early individuate a second neoplasia in 2 cases (lung cancer 1 pt, renal cell carcinoma 1 pt). Conclusions. In line with literature information, our preliminary data indicate that the integration of total body CT scans in the clinical staging allowed to individuate among Binet A CLL cases on clinical grounds 25% of cases with a more advanced stage. Although a more advanced stage did not correlate with both clinical and biological variables reflecting bad prognosis. A longer follow-up will allow to demonstrate whether the inclusion of total body CT scan in the initial work-up of patients with early-stage on clinical grounds provide relevant prognostic information.

2009 - New incidence and mortality data. 2003-2005 [Articolo su rivista]
Crocetti E, AIRTUM Working G. r. o. u. p.; Buzzoni C., Collaborators:Serraino D; Vicario, G; Angelin, T; Bessega, G; Bidoli, E; Brunetti, D; de Dottori, M; Forgiarini, O; French, S; Stanta, G; Zaina, L; Zanier, L; Zambon, P; Baracco, M; Bovo, E; Dal Cin, A; Fiore, Ar; Greco, A; Guzzinati, S; Monetti, D; Rosano, A; Stocco, Cf; Tognazzo, S; Egarter Vigl, E; Bellù, F; Vittadello, F; Bulatko, A; Lüthy, M; Facchinelli, G; De Valiere, E; Tschugguel, B; Dorfmann, H; Giacomin, A; Vercellino, Pc; Andreone, S; Ferretti, S; Marzola, L; Migliari, E; Carletti, N; Nenci, I; Vitarelli, S; Antonini, S; Federico, Massimo; Artioli, Me; Cirilli, C; Fracca, A; Rashid, I; Valla, K; De Lisi, V; Sgargi, P; Bozzani, F; Donato, A; Iannelli, A; Mari, C; Senatore, G; Zevola, A; Abbamonte, B; Alfano, Ia; Annunziato, L; Barone, S; Ferrante, A; Budroni, M; Cesaraccio, R; Pirino, D; Sechi, O; Piras, D; Sechi, A; Oggiano, M; Piffer, S; Franchini, S; Gentilini, Ma; Battisti, L; Cappelletti, M; Falcini, F; Amadori, D; Balducci, C; Benericetti, E; Bucchi, L; Caprara, L; Colamartini, A; Cordaro, C; Desiderio, F; Fabbri, C; Foca, F; Giorgetti, S; Montanari, E; Naldi, S; Nannini, R; Ravaioli, A; Ravegnani, M; Rinaldi, E; Salvatore, S; Serafini, M; Vattiato, R; Vitali, B; Pannozzo, F; Busco, S; Natali, M; Ramazzotti, V; Macci, L; Bugliarello, E; Bernazza, E; Tamburo, L; Rossi, M; Curatella, S; Sperduti, I; Fusco, M; Bellatalla, C; Fusco, M; Panico, M; Perrotta, C; Vassante, B; Crosignani, P; Tagliabue, G; Contiero, P; Fabiano, S; Maghini, A; Tittarelli, A; Codazzi, T; Frassoldi, E; Costa, E; Nobile, S; Vigano, C; Berrino, F; Mangone, L; Pezzarossi, A; Pellegri, C; Caroli, S; Valentini, M; Cavuto, S; De Felice, E; Vercelli, M; Orengo, Ma; Casella, C; Marani, E; Puppo, A; Celesia, Mv; Cogno, R; Grondona, Am; Giachero, G; Manenti, S; Quaglia, A; Garrone, E; Paci, E; Crocetti, E; Buzzoni, C; Caldarella, A; Corbinelli, A; Dainelli, G; Guadagni, M; Intrieri, T; Manneschi, G; Miccinesi, G; Nemcova, L; Sacchettini, C; Giusti, F; La Rosa, F; Stracci, F; Petrinelli, Am; Costarelli, D; Cassetti, T; Scheibel, M; Romagnoli, C; Mastrandrea, V; Zanetti, R; Rosso, S; Patriarca, S; Vicari, P; Sobrato, I; Gilardi, F; Maglietta, G; Gallesio, L; Tumino, R; Cilia, S; La Rosa, Mg; Cascone, G; Cianciolo, G; Frasca, G; Giurdanella, Mc; Martorana, C; Morana, G; Nicita, C; Rollo, P; Ruggeri, Mg; Sigona, A; Spata, E; Vacirca, S; Bisanti, L; Autelitano, M; Ghilardi, S; Bovini, A; Giubelli, C; Tessandori, R; Ardemagni, G; Traina, A; Candela, P; Contrino, Ml; Tisano, F; Madeddu, A; Ponz de Leon, M; di Gregorio, C; Roncucci, Luca; Benfatti, P; Losi, Lorena; Ponti, Giovanni; Pedroni, Monica; Rossi, G; Roncari, B; Maffei, S; Menigatti, M; Rossi, F; Pecone, L; Domati, F; Pastore, G; Magnani, C; Terracini, B; Alessi, D; Dal masso, P; Dama, E; Macerata, V; Maule, M; Mosso, Ml; Nonnato, M; Zuccolo, L; Merletti, F; Pannelli, F; Pascucci, C; Gennaro, V; Benfatto, L; Bianchelli, M; Lazzarotto, A; Viarengo, P.
abstract

In Italy cancer incidence and mortality rates are similar to those in northern European countries and in USA among males, but they are still lower than women.

2009 - Pattern of cancer risk in person with AIDS in Italy inthe HAART era [Articolo su rivista]
Dal Maso, L.; Polesel, J.; Serraino, D.; Lise, M.; Piselli, P.; Falcini, F.; Russo, A.; Intrieri, T.; Vercelli, M.; Zambon, P.; Tagliabue, C.; Zanetti, R.; Federico, Massimo; Limina, R. M.; Mangone, L.; De Lisi, V.; Stracci, F.; Ferretti, S.; Piffer, S.; Budroni, M.; Donato, A.; Giacomin, A.; Bellù, F.; Fusco, M.; Madeddu, A.; Vitarelli, S.; Tessandori, R.; Tumino, R.; Suligoi, B.; Franceschi, S.; for the, Cancer; AIDS Registries Linkage, Study
abstract

A record-linkage study was carried out between the Italian AIDS Registry and 24 Italian cancer registries to compare cancer excess among persons with HIV/AIDS (PWHA) before and after the introduction of highly active antiretroviral therapy (HAART) in 1996. Standardised incidence ratios (SIR) were computed in 21951 AIDS cases aged 16-69 years reported between 1986 and 2005. Of 101 669 person-years available, 45 026 were after 1996. SIR for Kaposi sarcoma (KS) and non-Hodgkin lymphoma greatly decreased in 1997-2004 compared with 1986-1996, but high SIRs for KS persisted in the increasingly large fraction of PWHA who had an interval of <1 year between first HIV-positive test and AIDS diagnosis. A significant excess of liver cancer (SIR=6.4) emerged in 1997-2004, whereas the SIRs for cancer of the cervix (41.5), anus (44.0), lung (4.1), brain (3.2), skin (non-melanoma, 1.8), Hodgkin lymphoma (20.7), myeloma (3.9), and non-AIDS-defining cancers (2.2) were similarly elevated in the two periods. The excess of some potentially preventable cancers in PWHA suggests that HAART use must be accompanied by cancer-prevention strategies, notably antismoking and cervical cancer screening programmes. Improvements in the timely identification of HIV-positive individuals are also a priority in Italy to avoid the adverse consequences of delayed HAART use.

2009 - Prognosis factors in low-grade Non-Hodgkin's lymphomas [Articolo su rivista]
Federico, Massimo; Molica, S.; Bellei, Monica; Luminari, Stefano
abstract

Low-grade non-Hodgkin lymphomas were once considered as a heterogenous group of lymphomas characterized by an indolent clinical course. Today, low-grade non-Hodgkin lymphomas are classified as a group of 10 distinct entities, each characterized by unique clinicobiologic features. Follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma, and marginal zone lymphoma are the most-investigated subtypes. Several studies have been performed to identify prognostic factors specific for each subtype in an effort to help clinicians in treatment decisions. The field of biologically specific associated parameters holds great potential but requires more research and work to produce translational results.

2009 - Prognostic tools in follicular lymphomas [Articolo su rivista]
Luminari, Stefano; Cox, M. C.; Montanini, Antonella; Federico, Massimo
abstract

Despite significant improvements in treatment modalities over the 10 years, the clinical course of patients with follicular lymphoma (FL) remains heterogeneous. Thus, prognostic indexes are still required to direct treatment choices and for the design of clinical trials. Investigators have conducted a variety of studies aimed at integrated assessment of biological and clinical features in order to identify novel prognostic factors and scoring systems. Genetic studies focused on tumor cells and the tumor microenvironment represent a step forward in understanding the biology of FL and are likely to provide new prognostic tools for future clinical use. Several prognostic factors have been identified and are currently used in combination to establish prognostic scores and to support therapeutic decisions. The FL International Prognostic Index (FLIPI) is currently used for defining individual risk of death. More recently, FLIPI2 was developed by the same group that built FLIPI as a new model for prognostic definition of patients with FL. The model was defined using prospectively collected data from patients who also received the monoclonal therapeutic antibody rituximab and stratifies patients into three risk categories for disease progression. Since many biological factors are not yet clinically validated or easily assessable, clinical data still represent the major source of prognostic information. The progressive development of new and more effective therapies for the treatment of FL makes the study of prognosis a dynamic and evolving area of clinical research.

2009 - Response-guided ABVD chemotherapy plus involved-field radiation therapy for intermediate-stage Hodgkin lymphoma in the pre-positron emission tomography era: a Gruppo Italiano Studio Linfomi (GISL) prospective trial. [Articolo su rivista]
E., Iannitto; V., Minardi; P. G., Gobbi; G., Calvaruso; C., Tripodo; Marcheselli, Luigi; Luminari, Stefano; F., Merli; L., Baldini; C., Stelitano; V., Callea; M., Petrini; F., Angrilli; G., Quarta; D., Vallisa; S., Molica; E., Liardo; G., Polimeno; M., Brugiatelli; Federico, Massimo
abstract

PURPOSE: In the pre-positron emission tomography era, the Gruppo Italiano Studio Linfomi (GISL) investigated the feasibility and efficacy of a treatment based on a response-tailored number of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) courses in 218 intermediate-stage Hodgkin lymphoma patients. PATIENTS AND METHODS: Patients with stage I/II showing at least one adverse prognostic factor and stage IIIA without adverse prognostic factors were recruited. Treatment included a first step of 3 ABVD courses, followed by an early-restaging. Patients in CR/CRu received 1 additional ABVD cycle, patients in PR received 3 more ABVD, and nonresponder patients went off study. Involved-field radiation therapy (RT) was recommended on chemotherapy completion. RESULTS: The median age was 30 years (range, 15-68 years) and 131 patients (61\%) were female. Seven percent of patients were in stage I, 78\% in stage II, and 15\% in stage III; B-symptoms, bulky tumor and erythrocyte sedimentation rate > 30 were recorded in 20\%, 26\%, and 43\% of cases, respectively. The CR/CRu rate was 62\% at early restaging, 72\% at the end of chemotherapy, and 95\% following RT. With a median follow-up of 74 months (range, 6-193 months), 7-year overall survival, relapse-free survival, and freedom from treatment failure were 91.8\% (95\% CI, 86\%-95.5\%), 89.2\% (95\% CI, 82.8\%-93.3\%), and 81.8\% (95\% CI, 75.2\%-86.7\%), respectively. Patients in CR/CRu on early restaging, receiving 4 ABVD, had an excellent outcome with 7-year RFS and cause-specific survival similar to those of the late responders treated with 6 ABVD (RFS, 87.5\% vs. 90.5\% and CSS, 96.6\% vs. 92.7\%, respectively). CONCLUSION: The response-guided ABVD program we report, based on standard clinical staging procedures, proved to be feasible and safe in patients with intermediate-stage Hodgkin lymphoma.

2009 - Second Malignancy After Treatment for Non-Hodgkin Lymphoma: a Systematic Review and a Meta-Analysis of Population-Based and Cohort Studies [Abstract in Rivista]
Sacchi, Stefano; Pirani, Monica; Marcheselli, Luigi; Marcheselli, Raffaella; Bari, Alessia; C., Cirilli; Federico, Massimo
abstract

Background: The risk of second malignancy in non-Hodgkin lymphoma (NHL) survivors have been described in several studies, but the available evidence have yielded conflicting results. Thus, we performed a systematic review and a meta-analysis on population-based and cohort studies to provide a quantitative assessment of the available evidence on the risk of secondary occurrence of cancer after treatment for NHL. Primary aims of our research were to evaluate the pooled Relative Risk (RR) of second cancer for overall malignancies and for every cancer.Methods: A Medline search from 1985 to 2008 was conducted for identification of relevant observational studies that provide estimates of RR, as measured by standardized incidence ratios (SIR) that is the observed-expected ratio of second malignancy appearing during follow up of NHL. The reference lists of identified articles were inspected to identify additional papers. Criteria for including studies in the meta-analysis were: a) studies on naïve patients with any stage of NHL, b) studies reporting measure of SIR or data allowing such outcome to be derived and c) English language. The article included, had to have been published in peer-reviewed literature. We did not exclude papers on the base of therapeutic regimens. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Pooled RR and 95% confidence interval (CI) were calculated using random effect models. Tests on heterogeneity and sensitivity analysis was conducted. Also, the publication bias was evaluated. Results: Eleven papers meet the inclusion criteria reporting RRs for all malignancies. These studies included 223,593 patients affected by NHL of which 14,952 presented a second cancer. RRs ranged from 0.93-1.90 and the meta-RR for second malignancy was 1.24 (95%CI: 1.11-1.39). The analysis on solid tumours, excluding haematological malignancies, based on seven studies did not show a significantly higher risk for secondary cancer: the meta-RR was 1.06 (95%CI: 0.84-1.34). However, some kind of cancer showed a statistically significant excess of risk, as lung cancer (meta-RR on nine studies: 1.46 95%CI: 1.33-1.59) and bladder cancer (meta-RR on eight studies: 1.42 95%CI: 1.33-1.51). Prostate (meta-RR on ten studies: 1.08 95%CI: 0.93-1.24) and breast cancer (meta-RR on eleven studies: 0.99 95%CI: 0.83-1.19) has demonstrated no evidence of association with NHL therapy. Moreover, we found a higher risk of developing Hodgkin lymphoma and myeloid leukemia (respectively meta-RR on seven studies: 6.44 95%CI: 5.59-11.55 and meta-RR on five studies: 7.81 95%CI: 2.59-24.46). Regarding leukemia, however we have to consider that they include either acute or chronic leukemia and sometime could also include higher risk myelodisplastic syndrome . No evidence of publication bias was observed. Conclusion: Although there exist a number of paper on this topic, until now there are not been attempts to perform a meta-analysis on RR of second malignancies after treatment for NHL. Indeed comparative analysis on the incidence of second cancer presents several issues, including the heterogeneity of NHL, the source of data, the time during which the study was performed, the different schedule of chemotherapy, the dosage of radiotherapy used in the different period of time and the length of follow-up. Although these problems could reduce the accuracy of the meta-analysis, our results indicate that NHL treatment is associated with a significantly higher risk of second malignancy, in particular for some specific cancer like lung and bladder and same haematological malignancies as Hodgkin lymphoma and myeloid leukemia.Finally, we think that it is important to determine by meta-analysis the incidence of each second cancer in survivor of NHL as for some malignancies screening test could be performed and early diagnosis could be made.

2009 - T-cell project: an international, longitudinal, observational study of patients with aggressive peripheral T-cell lymphoma [Articolo su rivista]
Federico, Massimo; Bellei, Monica; Pesce, Emanuela Anna; Zucca, E.; Pileri, S.; Montoto, S.; Weisemburger, D. D.; Ruediger, T.; Ko, Y. H.; Liang, R.; Zinzani, P. L.; Connors, J. M.; Horwitz, S. M.; Polliack, A.; Vose, J. M.
abstract

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of neoplasms that are derived from post-thymic lymphoid cells at different stages of differentiation and with different morphological patterns, phenotypes, and clinical presentations. PTCLs are highly diverse, reflecting the diverse cells from which they can originate and are currently sub-classified using World Health Organization (WHO) 2008 criteria. Peripheral T-Cell Lymphomas account for 5%-10% of all lymphoproliferative disorders in the Western hemisphere, with an overall incidence of 0.5-2 per 100,000 individuals per year, and have a striking epidemiological distribution, with higher incidence in Asia. The clinical features of PTCL are extremely heterogeneous. PTCLs express even more clinical diversity than B-cell non-Hodgkin's lymphomas, and there is a close, though not absolute, relationship between some unusual clinical features and certain histological subtypes.

2009 - The early- and intermediate- term toxicity to primitive hematopoietic progenitor cells of three chemotherapy regimens for advanced Hodgkin lymphoma [Articolo su rivista]
Gobbi, P. G.; Rosti, V.; Valentino, F.; Bonetti, E.; Merli, F.; Stelitano, C.; Dondi, Alessandra; Quarta, G.; Falorio, S.; Federico, Massimo
abstract

BACKGROUND: The early stem cell reservoir can be impaired by a few cycles of chemotherapy, and this impairment might persist after normalization of peripheral cytopenias. We directly evaluated the damage caused to marrow progenitor cells by 3 currently used chemotherapy regimens for advanced Hodgkin lymphoma. PATIENTS AND METHODS: Bone marrow samples from 37 patients randomly treated according to either the ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine), COPPEBVCAD (cyclophosphamide/vincristine/procarbazine/prednisone/epirubicin/bleomycin/vinblastine/lomustine/melphalan/ vindesine), or BEACOPP (bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone) schedule were taken a few days before the start of chemotherapy and 30 days and 6 months after its completion. Samples were cryopreserved, thawed in a single session, and cultured for 5 weeks to detect long-term culture-initiating cells (LTC-IC). RESULTS: On the basis of the numbers of LTC-IC detected and of their relative variations, the ABVD regimen was associated with the least early reduction and the best late recovery of LTC-IC. COPPEBVCAD produced the greatest early damage, but recovery was nearly complete by 6 months. BEACOPP caused intermediate early toxicity that persisted at 6 months. CONCLUSION: The different late toxicity exerted on marrow progenitors by these chemotherapy regimens should be carefully weighed in relation to both the expected early response rate and subsequent possibility of rescue in the case of first treatment failure.

2009 - The GISL HD2000 trial comparing ABVD with BEACOPP and with CEC as initial treatment of patients with advanced Hodgkin lymphoma [Articolo su rivista]
Luminari, S.; Federico, M.
abstract

2009 - Variation in "Standard care" for breast cancer across Europe: a EUROCARE-3 high resolution study [Articolo su rivista]
Allemani, C.; Storm, H.; Voogd, A. C.; Holli, K.; Izarzugaza, I.; Torrella Ramos, A.; Bielska Lasota, M.; Aareleid, T.; Ardanaz, E.; Colonna, M.; Crocetti, E.; Danzon, A.; Federico, Massimo; Garau, I.; Grosclaude, P.; Hèdelin, G.; Martinez Garcia, C.; Peignaux, K.; Plesko, I.; Primic Zakelj, M.; Rachtan, J.; Tagliabue, G.; Tumino, R.; Traina, A.; Tryggvadottir, L.; Vercelli, M.; Sant, M.
abstract

On a population-based sample of 13,500 European breast cancer patients mostly diagnosed in 1996-1998 and archived by 26 cancer registries, we used logistic regression to estimate odds of conservative surgery plus radiotherapy (BCS+RT) versus other surgery, in T1N0M0 cases by country, adjusted for age and tumour size. We also examined: BCS+RT in relation to total national expenditure on health (TNEH); chemotherapy use in N+ patients; tamoxifen use in oestrogen-positive patients; and whether 10 nodes were examined in lymphadenectomies. Stage, diagnostic examinations and treatments were obtained from clinical records. T1N0M0 cases were 33.0% of the total. 55.0% of T1N0M0 received BCS+RT, range 9.0% (Estonia) to 78.0% (France). Compared to France, odds of BCS+RT were lower in all other countries, even after adjusting for covariates. Women of 70-99years had 67% lower odds of BCS+RT than women of 15-39years. BCS+RT was 20% in low TNEH, 58% in medium TNEH, and 64% in high TNEH countries. Chemotherapy was given to 63.0% of N+ and 90.7% of premenopausal N+ (15-49years), with marked variation by country, mainly in post-menopause (50-99years). Hormonal therapy was given to 55.5% of oestrogen-positive cases, 44.6% at 15-49years and 58.8% at 50-99years; with marked variation across countries especially in premenopause. The variation in breast cancer care across Europe prior to the development of European guidelines was striking; older women received BCS+RT much less than younger women; and adherence to 'standard care' varied even among countries with medium/high TNEH, suggesting sub-optimal resource allocation. Copyright © 2010 Elsevier Ltd. All rights reserved.

2008 - A multicenter retrospective clinical study of CD5/CD10-negative chronic B cell leukemias. [Articolo su rivista]
Goldaniga, M; Ferrario, A; Cortelazzo, S; Guffanti, A; Pavone, E; Ambrosetti, A; Marcheselli, Luigi; Rossi, F; Luminari, Stefano; Rossi, A; Cro, L; Federico, Massimo; LAMBERTENGHI DELILIERS, G; Baldini, L.
abstract

CD5-negative chronic B cell lymphoproliferative disorders in leukemic phase (B-CLPD) are heterogeneous and relatively uncommon pathologies that often lack a histopathological definition because of the absence of accessible pathological tissue. We describe the clinical features and evolution-related variables of 156 patients with CD5/CD10-negative B-CLPD (median age 66 years, range 25-86). The median follow-up was 51 months (range 6-216), and overall 3- and 5-year survival was respectively 87 and 76%; 50 patients needed therapy at diagnosis, 56 during follow-up, and 50 remained untreated until the last control. A combined clinical, histological, cytomorphological, immunophenotypical, and cytogenetic diagnostic approach allowed the complete classification of only a minority of patients as being affected by splenic marginal zone or lymphoplasmacytic lymphoma; the majority of cases remained unclassifiable. Multivariate analysis showed that the clinicohematological variables adversely related to overall survival were serum LDH levels and age, whereas high serum LDH levels, hemoglobin levels of &lt;11 g/dl, and splenomegaly related to treatment-free time (in "wait and see" cases); only splenomegaly related to time to progression (in treated patients). In conclusion, our retrospective study describes the clinical features and variables related to evolution in a large group of patients with CD5/CD10-negative chronic B-cell lymphoid leukemias and underlines the fact that a probable lymphoplasmacytic or marginal zone normal cell origin can be supposed in such leukemic forms, but never surely demonstrated.

2008 - ABVD plus radiotherapy versus EVE plus radiotherapy in unfavorable stage IA and IIA Hodgkin's lymphoma: results from an Intergruppo Italiano Linfomi randomized study. [Articolo su rivista]
Pavone, V; Ricardi, U; Luminari, Stefano; Gobbi, P; Federico, Massimo; Baldini, L; Iannitto, E; Ucci, G; Marcheselli, Luigi; Orsucci, L; Angelucci, E; Liberati, M; Gavarotti, P; Levis, A; INTERGRUPPO ITALIANO LINFOMI, Iil
abstract

BACKGROUND: In 1997, the Intergruppo Italiano Linfomi started a randomized trial to evaluate, in unfavorable stage IA and IIA Hodgkin's lymphoma (HL) patients, the efficacy and toxicity of the low toxic epirubicin, vinblastine and etoposide (EVE) regimen followed by involved field radiotherapy in comparison to the gold standard doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) regimen followed by the same radiotherapy program. PATIENTS AND METHODS: Patients should be younger than 65 years with unfavorable stage IA and IIA HL (i.e. stage IA or IIA with bulky disease and/or subdiaphragmatic disease, erythrocyte sedimentation rate higher than 40, extranodal (E) involvement, hilar involvement and more than three involved lymph node areas). RESULTS: Ninety-two patients were allocated to the ABVD arm and 89 to the EVE arm. Complete remission (CR) rates at the end of treatment program [chemotherapy (CT) + RT] were 93% and 92% for ABVD and EVE arms, respectively (P = NS). The 5-year relapse-free survival (RFS) rate was 95% for ABVD and 78% for EVE (P < 0.05). As a consequence of the different relapse rate, the 5-year failure-free survival (FFS) rate was significantly better for ABVD (90%) than for EVE (73%) arm (P < 0.05). No differences in terms of overall survival (OS) were observed for the two study arms. CONCLUSIONS: In unfavorable stage IA and IIA HL patients, no differences were observed between ABVD and EVE arms in terms of CR rate and OS. EVE CT, however, was significantly worse than ABVD in terms of RFS and FFS and cannot be recommended as initial treatment for HL.

2008 - Estimating survival in newly diagnosed cancer patients: use of computer simulations to evaluate performances of different approaches in a wide range of scenarios. [Articolo su rivista]
Rashid, I; Marcheselli, Luigi; Federico, Massimo
abstract

Many empirical studies have proven the usefulness of period analysis in providing more up-to-date estimates of cancer patient survival than cohort-based methods. The aim of this paper is to provide a non-empirical evaluation of several survival approaches over a comprehensive range of scenarios using computer simulations. The simulation model included the following input parameters: number of annual patients, length of survival calculation, number of years of diagnosis, prognosis of cancer, follow-up period, and two additional parameters for modeling assumption on incidence and survival trends. The current study also introduced alternative cohort- and period-based approaches in addition to more traditional methods. Simulations showed that the choice of an appropriate survival approach is strongly dependent on the given scenario: period analysis was effective only for a limited number of circumstances, while alternative approaches appeared to be suitable for more realistic situations, when the follow-up period is different from the incidence period. The results of simulations could be useful for a quick identification of the most appropriate approach when estimating up-to-date cancer survival rates.

2008 - I tumori in provincia di Lecce nel 2003 [Monografia/Trattato scientifico]
Melcarne, A.; Rashid, I.; Federico, Massimo
abstract

Monografia sui dati di incidenza e sopravvivenza dei tumori nella provincia di Lecce.

2008 - I tumori in provincia di Salerno 2002-2003 [Monografia/Trattato scientifico]
Donato, A.; Federico, Massimo; Apicella, A. M.
abstract

Monografia sui dati di incidenza e sopravvivenza dei tumori nella provincia di Salerno.

2008 - IMPACT Working Group: effectiveness of service screening: a case-control study to assess breast cancer mortalità reduction. [Articolo su rivista]
Puliti, D; Miccinesi, G; Collina, N; DE LISI, N; Federico, Massimo; Ferretti, S; Finarelli, Ac; Foca, F; Mangone, L; Naldoni, C; Putrella, M; Ponti, A; Segnan, N; Sigona, A; Zarcone, M; Zorzi, M; Zappa, M; Paci, E.
abstract

The aim of this study was the evaluation of the impact of service screening programmes on breast cancer mortality in five regions of Italy. We conducted a matched case–control study with four controls for each case. Cases were defined as breast cancer deaths occurred not later than 31 December 2002. Controls were sampled from the local municipality list and matched by date of birth. Screening histories were assessed by the local, computerised, screening database and subjects were classified as either invited or not-yet-invited and as either screened or unscreened. There were a total of 1750 breast cancer deaths within the 50 to 74-year-old breast cancer cases and a total of 7000 controls. The logistic conditional estimate of the cumulative odds ratios comparing invited with not-yet-invited women was 0.75 (95% CI: 0.62–0.92). Restricting the analyses to invited women, the odds ratio of screened to never-respondent women corrected for self-selection bias was 0.55 (95% CI: 0.36–0.85). The introduction of breast cancer screening programmes in Italy is associated with a reduction in breast cancer mortality attributable to the additional impact of service screening over and above the background access to mammography.

2008 - INCIDENCE AND SURVIVAL OF MYELOID MALIGNANCIES IN 1102 PATIENTS IN PROVINCE OF MODENA, NORTHERN ITALY [Abstract in Rivista]
Bari, Alessia; I., Rashid; Marcheselli, Raffaella; G., Bonacorsi; G., Leonardi; Marasca, Roberto; P., Zucchini; F., Giacobbi; Federico, Massimo; Sacchi, Stefano
abstract

Background. Making a research on incidence and survival of myeloid malignancies we realised that few well documented population-based studies exist on epidemiology of myelodisplastic syndromes (MDS) and chronic myeloproliferative disorders (CMPD). Aims. The goal of our population-based study was to add and improve information about epidemiology of myeloid malignancies. In collaboration with Modena Cancer Registry (MCR) we focalized our attention above all on those haematological malignancies which until few years ago were not recorded in cancer registry because not considered neoplastic. Methods. We examined all new cases of AML, MDS, chronic myeloid leukemia (CML) and CMPD diagnosed in the Province of Modena (population 633.993 at 2001 Census) between 1997 and 2006. Death certificate, cytology and histology report, both local and national reports of hospital admission, ICD-9 code reported in medical records were used as sources for identifying new cases and their outcome. All cases were checked and validated by a haematologist (AB) and a pathologist (GB) by a review of the original pathology report. Clinical and follow-up data were retrieved by active search of discharge letters, review of hospital records and interview of general practitioners. Information on vital status was achieved from official population registries. Age-Standardized Rates (ASR) were calculated according to the World Standard population (Doll et al., 1966). The dates of diagnosis and death or the closing date of study (January 2008) were used to estimate survival. Relative survival was calculated according to Hakulinen approach. Results. A total of 1102 myeloid malignancies were identified of which 304 AML, 238 MDS, 29 CMML, 417 CMPD and 114 CML. The ASR (per 100,000 people) was calculated as 2.4 for AML, 1.3 for MDS, 0.1 for CMML, 3.2 for CMPD and 1 for CML. When reported to European Standard Population the incidence was 3.2 for AML, 2 for MDS, 0.2 for CMML, 4.4 for CMPD and 1.3 for CML. Compared with reports from other European countries our series seems to be characterized by a higher incidence of CMPD, by a lower incidence of MDS and similar incidence of AML. After a median follow-up of 55 months (range 7-128) the median survival for AML was 5 months, for MDS 23 months, for CMML 26 months; median survival for CMPD and CML was not reached. Relevant differences were observed among median survival of different subtypes of AML, MDS and CMPD. The 5-year relative survival for AML was 20% (for AML M3 74%), for MDS 27%, for CMML 23%, for CMPD 87% and for CML 53% (for CML Ph1+ 80%). Conclusions. Our population-based study provides the first analysis of incidence, survival and subtypes distribution of myeloid malignancies performed in Northern Italy. Our results may contribute to better understand the true epidemiology of these diseases, avoiding bias related to referral pattern to myeloid malignancy registries and due to recruiting patients into clinical trials. In the time of emerging innovative treatments the availability of precise epidemiological data could help clinicians in choosing the most appropriate and cost-effectiveness treatment.

2008 - Incidence of primary liver cancer in Italy between 1988 and 2002: an age-period-cohort analysis. [Articolo su rivista]
DAL MASO, L; Lise, M; Zambon, P; Crocetti, E; Serraino, D; Ricceri, F; Vercelli, M; DE LISI, V; Tagliabue, G; Federico, Massimo; Falcini, F; Cassetti, T; Donato, A; Fusco, M; Budroni, M; Ferretti, S; Tumino, R; Piffer, S; Bellu', F; Mangone, L; Giacomin, A; Vitarelli, S; Franceschi, S.
abstract

We conducted in Italy a study to evaluate trends of primary liver cancer (PLC) and to disentangle the period from birth-cohort effects on PLC incidence. Cases aged<80 years and diagnosed between 1988 and 2002 in 20 areas covered by population-based Cancer Registries were included. Age-standardised incidence rates and age-period-cohort effects were estimated. In 1998-2002, incidence rates of PLC were 21.1/100,000 men and 6.0/100,000 women. In both genders, incidence rates increased slightly between 1988-1992 and 1993-1997 but did not rise thereafter. Amongst men, PLC risk increased in every cohort born after 1913 and the rise became steeper for cohorts born in 1948. In women, an upward trend appeared only in the cohorts born after 1953. Incidence of PLC over the last two decades in Italy did not substantially change but huge geographical variability emerged, mainly due to different times and modalities of spread of hepatitis C virus.

2008 - Indications for breast magnetic resonance imaging. Consensus Document "Attualità in Senologia", Florence 2007 [Articolo su rivista]
Sardanelli, F; Giuseppetti, Gm; Canavese, G; Cataliotti, L; Corcione, S; Cossu, E; Federico, Massimo; Marotti, L; Martincich, L; Panizza, P; Podo, F; ROSSELLI DEL TURCO, M; Zuiani, C; Alfano, C; Bazzocchi, M; Belli, P; Bianchi, S; Cilotti, A; Calabrese, M; Carbonaro, L; Cortesi, L; DI MAGGIO, C; DEL MASCHIO, A; Esseridou, A; Fausto, A; Gennaro, M; Girometti, R; Ienzi, R; Luini, A; Manoukian, S; Morassutt, S; Morrone, D; Nori, J; Orlacchio, A; Pane, F; Panzarola, P; Ponzone, R; Simonetti, G; Torricelli, Pietro; Valeri, G.
abstract

The clinical use of breast magnetic resonance (MR) imaging is increasing, especially for applications requiring paramagnetic contrast-agent injection. This document presents a synthetic list of acceptable indications with potential advantages for women according to evidence from the literature and the expert opinion of the panel that developed this statement. We generally recommend that breast MR imaging be performed in centres with experience in conventional breast imaging [mammography and ultrasonography (US)] and needle-biopsy procedures (under stereotactic or US guidance) as well as in breast MR imaging and second-look US for findings not revealed by conventional imaging performed before MR imaging. In our opinion, there is no evidence in favour of breast MR imaging as a diagnostic tool to characterise equivocal findings at conventional imaging when needle-biopsy procedures can be performed, nor for the study of asymptomatic, non-high-risk women with negative conventional imaging. After a description of technical and methodological requirements, we define the indications and limitations of breast MR imaging for surveillance of high-risk women, local staging before surgery, evaluation of the effect of neoadjuvant chemotherapy, breast previously treated for carcinoma, carcinoma of unknown primary syndrome, nipple discharge and breast implants.

2008 - Second malignancies after treatment of diffuse large B-cell non-Hodgkin's lymphoma: a GISL cohort study [Articolo su rivista]
Sacchi, Stefano; Marcheselli, Luigi; Bari, Alessia; Marcheselli, Raffaella; Pozzi, Samantha; Gobbi, Pg; Angrilli, F; Brugiatelli, M; Musto, P; Federico, Massimo
abstract

BACKGROUND: Improved treatment has increased the life expectancy of patients with non-Hodgkin's lymphoma, but few studies have addressed the issue of second cancer in patients treated for diffuse large B-cell lymphoma. The aims of this study were to determine the incidence and time free of second cancers in this subset of patients. DESIGN AND METHODS: We evaluated a cohort of 1280 patients with diffuse large B-cell lymphoma who were first treated between 1988 and 2003. We utilized the central database of the Gruppo Italiano Studio Linfomi, which includes data on demographics, clinical characteristics, laboratory parameters, treatment and follow-up of all patients with non-Hodgkin's lymphoma enrolled in clinical trials. RESULTS: After a median follow-up of 51 months, 48 patients had developed a second cancer: 13 hematologic malignancies and 35 solid tumors. The overall standardized incidence ratio in our cohort (with a median age of 58 years) matched that of the general Italian population. The incidence ratio of second tumors was age related, and the age groups 20-39 and 40-59 years showed an increased risk. Overall, the cumulative incidence of second cancer was 8.2% at 15 years. A multivariate analysis showed that older age at the time of diagnosis of lymphoma had a negative influence on the time free of second tumors. CONCLUSIONS: In our cohort, only young patients showed an increased incidence ratio of second malignancies, while the incidence ratio in patients aged over 59 years matched the incidence in the Italian general population. Demographics, baseline characteristics, laboratory parameters and treatment modalities did not have any significant impact on the incidence ratio of a second cancer.

2008 - The oral protein-kinase C beta inhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines [Articolo su rivista]
Antonino, Neri; Marmiroli, Sandra; Pierfrancesco, Tassone; Luigia, Lombardi; Lucia, Nobili; Donata, Verdelli; Monica, Civallero; Maria, Cosenza; Bertacchini, Jessika; Federico, Massimo; DE POL, Anto; Giorgio Lambertenghi, Deliliers; Sacchi, Stefano
abstract

Deregulation of the protein kinase C (PKC) signalling pathway has been implicated in tumor progression. Here we investigated the PKC inhibitor enzastaurin for its activity against multiple myeloma (MM) cells. Enzastaurin suppresses cell proliferation in a large panel of human myeloma cell lines (HMCLs), with IC50 values ranging from 1.3 to 12.5 mu M and induces apoptosis, which is prevented by the ZVAD-fmk broad caspase inhibitor. These results are consistent with decreased phosphorylation of AKT and GSK3-beta, a downstream target of the AKT pathway and a pharmacodynamic marker for enzastaurin. Furthermore, enzastaurin cytotoxicity is retained when HMCLs were cocultured with multipotent mesenchymal stromal cells. Enzastaurin has additive or synergistic cytotoxic effects with bortezomib or thalidomide. Considering the strong anti-myeloma activity of enzastaurin in vitro and in animal models and its safe toxicity profile, phase II studies in MM patients of enzastaurin alone or in combination with other drugs are warranted.

2007 - Analisi geografica dei tumori diagnosticati in provincia di Modena negli anni 2000-2005 [Monografia/Trattato scientifico]
Pirani, Monica; Rashid, I.; Cirilli, C.; Federico, Massimo
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena negli anni 2000-2005

2007 - Cancer incidence in eastern Libya: The first report from the Benghazi Cancer Registry, 2003 [Articolo su rivista]
El Mistiri, M; Verdecchia, A; Rashid, I; El Sahlit, N; El Mangush, M; Federico, Massimo
abstract

Cancer registration in Northern Africa is still limited and, until now, there have been no population-based data available for Libya. In this paper, we present the first data collected and analyzed by the Benghazi Cancer Registry. Registration was carried out by active data collection; the registry staff routinely visited all hospitals and pathological laboratories in eastern Libya (1.6 million inhabitants) and collected information from all death registration offices. A huge archive of prevalent cases was established before the 2003 data were collected. A total of 997 cases of primary cancers were registered among residents in 2003. The world age-standardized incidence rate for all sites combined (except non-melanoma skin) was 118 per 100,000 for men and 95 per 100,000 for women. The most frequently diagnosed malignancies in males were lung cancer (19%) and colorectal cancer (10%), followed by cancers of the head and neck (9%) and bladder (9%). Among females, they were breast cancer (26%), cancer of the colon and rectum (9%), uterus (7%) and non-Hodgkin lymphoma (5%). Our study provides data on cancer incidence in eastern Libya, and confirms that cancer incidence is much lower than in western countries. Moreover, observed patterns indicate that the incidence of many cancers, including those of the lung, breast, colon, rectum and bladder is quite different from previous estimates based on the data available from the neighboring countries. (c) 2006 Wiley-Liss, Inc.

2007 - Estimated and observed cancer incidence in Italy: a validation study [Articolo su rivista]
Capocaccia, R; Buzzoni, C; Grande, E; Inghelmann, R; Bellu', F; Cassetti, T; DE DOTTORI, M; Donato, A; DE LISI, V; Falcini, F; Federico, Massimo; Ferretti, S; Fusco, M; Giacomin, A; Guzzinati, S; Mangone, L; Piffer, S; Rosso, S; Sechi, O; Tagliabue, G; Tumino, R; Vervelli, M; Vitarelli, S.
abstract

AIMS AND BACKGROUND: The study aimed to validate model-based incidence estimates by means of observed incidence rates provided by Italian cancer registries, for five major cancer sites (stomach, colon and rectum, lung, breast and prostate cancers) and for all cancers together. METHODS: Recent incidence rates observed by Italian population-based cancer registries were extracted from the data base of the Italian Association of Cancer Registries. Regional estimates of incidence rates for the same cancers were obtained by the MIAMOD method. Observed and estimated crude incidence rates and incidence trends were compared for the period of diagnosis 1985-2000. Eight Italian cancer registries and seven regions were selected for the analysis since they had incidence data available during the entire selected period. RESULTS AND CONCLUSIONS: An excellent agreement between estimated and observed crude incidence rates was found for all single cancer sites, regarding absolute incidence levels and time trends. A partial exception was breast, where empirical data showed a sudden increase in the last three years of observation, perhaps due to organized screenings in some Italian regions, and not captured by statistical models. Substantial underestimation of model-based incidence rates was found for all cancers combined, where the difference tended to increase with calendar year, up to a maximum of 20% in recent years. The greatest part of the discrepancy can be attributed to multiple cancers, which were included in cancer registries statistics but were not accounted for in MIAMOD estimates.

2007 - I tumori in provincia di Modena anni 1988-2005 [Monografia/Trattato scientifico]
Federico, Massimo
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

2007 - Incidence and clinicopathologic features of gastrointestinal stromal tumors. A population-based study. [Articolo su rivista]
Mucciarini, C.; Rossi, G.; Bertolini, Federica; Valli, R.; Cirilli, C.; Rashid, I.; Marcheselli, Luigi; Luppi, G.; Federico, Massimo
abstract

BACKGROUND: Although the diagnostic criteria and pathogenesis of gastrointestinal stromal tumors (GIST) have recently been elucidated, knowledge of the epidemiology of this malignancy is still limited. This study examined the incidence of GIST in the province of Modena, including pathologic features and clinical outcome. METHODS: Gastrointestinal mesenchymal tumors identified by the Modena Cancer Registry between 1991 and 2004 were analyzed with an immunohistochemical panel that included staining for CD-117 and PDGFRalpha. Size, mitotic rate, and other pathologic parameters were recorded. Each tumor was categorized into National Institutes of Health risk categories (very low, low, intermediate, and high risk). RESULTS: One hundred twenty-four cases were classified as GIST. The age-adjusted incidence rate was 6.6 per million. Seventy-five percent of patients were symptomatic; 34% had a previous or concomitant history of cancer. High-risk features were present in 47% of cases. Seventy-eight percent were submitted to radical surgery. After complete resection, the 5-year disease-free survival rates were 94%, 92%, 100%, and 40% for patients at very low, low, intermediate, and high risk, respectively. In multivariate analysis, high risk was the main predictor of recurrence. CONCLUSION: This population-based study shows that the incidence of GIST in Northern Italy is comparable to that reported in other European countries. Survival was favorable in lower risk categories and in most of the resected cases. In our study, resected patients at very low, low, and intermediate risk had a similar outcome. Our data support the need to consider high-risk patients after complete surgical resection for treatment with the best available approach.

2007 - Incidence and outcome of chronic myeloproliferative disorders: A population-based study from a cancer registry in northern Italy [Abstract in Rivista]
Bari, Alessia; Marcheselli, Raffaella; I., Rashid; G., Bonacorsi; O., Bonanno; P., Temperani; G., Leonardi; Federico, Massimo; Sacchi, Stefano
abstract

Background Because in the past Chronic Myeloproliferative Disorders (CMPD) were not considered to be malignant conditions, cancer registries rarely recorded data on these diseases. Thus, information on incidence and outcome of CMPD in the population is limited. The aim of the present study was to better define epidemiological data of CMPD by examining all cases identified by the Modena Cancer Registry (MCR). Materials and methods We considered all cases of CMPD diagnosed in the Province of Modena (population 633.993 at 2001 Census). Cases, except Chronic Myeloid Leukemia, diagnosed from 1997 to 2005, were identified using the MCR database and the archival files of the centralized hemolymphopathological laboratory at Modena Cancer Centre according to ICD-O-3 codes 9950, 9960-64. Death certificate, cytology and histology report, both local and national reports of hospital admission, ICD-9 code reported in medical records were used as sources for identifying new CMPD cases and their outcome. All cases were checked and validated by a hematologist (A.B.) and a pathologist (G.B.) by a review of the original pathology report. Uniform diagnostic criteria were adopted, because the large majority of bone marrow aspirate and biopsy were examined by the same pathologist (G.B.). Clinical and follow-up data were retrieved by active search of discharge letters, review of hospital records and interview of general practitioners. Information on vital status was achieved from official population registries. Age standardized rates (ASR) were calculated according to the World Standard population. The dates of diagnosis and death or the closing date of study (December 2006) were used to estimate survival. Observed survival and relative survival were calculated according to Kaplan-Meier method and the Hakulinen approach, respectively. Results According to the 2001 World Health Organization (WHO) classification, a total of 380 cases of CMPD were identified. There were 155 Essential Thrombocythemia (ET) (41% of all CMPD), 114 Policythemia Vera (PV) (30%), 75 Idiopathic Myelofibrosis (20%), 2 Hypereosinophilic Syndrome/Chronic Eosinophilic Leukaemia (0.5%), 1 Chronic Neutrophilic Leukemia (0.3%) and 31 CMPD not otherwise specified (8%). The ASR of CMPD was 3.2/100,000 varying slightly (from 2.5 to 4.1/100,000) during the study period (p = 0.11); the crude incidence rate was 6.6/100,000. Median age at diagnosis was 69 years. No statistically significant differences were observed between sex regarding incidence and age at diagnosis. Overall relative survival was 97%, 89% and 88% at 1, 3 and 5 years after diagnosis, respectively. Analyzing CMPD, we observed a better survival for ET and PV in comparison with other subtypes (p = 0.01). Conclusions To our knowledge, this study is the first in Italy providing information on the incidence and outcome of CMPD using population-based data. Our results confirm that the risk of developing CMPD increases with age. The incidence of CMPD was substantially stable during the study period. Overall survival patterns reflect the well known chronic course of these diseases. As expected, we observed important differences in overall survival by WHO subtypes. We believe that the availability of precise epidemiological data, in particular those regarding outcome could help clinicians in choosing the most appropriate cost-effective treatments.

2007 - Incidence and outcome of Myelodysplastic Syndromes in province of Modena [Abstract in Rivista]
Bari, Alessia; Marcheselli, Raffaella; Ivan, Rashid; Goretta, Bonacorsi; Roberto, Marasca; Francesca, Giacobbi; Patrizia, Zucchini; Federico, Massimo; Sacchi, Stefano
abstract

Background As in the past Myelodisplastic Syndromes (MDS) were considered preneoplastic conditions, rarely data on these diseases were collected by cancer registries. Thus, there are few well documented population-based studies on the incidence and outcome of MDS. The aim of this study was to collect epidemiological data and clinical characteristics of MDS by studying all cases identified by the Modena Cancer Registry (MCR). Materials and methods We examined all cases of MDS diagnosed in the Province of Modena (population 633.993 at 2001 Census). MDS from 1997 to 2005 were identified using the MCR database and the archival files of the centralized hemolymphopathological laboratory at Modena Cancer Centre according to ICD-O-3 codes 9980,9982-87,9989. Death certificate, cytology and histology report, both local and national reports of Hospital admission, ICD-9 code reported in medical records were used as sources for identifying new MDS cases and their outcome. After collection, all cases were checked and validated by a hematologist (A.B.) and a pathologist (G.B.) by a review of the original pathology report. The large majority of bone marrow aspirate and biopsy were examined by the same pathologist (G.B.) making diagnostic criteria uniform. Clinical and follow-up data were retrieved by active search of discharge letters, review of hospital records, and interview of general practitioners. Information on vital status was achieved from official population registries. Age standardized rates (ASR) were calculated according to the World Standard population (Doll et al, 1966). The dates of diagnosis and death or the closing date of study (December 2006) were used to estimate survival. Observed survival and relative survival were calculated according to Kaplan-Meier method and the Hakulinen approach, respectively. Results A total of 205 cases of MDS were identified. The ASR of MDS was 1.2/100,000 varying slightly (from 0.9 to 1.5/100,000; p > 0.05) during the study period, and the crude incidence rate was 3.6/100,000. Median age at diagnosis was 75 years for men and 78 for women. Overall, 58% of patients aged more than 75 years, while only 1% were less than 45 years old. According to French, American and British (FAB) classification there were 35 cases (17% of all MDS) of Refractory Anemia (RA), 51 (25%) of RA with ringed sideroblasts, 73 cases (36%) of RA with excess of blasts (RAEB), 11 (5%) of RAEB in transformation, 31 (15%) of MDS not otherwise specified and 4 (2%) of other MDS. Overall the prognosis of MDS was poor, although we found statistically significant differences by clinical subtypes. In our MDS population the relative survival was 68%, 36% and 26% at 1, 3 and 5 years, respectively. Conclusions To our knowledge, this study is the first in Italy providing information on the incidence and outcome of MDS using population-based data. Our results confirm that the risk of developing MDS increases with age for both men and women. The incidence of MDS was substantially stable during the study period. Overall survival was poor reflecting the aggressiveness of these diseases and the advanced age of patients at time of diagnosis. As expected, we observed important differences in overall survival by FAB subtypes. In the last few years, innovative treatments for MDS are emerging and we believe that the availability of precise epidemiological data could help clinicians in choosing the most appropriate treatment.

2007 - Incidence, clinical characteristics and survival of malignant lymphomas: a population-based study from a cancer registry in northern Italy. [Articolo su rivista]
Luminari, Stefano; Cesaretti, Marina; I., Rashid; Mammi, Caterina; Montanini, Antonella; E., Barbolini; Bellei, Monica; E., Pennese; A., Sirotti; Marcheselli, Luigi; G., Partesotti; Bari, Alessia; Maiorana, Antonino; G., Bonacorsi; Federico, Massimo
abstract

We conducted a population-based study of peripheral lymphomas (PL) that had beendiagnosed between 1997 and 2003 in the province of Modena, Italy, with the aim ofproviding updated incidence, clinical and survival data for these cancers.We evaluated theincidence patterns and time trends of 1582 cases of PL that had been reclassified accordingto the WHO classification of hematological malignancies. Data regarding clinical characteristics,treatment and outcome were also collected for each case. The WorldAge-Standardized Rate (ASR) was calculated as 13.4, 2.2 and 3.4 per 100,000 peoplefor B-cell non-Hodgkin’s lymphoma (NHL), T-cell NHL and Hodgkin’s Lymphoma (HL),respectively, with an increase of 1.62% per year during the study period. The lymphomasubtype showing the highest incidence was found to be diffuse large B-cell lymphoma(DLBCL) with an ASR of 4.8. Compared with reports from other western countries, ourseries is characterized by a higher incidence of HL and indolent B-NHL in general, and ofCLL/SLL (ASR¼3.3) and marginal zone NHL (ASR¼1.5), in particular, and also by alower incidence of FL (ASR¼2). After a median follow-up of 54 months, the 5-year relativesurvival for the whole series was found to be 70% with a statistically significant improvementfor cases diagnosed during 2002–2003 (from 66 to 74%; p¼0.03). Survival improvementwithin the study period was also evident for patients with DLBCL, HL and T-NHL.Our study provides a comprehensive description of both the epidemiological and clinicalfeatures of PL cases in Modena and our data also reflect the major advances in thecurability of some histological subtypes of this disease. The usefulness of a populationbasedapproach to better characterizing different lymphoma subtypes is also demonstrated.

2007 - Long term results of a randomized study performed by Intergruppo Italiano Linfomi comparing Mini-CEOP vs P-VEBEC in elderly patients with diffuse large B-cell lymphoma. [Articolo su rivista]
Merli, F; Bertini, M; Luminari, Stefano; Mozzana, R; Botto, B; Liberati, Am; Baldini, L; Cabras, G; DI VITO, F; Orsucci, L; Naglieri, E; Polimeno, G; Marcheselli, Luigi; Pennese, E; Vitolo, U; Federico, Massimo; Gallo, E.
abstract

The Intergruppo Italiano Linfomi started, in 1996, a randomized trial for the initial treatment of elderly patients (older than 65 years) with Diffuse Large B-Cell Lymphoma (B-DLCL) comparing 6 courses of Mini-CEOP vs 8 weeks of P-VEBEC chemotherapy. Study objectives were survival, response and Quality of Life (QoL). Two hundred and thirty-two patients were evaluable for final analysis. Complete Response (CR) and Overall Response Rates (ORR) were 54% vs 66% (p = 0.107) and 90% vs 78% (p = 0.021) for P-VEBEC and Mini-CEOP, respectively. With a median follow-up of 72 months, the 5-year Overall Survival (OS), Relapse Free Survival (RFS), and Failure Free Survival (FFS) were 32%, 52%, and 21%, respectively. Subjects achieving a CR showed improvement of QoL regardless of treatment arm. Both Mini-CEOP and P-VEBEC determined a similar outcome for elderly patients with B-DLCL, with a third of patients alive after more than 6 years of follow-up. Both regimens can be considered equally for combination treatment with anti-CD20 monoclonal antibody.

2007 - Multicenter comparative multimodality surveillance of women at genetic-familial risk for breast cancer (HIBCRIT study): interim results. [Articolo su rivista]
Sardanelli, F; Podo, F; D'Agnolo, G; Verdecchia, A; Santaquilani, M; Musumeci, R; Trecate, G; Manoukian, S; Morassut, S; DE GIACOMI, C; Federico, Massimo; Cortesi, L; Concione, S; Cirillo, S; Marra, V.
abstract

PURPOSE: To prospectively compare clinical breast examination (CBE), mammography, ultrasonography (US), and contrast material-enhanced magnetic resonance (MR) imaging for screening women at genetic-familial high risk for breast cancer and report interim results, with pathologic findings as standard. MATERIALS AND METHODS: Institutional review board of each center approved the research; informed written consent was obtained. CBE, mammography, US, and MR imaging were performed for yearly screening of BRCA1 or BRCA2 mutation carriers, first-degree relatives of BRCA1 or BRCA2 mutation carriers, or women enrolled because of a strong family history of breast or ovarian cancer (three or more events in first- or second-degree relatives in either maternal or paternal line; these included breast cancer in women younger than 60 years, ovarian cancer at any age, and male breast cancer at any age). RESULTS: Two hundred seventy-eight women (mean age, 46 years +/- 12 [standard deviation]) were enrolled. Breast cancer was found in 11 of 278 women at first round and seven of 99 at second round (14 invasive, four intraductal; eight were

2007 - Prognostic relevance of serum beta2 microglobulin in patients with follicular lymphoma treated with anthracycline-containing regimens. A GISL study. [Articolo su rivista]
Federico, Massimo; C., Guglielmi; Luminari, Stefano; C., Mammi; Marcheselli, Luigi; U., Gianelli; Maiorana, Antonino; F., Merli; Bellei, Monica; Pozzi, Samantha; C., Stelitano; A., Lazzaro; P. G., Gobbi; L., Baldini; S., Bergantini; V., Fregoni; M., Brugiatelli
abstract

Background and ObjectivesAlthough serum b2 microglobulin (b2M) is an easy parameter to measure, and overexpressedin a large number of lymphoproliferative diseases, its prognostic value hasbeen largely underestimated. The present study examined the influence of b2M levelson overall survival (OS) of patients with follicular lymphoma (FL).Design and MethodsThe prognostic role of b2M was evaluated in 236 patients with FL identified from thedatabases of the Gruppo Italiano per lo Studio dei Linfomi (GISL) and treated withanthracycline-based regimens from 1993 to 2003.ResultsElevated serum b2M levels were found in 82 patients (35%). According to multivariatelogistic regression analysis, elevated b2M levels were associated with elevatedlactate dehydrogenase (LDH) (p=0.021), age (p=0.029), and number of involvednodal areas (p&lt;0.001). The percentage of elevated b2M levels increased progressivelywith increasing FLIPI scores (17%, 38%, and 63% in the low-, intermediate-, andhigh-risk groups, respectively). Five-year OS was 61% (95% CI, 47-73%) and 89% (95%CI, 82-93%) for patients with elevated vs normal b2M levels respectively (p&lt;0.001).Cox regression analysis showed that b2M level had an independent and stable prognosticvalue (HR=3.0; 95%CI, 1.6-5.7). In a multivariate analysis the impact of b2Mlevel on survival was independent of FLIPI score, with a HR of 2.94 (95% CI, 1.54-5.62).Interpretation and ConclusionsOur results demonstrate that in patients treated in the pre-rituximab era, b2M levelwas an independent prognostic marker in addition to FLIPI score. We thus suggestthat b2M be routinely assessed and tested in future prognostic studies of FL patientstreated with combination chemotherapy and anti-CD20 agents.

2007 - Revised response criteria for malignant lymphoma. [Articolo su rivista]
Cheson, Bd; Pfistner, B; Juweid, Me; Gascoyne, Rd; Specht, L; Horning, Sj; Coiffier, B; Fisher, Ri; Hagenbeek, A; Zucca, E; Rosen, St; Stroobants, S; Lister, Ta; Hoppe, Rt; Dreyling, M; Tobinai, K; Vose, Jm; Connors, Jm; Federico, Massimo; Diehl, V; THE INTERNATIONAL HARMONIZATION PROJECT ON, Lymphoma
abstract

PURPOSE: Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. METHODS: The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations. RESULTS: New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkin's and Hodgkin's lymphoma. Standardized definitions of end points are provided. CONCLUSION: We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.

2007 - Rituximab in combination with fludarabine and cyclophosphamide in the treatment of patients with recurrent follicular lymphoma [Articolo su rivista]
Sacchi, Stefano; Pozzi, Samantha; Marcheselli, Raffaella; Federico, Massimo; Tucci, A; Merli, F; Orsucci, L; Liberati, M; Vallisa, D; Brugiatelli, M.
abstract

The current study was conducted to asses the safety profile and clinical activity of rituximab in combination with fludarabine and cyclophosphamide in patients with recurrent follicular lymphoma (FL). METHODS: This study was a noncomparative, multicenter, phase II study. Between March 2000 and December 2002, 54 patients with recurrent FL were enrolled in the FC+R trial. Patients received fludarabine at a dose of 25 mg/m(2) and cyclophosphamide at a dose of 300 mg/m(2) daily for 3 consecutive days, every 3 weeks for 4 cycles. Rituximab was administered at a dose of 375 mg/m(2) beginning 2 weeks after the first course of fludarabine and cyclophosphamide and then on Day 1 of each cycle thereafter. The planned treatment duration was 10 weeks. RESULTS: Overall, 92% of patients completed the planned therapy in 10 to 14 weeks and 74% achieved a complete response (CR). Among patients with BCL2-positive bone marrow, 86% obtained a molecular disease remission (MR). The median survival from treatment (SFT), the duration of disease remission (DR), and time to disease progression (TTP) had not been reached after a median follow-up of 45 months. Of the baseline characteristics, &gt;2 previous treatments, BCL2-positive bone marrow, and low Follicular Lymphoma International Prognostic Index (FLIPI) score were found to be associated with better DR and/or TTP. Hematologic toxicity was transient and reversible, with the exception of 3 patients with severe and prolonged neutropenia. Three patients presented with infections, 1 of whom died of bronchopneumonia. CONCLUSIONS: The FC+R scheme, a nonanthracycline-containing regimen lasting up to 10 weeks, was found to be relatively well-tolerated and demonstrated significant antilymphoma activity with excellent clinical CR and molecular response rates.

2007 - Secondary malignancies after treatment of aggressive non-Hodgkin lymphoma: A GISL cohort study on 1259 patients [Abstract in Rivista]
Sacchi, Stefano; Luigi, Marcheselli; Bari, Alessia; Marcheselli, Raffaella; Pozzi, Samantha; Giovanni, Quarta; Nicola Di, Renzo; Alberto, Fragasso; Francesco, Angrilli; Federico, Massimo
abstract

BACKGROUND Secondary malignancies have been associated with Non Hodgkin Lymphoma (NHL) treatment. Nevertheless few analyses have addressed this issue focusing on aggressive lymphoma. Aims of this study were to determine the incidence and the risk factors for developing secondary cancer during long term follow up of patients treated for aggressive lymphoma. METHODS For the purpose of this study we identified in the GISL database, 1259 naïve patients with histologically confirmed diagnosis of aggressive NHL. Observed cancer were classified by site. The incidence numbers of second neoplasia was compared to the incidence of malignancies in the Italian population. The standardized incidence ratio was calculated from the ratio between observed and expected number of cancers. Absolute excess risk was calculated by subtracting the expected from the observed cases and dividing by the person-years at risk. The Time Free 2nd Tumour (TF2T) was measured from the end of the first treatment to last follow-up or date of diagnosis. Cumulative incidences were estimated either with a Kaplan-Meier estimate or by Gooley’s method. Effects of potential risk factors on second cancer rates were examined in a Cox proportional-hazard model. RESULTS The cohort consisted of 1259 patients enrolled in GISL trials in the period 1988–2003, accounting for 6180 person-year at risk of second tumor. Median age at diagnosis was 58 years. All patients were treated with chemotherapy either alone or in combination with radiotherapy. During follow up, 44 patients (3.5%) developed a second cancer. Twelve out of 44 patients developed hematological malignancies and 32 solid tumors, including 7 lung cancer, 6 colorectal cancer, 4 prostate cancer and 15 other type of cancers. The median time for developing second tumors was 42 months. The risk of secondary malignancy overall was not increased. The analysis of risk by cohort of age at diagnosis of second cancer showed an excess of risk for the cohort age 20–39 and 40–59 years. Cumulative incidence of second malignancy, estimated by Kaplan Meier and by Gooley’s method at 5, 10 and 15 years was 3.2%, 6.9% and 13.8%, and 2.7%, 5.2% and 9.6%, respectively. By univariate analysis we observed a significant negative impact on TF2T for age at first treatment and only marginally significant for elevated LDH level. Further, we performed a Cox regression analysis with gender, age at 1st treatment and LDH >UNL that showed the prognostic ability of these variables in predicting the risk of second tumour. We divided the log(HR) predicted from multivariate analysis, at the 33° and the 66° percentiles to obtain a score system. We observed three groups with significant difference (p< .0001) in the risk of developing second cancers. CONCLUSIONS Our results showed that the risk of second malignancy overall was not increased in patients treated for aggressive lymphoma. Cancer risk was age-related, as demonstrated by the excess of risk observed in the cohort age 20–39 and 40–59 years. Further, utilizing age, male gender and LDH in a Cox regression analysis, we demonstrated the prognostic value of these variables and we produced a score system able to identify groups with different risk of developing

2006 - A model for predicting the risk of developing mild anemia (MA) in patients with lymphoid malignancy. A study of the Gruppo Italiano Studio Linfomi (GISL) [Abstract in Rivista]
Luminari, Stefano; Marcheselli, Luigi; I., Mancarella; Bellei, Monica; Montanini, Antonella; C., Mammi; E., Barbolini; Cesaretti, Marina; Pozzi, Samantha; M., Lombardo; Sacchi, Stefano; Federico, Massimo
abstract

Background: So far no predictive model has been defined to predict the risk of developing MA in cancer patients.Methods and objectives: All cases registered from 1991 to 2005 in one of GISL clinical trials, with a confirmed diagnosis of Aggressive lymphoma (AL), Follicular lymphoma (FL) or Hodgkin’s lymphoma (HL), were selected for the study. Patients should have available data on clinical features at diagnosis, treatment details and hematological toxicity. MA was defined as the presence of baseline Hb levels below11 g/dl or grade 1–4 hemoglobin toxicity defined according to WHO criteria. Theaim of the study was to develop a model to predict the risk of developing MA forpatients with Lymphoid Malignancy (LM).Results: One thousand eight hundred and seventy four patients were included inthe study: AL, FL and HL was the diagnosis in 830, 218 and 687 case respectively;median age was 54, 57 and 32 years for AL, FL and HL respectively and thefrequency of female patients was 43%, 48% and 49% for the three groups. MedianHb level at diagnosis was 12.9 g/dl, 13.2 g/dl and 12.3 g/dl for AL, FL and HLrespectively with 20% of patients with showing MA. All patients received an adequateanthracycline based CT regimen. Overall 38% of patients with Hb baseline levels above 11 g/dl developed MA during chemotherapy. CT regimens were divided intothree groups based on MA risk (group 1: MA risk 0 to 25%; group 2: MA risk 26% to50%; group 3; MA risk above 50%). In the Logit multivariate analysis Age (above 55yrs), Female gender, CT groups (2–3 versus 1) Hb levels and bulky disease were factorsindependently correlated with the risk of developing MA. A prediction model wasdefined using previously defined parameters which allowed the identification of threegroups of patient with a different risk of MA. Patients at low, intermediate-Low,Low-High and high risk had a probability of MA of 5%, 25%, 38% and 52%respectively (P < 0.0001).Conclusion: The risk of developingMA in patients with LM undergoing chemotherapycan be predicted with a simple assessment of clinical and treatment features. Patientsat high risk of MA could be considered for anemia prevention programs.

2006 - Breast cancer screening in women at increased risk according to different family histories: an update of the Modena Study Group experience [Articolo su rivista]
Cortesi, L; Turchetti, D; Marchi, I; Fracca, A; Canossi, B; Battista, R; Ruscelli, Silvia; Pecchi, Ar; Torricelli, Pietro; Federico, Massimo
abstract

Background: Breast cancer ( BC) detection in women with a genetic susceptibility or strong family history is considered mandatory compared with BC screening in the general population. However, screening modalities depend on the level of risk. Here we present an update of our screening programs based on risk classification. Methods: We defined different risk categories and surveillance strategies to identify early BC in 1325 healthy women recruited by the Modena Study Group for familial breast and ovarian cancer. Four BC risk categories included BRCA1/2 carriers, increased, intermediate, and slightly increased risk. Women who developed BC from January 1, 1994, through December 31, 2005 (N = 44) were compared with the number of expected cases matched for age and period. BRCA1/2 carriers were identified by mutational analysis. Other risk groups were defined by different levels of family history for breast or ovarian cancer (OC). The standardized incidence ratio ( SIR) was used to evaluate the observed and expected ratio among groups. All statistical tests were two-sided. Results: After a median follow-up of 55 months, there was a statistically significant difference between observed and expected incidence [SIR = 4.9; 95% confidence interval (CI) = 1.6 to 7.6; p < 0.001]. The incidence observed among BRCA carriers (SIR = 20.3; 95% CI = 3.1 to 83.9; P < 0.001), women at increased ( SIR = 4.5; 95% CI = 1.5 to 8.3; P < 0.001) or intermediate risk ( SIR = 7.0, 95% CI = 2.0 to 17.1; P = 0.0018) was higher than expected, while the difference between observed and expected among women at slightly increased risk was not statistically significant (SIR = 2.4, 95% CI = 0.9 to 8.3; P =.74). Conclusion: The rate of cancers detected in women at high risk according to BRCA status or strong family history, as defined according to our operational criteria, was significantly higher than expected in an age-matched general population. However, we failed to identify a greater incidence of BC in the slightly increased risk group. These results support the effectiveness of the proposed program to identify and monitor individuals at high risk, whereas prospective trials are needed for women belonging to families with sporadic BC or OC.

2006 - Caratterizzazione di proteine nel tessuto e nel liquido interstiziale di neoplasie della mammella [Abstract in Atti di Convegno]
Barchetti, A; Cortesi, L; Rossi, E; Bellei, E; Tomasi, A; Iannone, A; Federico, M.
abstract

La classificazione dei tumori della mammella si basa attualmente sui parametri clinici e sulla morfologia cellulare; l’analisi immunoistochimica utilizza un numero ristretto di fattori prognostici e predittivi correlati a diverse funzioni cellulari come la proliferazione, l’angiogenesi, l’invasione e la metastatizzazione. Questi parametri si limitano a classificare i pazienti in sottogruppi con differente prognosi mentre l’uso di nuove tecnologie, quali lo studio delle proteine attraverso elettroforesi bidimensionale (2D), potrebbe portare ad un approccio terapeutico individualizzato e ad una ottimizzazione del trattamento. Lo scopo del nostro studio è quello di individuare nuovi markers nell’ambito dei tumori invasivi della mammella confrontando il profilo di espressione proteica di tessuto normale, patologico, di TIF (tumoral interstitial fluid) e di NIF (normal interstitial fluid). Nel microambiente tumorale si concentrano infatti un gran numero di molecole in parte secrete, in parte trasportate da vescicole di membrana o liberate in seguito a morte cellulare. Abbiamo ottenuto 8 biopsie mammarie da pazienti affette da carcinoma duttale infiltrante (G3) e carcinoma lobulare infiltrante (G2/3). L’indagine è stata condotta utilizzando circa 200 mg di tessuto mammario di carcinoma duttale e di tessuto adiacente sano. I frammenti di biopsia, sospesi in tampone PBS, sono stati incubati in CO2 5% a 37°C per un’ora e successivamente centrifugati 20 min. a 3000g. Da questa coltura è stato recuperato e analizzato il surnatante contenente le proteine rilasciate dal tessuto. Successivamente l’estrazione proteica è stata effettuata anche sul pellet di tessuto bioptico polverizzato in azoto e sonicato in tampone di lisi. Per ciascuna analisi 100ug di proteine sono state sottoposte ad elettroforesi 2D e visualizzate con metodica silver staining. Gli spots di interesse sono stati caratterizzati con la tecnica HPLC-ESI-MS/MS in seguito a purificazione e digestione con tripsina. L’analisi preliminare delle mappe bidimensionali attraverso il programma PDQuest (BIO-RAD) ha evidenziato spots proteici la cui intensità variava significativamente nei campioni tumorali. Da segnalare un’aumentata espressione dell’oncogene mitogeno DJ-1(PARK 7), coinvolto in pathways di trasduzione del segnale Ras dipendenti e delle proteine LYPA (Acyl-protein thioesterase) e LDHB (lactate dehydrogenase B) la cui overespressione è stata segnalata in linee cellulari di tumore mammario resistenti al trattamento anti-estrogenico. È stato inoltre riscontrato un aumentato livello di PSA1 (Prostatic Specific Antigen), una proteasi serinica associata in letteratura ad un basso indice di proliferazione e ad una prognosi favorevole. L’analisi e il confronto di un maggiore numero di casi permetterà di chiarire il significato e di ottenere informazioni specifiche sul pattern di espressione genica dei differenti stadi e istotipi del carcinoma mammario. Inoltre il confronto con pattern proteici sierici potrebbe essere di aiuto nell’identificazione di nuovi e predittivi marker ematici di neoplasia.

2006 - I tumori ereditari e counselling genetico [Capitolo/Saggio]
L., Cortesi; E., Razzaboni; Federico, Massimo
abstract

Paragrafo di libro sullo studio dei tumori ereditari e delle principali forme ereditarie, della consulenza genetica e dei suoi obiettivi.

2006 - I tumori in provincia di Salerno 2000-2001 [Monografia/Trattato scientifico]
Donato, A.; Federico, Massimo; Apicella, A. M.; Ferrentino, A.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Salerno

2006 - Introduction of Combined Chemotherapies Plus Rituximab (R) Has Improved Outcome of Previously Untreated and Relapsed Follicular Lymphoma (FL) Patients (pts).. [Abstract in Rivista]
Sacchi, Stefano; Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Luminari, Stefano; Federico, Massimo; Francesco, Angrilli; Marco, Lombardo; Chiara, Broglia; Giovanni, Quarta; Maura, Brugiatelli
abstract

Some data suggest that there are been no improvement in survival of FL Pts in the last three decades of the 20th century. However that review ended in 1992, before the introduction of R treatment. Most recently reported data, show that evolving chemotherapies, including the incorporation of R has led to outcome improvement. Between 1994 and 2004, 344 Pts with FL were enrolled in different GISL Trials. For the purpose of this study we considered 270 Pts with similar characteristics enrolled in trials including or not R. The first group accounts for 176 naive Pts treated with Antracycline plus Fludarabine containing regimens (Cohort #1: 125 Pts) or plus R (Cohort #2: 51Pts). The second group accounts for 99 relapsed Pts treated with Antracycline plus Fludarabine containing regimens (Cohort #3: 40 Pts) or plus R (Cohort #4: 59 Pts). To evaluate the impact of the incorporation of R in front line and salvage therapies we assessed the patients OS, FFS, TTF, SAR in these different Cohorts of Pts. Descriptive analysis of prognostic features showed differences in the distribution among groups. To compensate for these variations we also performed Cox regression analysis. Previously Untreated patients. Regarding group #1 and #2 that enrolled Pts with clinical stage IIB, III and IV, FFS and OS according to treatment did not show any statistical differences. The univariate analysis of baseline clinical features showed an impact on OS and FFS for clinical stage, LDH level, involvement of more than 4 nodal sites and presence of extranodal involvement. The prevalence of this characteristics were higher in group #2 than group #1. Thus the FFS from group #2 vs. group #1 was adjusted for variation in prognostic features by Cox regression analysis, that shows a failure Hazard Radio reduction (HR) of 40 % in Pts who received R. Because of difference in follow up (FU) (49 months in Cohort #1 vs 21 months in Cohort #2), to evaluate differences in OS we utilized exact Log Rank test for unequal FU. So far, a trend exists for better OS in R treated patients, although the difference is not statistically significant. Relapsed Patients. Clinical characteristics were similar in the two Cohorts of pts. TTF was better in R treated Pts and the difference was statistically significant (66% vs. 53% at 3 yrs, p=0.023) The analysis of SAR demonstrated a better result for R Cohort with a statistically significant difference (88% vs. 68% at 3 yrs, p=0.022). OS according to treatment protocol, showed advantage for patients in R Cohort and the difference was statistically significant (92% vs. 70% at 5 yrs, p=0.004). Conclusion. In naïve patients our retrospective analysis showed a reduction of HR for FFS and a trend toward better OS in R treated Pts. In relapsed Pts all outcome parameters as OS, TTF and SAR had significant improvement in the Cohort treated with R. Although any conclusions between nonrandomized groups maybe subject to differences in observed and unobserved prognostic features, we believe that improvement have occurred in the management of FL Pts with the introduction of combined chemotherapy with R.

2006 - L'incidenza dei tumori nella provincia di Modena: previsioni per il periodo 2002-2006 [Articolo su rivista]
Fracca, A.; Rashid, I.; Cirilli, C.; Cavrini, G.; Federico, Massimo
abstract

Obiettivo: previsioni di incidenza tumorale in provincia di Modena per ilperiodo 2002-2006 secondo l'utilizzo di una metodologia APC (Age Period Cohort) bayesiani.Disegno: studio su base dipopolazione.Setting: pazienti con diagnosi di neoplasia primaria registrati dal Registro Tumori di Modena tra il 1988 e il 2001.Outcome principali: numero di casi, tassi d'incidenza grezzi e standardizzati.Risultati: complessivamente, nel periodo 2002-2006, è previsto un aumento dei casi di tumore per entrambi i sessi a eccezione dei tumori dello stomaco e dei tumori polmonari maschili, per i quali è previsto un calo. Il numero di casi previsti per il 2002 si discosta dal dato osservato dello 0,7%.Conclusione: le stime risultano attendibili per la maggior parte delle sedi, anche se deve essere usata cautela nel loro utilizzo. In modo particolare le proiezioni di incidenza per i tumori della mammella e della prostata sono risultate chiaramente sovrastimate, a causa dell'effetto di anticipazione diagnostica che provoca un aumento del numero di casi diagnosticati negli ultimi anni.

2006 - Mastectomy rates are decreasing in the era of service screening: a population-based study in Italy (1997-2001) [Articolo su rivista]
Zorzi, M; Puliti, D; Vettorazzi, M; De Lisi, V; Falcini, F; Federico, Massimo; Ferretti, S; Moffa, If; Mangone, L; Mano, Mp; Naldoni, C; Ponti, A; Traina, A; Tumino, R; Paci, E.
abstract

We enrolled all 2162 in situ and 21 148 invasive cases of breast cancer in 17 areas of Italy, diagnosed in 1997-2001. Rates of early cancer increased by 13.7% in the screening age group (50-69 years), and breast conserving surgery by 24.6%. Advanced cancer rates decreased by 19.4%, and mastectomy rates by 24.2%. Service screening did not increase mastectomy rates in the study population.

2006 - MOPPEBVCAD chemotherapy with limited and conditioned radiotherapy in advanced Hodgkin's lymphoma: 10-year results, late toxicity, and second tumors [Articolo su rivista]
Pg, Gobbi; C., Broglia; A., Levis; A., La Sala; F., Valentino; T., Chisesi; Sacchi, Stefano; F., Corbella; L., Cavanna; E., Iannitto; V., Pavone; S., Molica; Gr, Corazza; Federico, Massimo
abstract

Purpose: MOPPEBVCAD (mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine) chemotherapy with limited radiotherapy was devised in 1987 to reduce late toxicity and second tumor incidence while trying to improve effectiveness through increases of dose intensity and dose density. Late results, toxicity, and second tumor incidence were reviewed in all the patients treated. Experimental Design: The drugs of three previous alternating regimens [CAD (lomustine, melphalan, and vindesine), MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), and ABV (doxorubicin, bleomycin, and vinblastine)] were intensified and hybridized, the cumulative dose of mechlorethamine was lowered, and irradiation was delivered to no more than two sites either bulky or partially responding to chemotherapy. Results: A total of 307 previously untreated advanced-stage patients underwent MOPPEBVCAD chemotherapy. Radiotherapy was delivered to 118 of 307 patients (38%). Remission was complete in 290 patients (94%). With a median follow-up of 114 months, 10-year overall, disease-free, and failure-free survival rates were 79%, 84%, and 71%, respectively. Forty-two patients relapsed and 60 died. The causes of death were Hodgkin's lymphoma in 36 patients, second neoplasms in 12, cardiorespiratory diseases in 4, pulmonary diseases in 2, and unknown in 6. Sixteen second tumors (of which nine were myelodysplasia and/or acute leukemia) were diagnosed in all. Outside this series of 307 patients, MOPPEBVCAD obtained complete responses in 12 of 15 relapsed and 9 of 9 refractory patients who had previously been treated with other regimens. Conclusions: Clinical response and long-term results are very satisfactory, whereas the second tumor incidence was lower than would have been expected with MOPP analogues. Given its response/late toxicity balance, MOPPEBVCAD does not undermine the leading role of ABVD as first-line regimen but can be indicated as a very effective second-line conventional therapy.

2006 - Prevalence of BRCA1 genomic rearrangements in a large cohort of Italian breast and breast/ovarian cancer families without detectable BRCA1 and BRCA2 point mutations [Articolo su rivista]
Agata, S; Viel, A; Della Puppa, L; Cortesi, L; Fersini, G; Callegaro, M; Palma, Md; Dolcetti, R; Federico, Massimo; Venuta, S; Miolo, G; D'Andrea, E; Montagna, M.
abstract

The presence of genomic rearrangements of the BRCA1 gene in breast and/or ovarian cancer families has been intensively investigated in patients from various countries over the last years. A number of different rearrangements have been reported by several studies that clearly document the involvement of this mutation type in genetic predisposition to breast and ovarian cancer. Population-specific studies are now needed to evaluate the prevalence of genomic rearrangements before deciding whether to include ad hoc screening procedures into standard diagnostic mutation detection approaches. Indeed, the vast majority of the studies have been performed on small, highly selected, sample sets because of the limitations imposed by the laborious technical approaches. Moreover, prevalence figures are likely to differ across different countries according to the ethnic origin of each specific population. Here we analyze a large cohort of 653 Italian probands, negative for BRCA1 and BRCA2 point mutations, gathered from four National Institutions. We report the identification of BRCA1 genomic rearrangements in 12 independent families. Noteworthy, half of the probands carry mutations that recur in more than one Italian family. Considering the whole spectrum of Italian BRCA1 gene rearrangements identified thus far in consecutive patients, we estimate that alterations of this type account for 19% (95% CI: 0.11 < 0.19 < 0.28) of the BRCA1 mutation positive families. We conclude that the search for major genomic rearrangements is essential for an accurate and comprehensive BRCA1 mutation detection strategy in Italy.

2006 - Prognosis of follicular lymphomas [Articolo su rivista]
Luminari, Stefano; Federico, Massimo
abstract

Follicular lymphoma (FL) is as an indolent neoplasia with median survival measured in decades. Nevertheless, some patients have poor progression-free survival and overall survival. Several treatment approaches are proposed for patients with FL, however criteria to rationalize treatment decisions are lacking. Studies have been performed to build up prognostic indices that are useful for defining risk-adapted treatment recommendations. Available indices are based on parameters that have an independent role in predicting patient survival and that are variably correlated with the features of the disease, with the characteristics of the patient and with the effects of treatment. Two new prognostic indices have recently been proposed for FL: the Italian Lymphoma Intergroup (ILI) index and the Follicular Lymphoma International prognostic Index (FLIPI). Both indices are based on large series of patients and exhibit differences in their ability to discriminate between patients with different probabilities of survival. In recent years, with the advent of gene expression profile studies, our knowledge of the biology of FL is changing as novel data become available about the lymphoma cell and about the role of the microenvironment; these studies have already provided novel prognostic tools for identifying patients with more aggressive disease. Further data and large international cooperative studies are needed to translate into clinical practice the novel acquisitions of biology and therapeutics. Copyright

2006 - Prognosis of screen-detected breast cancers: results of a population based study [Articolo su rivista]
Cortesi, L; Chiuri, Ve; Ruscelli, Silvia; Bellelli, V; Negri, R; Rashid, I; Cirilli, C; Fracca, A; Gallo, E; Federico, Massimo
abstract

Background: The reduced mortality rate from breast carcinoma among women offered screening mammography is demonstrated after 15-20 years of follow-up. However, the assessment of 5-year overall and event-free survival could represent an earlier measure of the efficacy of mammography screening program (MSP). Methods: All cases of breast cancer diagnosed in the Province of Modena between years 1996 and 2000 in women aged 50 to 69 years, were identified through the Modena Cancer Registry (MCR). Stage of disease and treatment information were obtained from clinical records. All the events occurring up to June 30, 2003 were retrieved by experienced monitors. Five-year overall and event-free survival were the principal end-points of the study. Results: During a 5-year period, 587 primary breast cancers were detected by the MSP and 471 primary breast cancers were diagnosed out of the MSP. The screen-detected breast cancers were smaller, more likely node negative, with low histological grade, low proliferative activity and positive receptors status. Furthermore, the breast cancer diagnosed through the MSP more frequently received a conservative surgery. The 5-year survival rate was 94% in the screen-detected group, versus 84% in the other group (p = 0.0001). The rate of 5-year event-free survival was 89% and 75% for the MSP participants and not participants, respectively (p = 0.0001). Conclusions: Our data confirm a favourable outcome of screen-detected breast cancers in terms of five-year overall and event-free survival, which reflect the good quality assurance parameters of the MSP. Finally, a cancer registry should be implemented in every area covered by screening programs.

2006 - Ricerca di biomarkers nel tumore ovarico mediante analisi proteomica [Abstract in Atti di Convegno]
Rossi, E; Cortesi, L; Barchetti, A; Bellei, E; Monari, E; Tomasi, A; Iannone, A; Abrate, M; Federico, M.
abstract

Il carcinoma ovarico rappresenta la quarta causa di morte nel sesso femminile in Europa e negli Stati Uniti. Nell’80 % dei casi infatti, la diagnosi avviene in uno stadio avanzato poiché la maggior parte delle neoplasie ovariche rimane clinicamente asintomatica negli stadi I e II. La sola terapia chirurgica assicura una sopravvivenza a cinque anni del 90 % delle pazienti diagnosticate allo stadio I, percentuale che si riduce al 35% negli stadi più avanzati. Il nostro obbiettivo è quello di utilizzare l’elettroforesi bidimensionale (2DE) e la spettrometria di massa per identificare e caratterizzare nuovi specifici biomarkers tumorali ovarici che permettano di effettuare una diagnosi precoce, di monitorare la progressione tumorale e di impostare una terapia mirata. Le indagini preliminari sono state effettuate su campioni bioptici di tessuto ovarico sano e tumorale, e su liquido proveniente da lavaggio peritoneale. Le proteine sono state estratte da circa 100 mg di tessuto congelato in azoto liquido, polverizzato in un mortaio e risospeso in tampone di lisi contenente urea, tiourea, CHAPS, Tris-HCl, ampholine pH 3-10 e inibitori delle proteasi. Dopo incubazione a temperatura ambiente per un’ora, i campioni sono stati sonicati e centrifugati. Il pellet, ottenuto dopo precipitazione in acetone freddo, è stato risospeso in un buffer di reidratazione (urea, tiourea, CHAPS, DTT e ampholine) e il contenuto proteico totale misurato con il metodo Bradford. L’isoelettrofocalizzazione (IEF) è stata effettuata caricando 80 g di proteine totali su IPG strips a range di pH 3-10 non lineare, fino al raggiungimento di 70000 Vh finali. Le proteine focalizzate sono state ridotte con DTT e alchilate con Iodoacetamide in tampone di equilibrazione (Urea, Tris-HCl, Glicerolo, SDS, Blu di Bromofenolo) prima della separazione elettroforetica su gels di poliacrilamide (SDS–PAGE), a concentrazione omogenea 10% e a gradiente 8-16%. I gel sono stati infine colorati con metodica Silver-staining massa-compatibile. L’analisi con il programma PDQuest ha evidenziato la presenza di numerosi spot proteici differenzialmente espressi nei campioni tumorali rispetto ai controlli sani; la spettrometria di massa ESI-Q-TOF-MS/MS porterà all’identificazione delle proteine di interesse. Per quanto riguarda il liquido derivato da lavaggio peritoneale, prima dell’analisi 2DE le aliquote prelevate sono state concentrate con filtri Amicon aventi cut-off di PM 5 KDa. Parallelamente alla 2DE, sui campioni tissutali è stata effettuata anche l’analisi con tecnologia SELDI-TOF (Surface Enhanced Laser Desorption Ionisation-Time of Flight). I risultati ottenuti hanno evidenziato variazioni significative dell’espressione di numerose proteine, soprattutto a basso peso molecolare (<20 KDa). Lo scopo dello studio ha la finalità di giungere all’identificazione di biomarcatori specifici del tumore ovarico che possono essere evidenziati anche nel liquido peritoneale ed eventualmente nel siero, fungendo da fattori prognostici della malattia ed anche predittivi di risposta al trattamento con derivati del platino.

2006 - Ricerca di markers diagnostici, prognostici e predittivi in carcinomi mammari attraverso analisi proteomica [Abstract in Atti di Convegno]
Pecorari, L; Silvestri, C; Candini, O; Rossi, E; Bellei, E; Bussolari, R; Iannone, A; Federico, M; Cortesi, L; Calabretta, B.
abstract

Le basi molecolari dei tumori sporadici della mammella sono solo in parte conosciute: un comune meccanismo molecolare, che è stato riportato in circa il 75% dei casi, è l’attivazione della proteina oncogenica ad attività Serin/Treonin chinasica AKT. Una delle principali funzioni di pAKT (la cui forma attiva è fosforilata) è quella di promuovere la sopravvivenza cellulare mediata da fattori di crescita bloccando i meccanismi intrinseci dell’apoptosi. Recentemente numerosi studi si sono concentrati sull’approfondimento del ruolo dell’oncoproteina AKT nel carcinoma mammario; la conclusione comune a questi studi è che si possano ottenere benefici clinici rilevanti dall’appropriata combinazione terapeutica tra chemioterapici convenzionali e inibitori specifici di pAKT. Sarebbe inoltre di notevole importanza chiarire in che modo la valutazione dell’attività di pAKT possa essere interpretata ai fini diagnostici, prognostici e predittivi in pazienti con carcinoma mammario. Questo progetto di ricerca si propone di approfondire questi aspetti utilizzando un approccio basato su tecniche di analisi proteomica. Su diversi tipi di linee continue di carcinoma mammario con diverse caratteristiche e diverso grado di aggressività (ErbB2+ / ErbB2- / BRCA1 mutato / BRCA1 w.t.) sono stati eseguiti e sono tuttora in corso, esperimenti d’inibizione/deplezione della proteina pAkt. In particolare dalla linea SKBr3 è stato possibile ottenere estratti proteici contenenti una discreta quota di pAKT; inoltre esperimenti di immunoprecipitazione selettiva hanno consentito di isolare gli interattomi di pAKT e di AKT non fosforilata. Questi immunoprecipitati sono poi stati sottoposti ad elettroforesi bidimensionale e gli spot indicativi di proteine varianti (associate quindi ad una forma rispetto all’altra) analizzati tramite spettrometria di massa. Attualmente una sola nuova potenziale proteina cliente, Elongation Factor 1 alfa (EF1a), è stata identificata ed è in via di caratterizzazione. Per approfondire il ruolo di questa proteina (nota per essere iperespressa in diversi tipi di carcinoma tra i quali l’ovarico, il mammario e il prostatico) sono stati condotti studi di “RNAinterference” che hanno permesso di asserire che in cellule di carcinoma mammario la riduzione dell’espressione di EF1a (livelli diminuiti del 60%) porta ad una riduzione del 30% della clonogenicità. Sembra inoltre che diminuiti livelli d’espressione di EF1 associati a trattamenti a base di 17AAG (inibitore selettivo dell’attività di HSP90 che causa forti riduzioni ai livelli di pAKT) abbiano un effetto sinergico nella riduzione della proliferazione cellulare. Parallelamente a questi studi, stiamo programmando un’analisi globale di tutte le proteine che manifestano una espressione differenziale dopo l’inibizione di pAKT (globale, perché non si riferisce alle sole proteine dell’interattoma, ma all’estratto totale). Questo verrà realizzato tramite confronto diretto delle mappe proteiche ottenute dopo elettroforesi bidimensionale degli estratti totali (trattamento inibitorio specifico vs. controllo) individuando e identificando gli “spots” che rappresentano proteine la cui espressione varia a seguito dell’inibizione dell’attività chinasica di pAKT. La scoperta di nuove proteine substrato della attività chinasica di pAKT e l’approfondimento dei meccanismi biologici e molecolari da essa regolati, rappresentano un importante punto di partenza per la progettazione di strategie terapeutiche ottimali e per la validazione di nuovi markers diagnostici, prognostici o predittivi in situazioni di carcinoma mammario.

2006 - Rituximab (R) in Combination with Fludarabine (F) and Cyclophosphamide (C) in Relapsed Follicular Lymphoma (FL) Patients (pts).Final Results of FC + R Phase II Trial by the GISL. [Abstract in Rivista]
Sacchi, Stefano; Pozzi, Samantha; Marcheselli, Raffaella; Luminari, Stefano; Federico, Massimo; Alessandra, Tucci; Francesco, Merli; Loretta, Orsucci; Giulia, Cervetti; Ubaldo, Occhini; Marina, Liberati; Vincenzo, Callea; Maura, Brugiatelli; Luca, Baldini
abstract

Blood (ASH Annual Meeting Abstracts) 2006 108: Abstract 2763© 2006 American Society of HematologyThis Article Services Email this article to a friend Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sacchi, S. Articles by Baldini, L. Search for Related Content PubMed Articles by Sacchi, S. Articles by Baldini, L. Social Bookmarking What's this? Poster Board #-Session: 941-II Rituximab (R) in Combination with Fludarabine (F) and Cyclophosphamide (C) in Relapsed Follicular Lymphoma (FL) Patients (pts).Final Results of FC + R Phase II Trial by the GISL. Stefano Sacchi, MD1, Samantha Pozzi, MD1,*, Raffaella Marcheselli, BS1,*, Stefano Luminari, MD1,*, Massimo Federico, MD1, Alessandra Tucci, MD2,*, Francesco Merli, MD3,*, Loretta Orsucci, MD4,*, Giulia Cervetti, MD5,*, Ubaldo Occhini, MD6,*, Marina Liberati, MD7,*, Vincenzo Callea, MD8,*, Maura Brugiatelli, MD9 and Luca Baldini, MD10,* 1 Dipartimento di Oncologia ed Ematologia, Universita di Modena, Modena, Italy; 2 Dipartimento di Medicina Interna, Ospedale, Brescia, Italy; 3 Dipartimento di Ematologia, Ospedale, Reggio Emilia, Italy; 4 Dipartimento di Ematologia, Ospedale, Torino, Italy; 5 Dipartimento di Ematologia, Universita di Pisa, Pisa, Italy; 6 Servizio di Ematologia, Ospedale, Arezzo, Italy; 7 Ist. Scienze Oncologiche, Universita di Perugia, Perugia, Italy; 8 Dipartimento di Ematologia, Ospedale, Reggio Calabria, Italy; 9 Divisione di Ematologia, Ospedale, Messina, Italy and 10 Dipartimento di Scienze Mediche, Universita di Milano, Milano, Italy . AbstractFifty-four Pts entered this trial between January 2000 and December 2002. Eligible Pts had histologic documentation of CD 20+ relapsed FL, according to the revised European/American Lymphoma classification, that required treatment, measurable lesion, and an ECOG performance status of 0 or 1. Pts were further required to be aged 18–70 years, and to have undergone < 3 previous lines of chemotherapy. Pts received FC + R chemoimmunotherapy consisting of F 25 mg/m2 and C 300 mg/m2/day for 3 consecutive days every 3 weeks for 4 cycles. R 375 mg/m2 I.V. infusion was administered starting 2 weeks following the first FC course and then on day 1 of each cycle thereafter. Clinical response were defined according to the International Working Group recommendations. BCL 2 analysis was performed by PCR assay. DR, TTP and OS were analyzed by Kaplan-Meier method. Cox analysis was used to analyse the association of baseline prognostic factors with response to treatment, DR,TTP and OS. The overall response rate for all 54 Pts by ITT analysis was 90%; forty Pts (74%), obtained complete responses. Progression occurred in 3 Pts ( 6% ) and 2 Pts dropped out of the trial: 1 for toxicity and 1 refused to start with therapy. A univariate analysis of baseline prognostic factors demonstrated that none of these factors predicted for response to treatment. There were 29 Pts out of 45 tested, positive for BCL 2 before therapy. Among these, 22 Pts were evaluated after treatment and 19 ( 86%) converted to BCL negativity. At last follow up (FU), 40 Pts were alive, 31 with ongoing response and 9 with progressive disease. The median DR, TTP and OS have not been reached after a median FU time of 45 months ( range, 1 to 74 months ). The median DR in the 49 Pts who have reached CR or PR was 35 months ( range, 6 to 70 months). None of the baseline prognostic characteristics was significantly related to DR. The median TTP in all 54 Pts, was 36 months ( range, 1 to 74 months ).BCL2 positivity and < 2 previous treatments were related with better TTP (p<0.05 ) OS rate at 4 years was 75%. Toxicity was evaluable in 52 Pts. The most common severe side effects were hematologic, and included 21 cases of neutropenia, 3 cases of thrombocytopenia and 2 cases of anemia. Infectious complications manifested in 3 Pts and 1

2006 - Role of interferon-alpha administration after 2-deoxycoformycin in the treatment of hairy cell leukemia patients [Articolo su rivista]
Marotta, G.; Frassoldati, A.; Zinzani, P.; Annino, L.; Brugiatelli, M.; Ambrosetti, A.; Lenoci, M.; Federico, Massimo; Foa, R.; Lauria, F.; the Italian Cooperative Group for, Hcl
abstract

BACKGROUND AND OBJECTIVE: Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder which is treated effectively by interferon-alpha (IFN-alpha), deoxycoformycin (DCF) and 2-clorodeoxyadenosine (2-CdA). As a third of patients treated with DCF do not achieve a complete remission (CR) and many of them tend to relapse, we evaluated the potential role of IFN-alpha, randomly administered after DCF, in increasing the number of patients attaining CR and/or duration of CR. METHODS: From March 1997 to December 2000, 167 previously untreated HCL patients, from 37 Italian institutions, were enrolled in the study. A total of 138 males and 29 females, with a median age of 55 yr were included in the study. All patients received six courses of DCF 4 mg/m(2) i.v. every other week and then two additional courses once a month. Complete and partial responders were randomly assigned to receive or not receive IFN-alpha at a dose of 3 MU s.c. three times a week for 6 months. RESULTS: Of the 167 patients enrolled in the study, 145 (86.8%) obtained a CR or a partial remission (PR) and were therefore suitable for randomization. One hundred and thirty-five patients were successively randomized to receive IFN-alpha (63 cases; arm A) or not (72 cases; arm B). Progression of disease was observed in eight (arm A) and 12 (arm B) patients with a median time of 27.8 and 26.9 months, respectively. As far as the improvement in response was concerned, no significant difference in the two subgroups was observed. In fact, five patients in arm A and six patients in arm B showing a good PR at the end of DCF therapy, subsequently attained a late CR. CONCLUSIONS: From our data there does not appear to be any significant role for IFN-alpha in improving the proportion and the duration of CR in HCL patients previously treated with DCF.

2006 - Significance of early changes in the serum CA-125 antigen level on overall survival in advanced ovarian cancer [Articolo su rivista]
Markman, M; Federico, Massimo; Liu, Py; Hannigan, E; Alberts, D.
abstract

Objective. The relationship between survival and early changes in the serum level of the CA-125 antigen in patients with advanced ovarian cancer remains poorly defined. Methods. To explore this issue, the serum CA-125 values from 101 patients with advanced ovarian cancer who participated in a Southwest Oncology Group trial (SWOG 8412), which compared the systemic delivery of cisplatin/cyclophosphamide vs. carboplatin/cyclophosphamide (both delivered every 28 days for 6 cycles) in suboptimal residual stage III and IV ovarian cancer, were evaluated. All patients in this analysis had CA-125 values available for at least 8 weeks following initiation of chemotherapy. Cox proportional hazards regression was used in multivariate analysis to determine the prognostic significance of the CA-125 concentration. Results. While pretreatment CA-125 values did not correlate with survival, the concentration of this tumor marker 8 weeks after initiation of therapy was a powerful independent prognostic factor. The median survivals for patients (n = 51) with a CA-125 < 35 U/ml, vs. patients (n = 50) with a CA-125 > 35 U/ml, at this time point, were 26 months and 15 months, respectively (P = 0.0001). Further, women with serum CA-125 values < 50% of their pretreatment concentration at 8 weeks experienced a median survival of 21 months, compared to only 10 months for individuals with tumor marker levels > 50% of their baseline value (P = 0.0003). Conclusion. Reduction in the serum CA-125 concentration over the initial two cycles of platinum-based chemotherapy is a powerful independent predictor of survival for patients with suboptimal stage III or IV ovarian cancer. Patients without significant declines in CA-125 after two cycles of platinum-based chemotherapy have a particularly poor prognosis. (c) 2006 Elsevier Inc. All rights reserved.

2006 - Splenic marginal zone lymphoma: a prognostic model for clinical use. [Articolo su rivista]
Arcaini, L; Lazzarino, M; Colombo, N; Burcheri, S; Boveri, E; Paulli, M; Morra, E; Gambacorta, M; Cortelazzo, S; Tucci, A; Ungari, M; Ambrosetti, A; Menestrina, F; Orsucci, L; Novero, D; Pulsoni, A; Frezzato, M; Gaidano, G; Vallisa, D; Minardi, V; Tripodo, C; Callea, V; Baldini, L; Merli, F; Federico, Massimo; Franco, V; Iannitto, E; INTEGRUPPO ITALIANO, Linfomi
abstract

The Integruppo Italiano Linfomi (IIL) carried out a study to assess the outcomes of splenic marginal zone lymphoma and to identify prognostic factors in 309 patients. The 5-year cause-specific survival (CSS) rate was 76%. In univariate analysis, the parameters predictive of shorter CSS were hemoglobin levels below 12 g/dL (P &lt; .001), albumin levels below 3.5 g/dL (P = .001), International Prognostic Index (IPI) scores of 2 to 3 (P &lt; .001), lactate dehydrogenase (LDH) levels above normal (P &lt; .001), age older than 60 years (P = .01), platelet counts below 100,000/microL (P = .04), HbsAg-positivity (P = .01), and no splenectomy at diagnosis (P = .006). Values that maintained a negative influence on CSS in multivariate analysis were hemoglobin level less than 12 g/dL, LDH level greater than normal, and albumin level less than 3.5 g/dL. Using these 3 variables, we grouped patients into 3 prognostic categories: low-risk group (41%) with no adverse factors, intermediate-risk group (34%) with one adverse factor, and high-risk group (25%) with 2 or 3 adverse factors. The 5-year CSS rate was 88% for the low-risk group, 73% for the intermediate-risk group, and 50% for the high-risk group. The cause-specific mortality rate (x 1000 person-years) was 20 for the low-risk group, 47 for the intermediate-risk group, and 174 for the high-risk group. This latter group accounted for 54% of all lymphoma-related deaths. In conclusion, with the use of readily available factors, this prognostic index may be an effective tool for evaluating the need for treatment and the intensity of therapy in an individual patient.

2006 - Survival from rare cancer in adults: A population-based study [Articolo su rivista]
Gatta, G.; Ciccolallo, L.; Kunkler, I.; Capocaccia, R.; Berrino, F.; Coleman, M. P.; De Angelis, R.; Faivre, J.; Lutz, J. M.; Martinez, C.; Möller, T.; Sankila, R.; Oberaigner, W.; Storm, H. H.; Aareleid, T.; Jechova, M.; Rousarova, M.; Hakulinen, T.; Hédelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Macé Lesec'h, J.; Chaplain, G.; Carli, P. M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, B.; Grosclaude, P.; Estève, J.; Kaatsch, P.; Ziegler, H.; Hölzel, D.; Schubert Fritschle, G.; Tryggvadottir, L.; Allemani, C.; Baili, P.; Crosignani, P.; Micheli, A.; Sant, M.; Taussig, E.; Sowe, S.; Ferretti, S.; Conti, E.; Vercelli, M.; Quaglia, A.; Pannelli, F.; Federico, Massimo; Artioli, M. E.; PONZ DE LEON, Maurizio; Benatti, Piero; De Lisi, V.; Servente, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafa, L.; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P.; Guzzinati, S.; Carrani, E.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Dalmas, M.; Langmark, F.; Andersen, A.; Pinheiro, P.; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pleško, I.; Obsitníkováa, A.; Pompe Kirn, V.; Primic Zakelj, M.; Izarzugaza, I.; Martinez Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Peris Bonet, R.; Barlow, L.; Jundt, G.; Bouchardy, C.; Coebergh, J. W. W.; van der Does van den Berg, A.; Visser, O.; Godward, S.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, C.; Verne, J.; Møller, H.; Bell, J.; Botha, H.; Lawrence, G.; Black, R.; Steward, J. A.
abstract

Backround: Rare cancers are a challenge to clinical practice, and treatment experience, even in major cancer centres to which rare cancers are usually referred, is often limited. We aimed to study the epidemiology of rare cancers in a large population of several countries. Methods: We analysed survival by age, sex, subsite, and morphology in 57 144 adults with 14 selected rare cancers diagnosed 1983-94. Variations in survival over time and between European regions were also assessed for variations in quality of care. We also estimated the adjusted relative excess risk of death for every rare cancer. Findings: Overall 5 -year relative survival was good (ie, >65%) for placental choriocarcinoma (85.4% [95% CI 81.4-89.5]), thyroid medullary carcinoma (72.4% [69.2-75.5]), ovarian germ-cell cancer (73.0% [70.0-76.0]), lung carcinoid (70.1% [67.3-72.9]), and cervical adenocarcinoma (65.5% [64.3-66.6]); intermediate (ie, 35-65%) for testicular cancer at age 65 years or older (64.0% [59.3-68.7]), sarcoma of extremities (60.0% [58.9-61.2]), digestive-system endocrine cancers (55.6% [54.9-56.3]), anal squamous-cell carcinoma (53.1% [51.5-54.8]), and uterine sarcoma (43.5% [42.0-44.9]); low for carcinoma of adrenal-gland cortex (32.7% [28.3-37.2]) and bladder squamous-cell carcinoma (20.4% [18.8-22.0]); and poor for angiosarcoma of liver (6.4% [1.8-11.0]) and mesothelioma (4.7% [4.3-5.2]). Survival was usually better for women than men and poor in those aged 75 years or older. Survival significantly improved over time for ovarian germ-cell cancer, sarcomas of extremities, digestive-system endocrine tumours, anal squamous-cell carcinoma, and angiosarcoma of liver. Survival in northern Europe was higher than in the other geographic groupings for most cancers. Interpretation: Because effective treatments are available for several of the rare cancers we assessed, further research is needed to ascertain why survival is lower in some European countries than in others, particularly in older patients. Audit of best practice for rare cancers with treatment protocols would be useful.

2006 - The length of treatment of aggressive non-Hodgkin's lymphomas established according to the international prognostic index score: long-term results of the GISL LA03 study [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Pg, Gobbi; Sacchi, Stefano; N., Renzo; M., Lombardo; F., Merli; L., Baldini; C., Stelitano; G., Partesotti; G., Polimeno; Montanini, Antonella; C., Mammi; M., Brugiatelli
abstract

Objectives: To compare two different schedules of two different anthracycline-containing regimens, where length of treatment is modulated according to the international prognostic index (IPI) in patients with aggressive non-Hodgkin's Lymphoma (NHL). Methods: In 1993 the Gruppo Italiano per lo Studio dei Linfomi (GISL) started a randomized 2 x 2 factorial phase III clinical trial for patients with newly diagnosed aggressive NHL comparing ProME(Epidoxorubicin)CE-CytaBOM (PE-C) to ProMI(Idarubicin)CE-CytaBOM (PI-C) and a fixed to a flexible treatment schedule where anthracycline dose was to be modulated according to observed hematological toxicity. Patients with low or low-intermediate IPI (IPI 0-2) and those with intermediate-high or high IPI (IPI 3-5) should receive six or eight courses, respectively. Involved-field radiotherapy was allowed for patients with initial bulky disease or with residual masses. Results: Three hundred and fifty-six patients were registered into the study and randomized. Patients were well balanced among the four study arms in terms of clinical characteristics and prognostic factors. Three hundred and forty-five patients were available for evaluation of study endpoints. At the end of induction therapy complete remission rate was 61%, 5-year failure-free survival (FFS) rate was 40% and 5-year overall survival (OS) rate was 59%; no differences were observed according to treatment arms. Patients in the flexible arm received higher dose intensity of anthracycline (P < 0.001) with no apparent increase in toxicity. However, the flexible schedule was not superior to the fixed one. Patients with IPI 3-5 showed lower response rates (45% vs. 67%: P < 0.0001) and lower 5-year FFS (29% vs. 45%: P < 0.0001) compared to those with IPI 0-2. Conclusions: six courses of fixed or flexible PE-C or PI-C can determine a promising success rate in patients with advanced aggressive NHL with IPI 0-2, whereas the same regimens are less effective in patients with IPI 3-5, even if two additional courses are delivered. For the latter group of patients innovative approaches are warranted.

2006 - The Oral PKC-ß Inhibitor Enzastaurin (LY317615) Suppress Phosphorylation and Induces Apoptosis in Multiple Myeloma Cell Lines by Inhibition of AKT Pathway. [Abstract in Rivista]
Antonino, Neri; Marmiroli, Sandra; Pierfrancesco, Tassone; Luigia, Lombardi; Lucia, Nobili; Donata, Verdelli; Civallero, Monica; Cosenza, Maria; Jessika, Bertacchini; Federico, Massimo; DE POL, Anto; Giorgio Lambertenghi, Deliliers; Sacchi, Stefano
abstract

The PKC pathway has been shown to play a role in the regulation of cell proliferation in several hematologic malignancies. In this study we tested the oral PKC-ß inhibitor, Enzastaurin (LY317615 - Eli Lilly) for its therapeutic efficacy in Multiple Myeloma (MM). We first analyzed PKC-ß I and II expression by Western blot in a panel of 19 human MM cell lines, showing that 9 cell lines express either 1 or both isoforms. We next examined the growth inhibition effect of Enzastaurin in the same panel of MM cell lines using either WST-1 or MTT assay and cell viability assessment by Tripan Blue exclusion. Eighteen cell lines have IC50 value ranging from 1,2 µM to 12,5 µM. To examine molecular mechanisms whereby Enzastaurin induces cytotoxicity, we performed cell cycle profiling using PI and observed a significant increase of the percentage of cells in the sub G0–G1 fraction. To determine whether Enzastaurin-induced cell death is mediated by apoptosis, we studied by ELISA and Western blot caspase 3 and PARP cleavage. We observed induction of caspase 3 and PARP cleavage in a dose and time dependent fashion. Notably, the broad caspase (Z-VAD-FMK) inhibitor reduced Enzastaurin-induced cytotoxicity. We next determined whether Enzastaurin could inhibit AKT phosphorylation in MM cell lines with constitutive phosphorylation of AKT. Enzastaurin decreased AKT phosphorylation in a dose and time dependent fashion. Phosphorylation of GSK3ß, a downstream target protein of AKT, was also markedly inhibited. Phosphorylation of PDK-1, a known upstream activator of AKT, was not affected by Enzastaurin. In conclusion, our results indicate that Enzastaurin-induced cytotoxicity is mediated via activation of caspase. This effect is associated with significant inhibition of AKT activity and its downstream target GSK3 ß. Enzastaurin does not alter the phosphorylation of the upstream AKT activator PDK-1. These data suggest that Enzastaurin inhibit AKT signalling pathway and support its evaluation in a murine model of human MM.

2006 - The prognosis of follicular lymphomas: The F2-project [Articolo su rivista]
Federico, Massimo; Bellei, Monica; Pro, B.; Lopez Guillermo, A.; Vitolo, U.; Luminari, Stefano; Pileri, S.; Solal Céligny, P.
abstract

Follicular lymphoma (FL) accounts for 10–15% of non-Hodgkin’s lymphomas in western countries. Although patients with FL experience a relatively indolent course and usually exhibit dramatic responses to initial therapy, they should be considered affected by a fatal malignancy. There is a tendency to relapse over time, the response to salvage treatments is of shorter duration after every relapse, and patients eventually die of disease-related causes. Several treatment approaches are offered to patients with FL; however, criteria to rationalize treatment decisions are still lacking in many instances.

2006 - The role of anthracyclines in follicular lymphomas [Articolo su rivista]
Luminari, Stefano; Federico, Massimo
abstract

This article does not have an abstract.

2006 - The role of dose size in a chemotherapy regimen (ProMECE-CytaBOM) for the first-line treatment of large B-cell lymphomas: a randomized trial by the Gruppo Italiano Studio Linfomi (GISL) [Articolo su rivista]
Gobbi, Pg; Broglia, C; Valentino, F; Mammi, C; Lombardo, M; Merli, F; Luminari, Stefano; Polimeno, G; Riezzo, A; Lambelet, P; Rovati, A; Corazza, Gr; Federico, Massimo
abstract

Background: It is still unclear the actual contribute of dose intensity (DI), dose size (DS) and dose density (DD) in the conventional chemotherapy of large, B-cell non-Hodgkin lymphomas. Methods: A prospective, randomized trial compared the cyclic schedule of ProMECE-CytaBOM chemotherapy (cyc-PC, 6 cycles) with a modified version of it, which administered the same drugs sequentially (seq-PC), with the same planned cumulative DI and an 83% DD, within the same time frame (113 days), but with three times higher DS of all the drugs except vincristine. Results: Fifty-six patients received cyc-PC and 52 seq-PC. The actual mean cumulative DI was 0.79 +/- 0.15 with cyc-PC, 0.78 +/- 0.17 with seq-PC. Response was complete in 59% and 52%, partial in 20% and 21%, null in 5% and 6%, respectively. There were four toxic deaths (two per arm). Relapses occurred in 36% and 37%, respectively. Toxicity was similar in both arms. Overall, failure-free, progression-free and disease-free survival (median follow-up: 54 months) were statistically indifferent. Conclusions: The very similar DI actually delivered in both arm seems to be the main common determinant of the indifferent results recorded. Increasing DS - at least within the limits clinically attainable without stem cell rescue - does not improve results.

2006 - The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin's lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL) [Articolo su rivista]
Morabito, F; Stelitano, C; Luminari, Stefano; Mammi, C; Marcheselli, Luigi; Callea, V; Gentile, M; Polimeno, G; Merli, F; Molica, S; Gobbi, P; Angrilli, F; Brugiatelli, M; Federico, Massimo
abstract

GISL recently conducted an exhaustive survey of 1078 patients with Hodgkin's Lymphoma (HL) enrolled between 1988 and 2002 in different prospective trials. Treatment failure was observed in 82 out of 1078 patients; of these 82 patients with refractory HL, complete information was available for 72, who form the evaluable population of the present study. After the initial therapy failure, 51 patients were treated with conventional salvage chemotherapy ( CC) (n = 24) or high-dose chemotherapy (HDC) (n = 27); 4-year overall survival ( OS) was 81% in the HDC group versus 38% in the CC group ( P = 0.019). The remaining 21 patients had rapidly progressive disease and died. After a median follow-up of 2.8 years, the projected OS for all 72 patients is 58 and 49% at 3 and 5 years, respectively. Age <45 years, the absence of systemic symptoms and a PS <1 predicted a significantly longer OS. Interestingly, the majority of patients with two or three negative prognostic factors did not receive potentially curative therapy. In conclusion, HDC seems to be a reasonable option for selected patients with refractory HL, although the majority of them did not receive a transplant. Finally, patients with a high-risk score had little chance of receiving potentially curative treatment.

2006 - Unlike ABVD and MOPPEBVCAD, Stanford V chemotherapy does not tollerate the combination with a reduced and conditioned radiotherapy for the treatment of advanced Hodgkin Lymphoma [Articolo su rivista]
Gobbi, P. G.; Levis, A.; Chisesi, T.; Pavone, V.; Federico, Massimo; Brugiatelli M., : on behalf of the Intergruppo Italiano Linfomi
abstract

no abstract

2006 - Very high levels of soluble CD30 recognize the patients with classical Hodgkin's lymphoma retaining a very poor prognosis [Articolo su rivista]
Visco, C; Nadali, G; Vassilakopoulos, Tp; Bonfante, V; Viviani, S; Gianni, Am; Federico, Massimo; Luminari, Stefano; Peethambaram, P; Witzig, Te; Pangalis, G; Cabanillas, F; Medeiros, Lj; Sarris, Ah; Pizzolo, G.
abstract

Objectives: To evaluate the prognostic role of pretreatment serum levels of soluble CD30 (sCD30) in patients with advanced stage classical Hodgkin's lymphoma (cHL) treated with adriamycin, bleomycin, vinblastine, and dacarbazine or equivalent regimens. Methods: We identified 321 previously untreated patients with cHL who presented to the participating centers between 1985 and 2002, and had serum samples available for the determination of sCD30 levels. Results: With a median follow-up of 72 months, the actuarial 5-year overall survival was 82%, and failure-free survival (FFS) was 71%. The median serum level of sCD30 was 65 U/mL (range: 1-2230), and was significantly higher (P < 0.0001) when compared with a group of 113 healthy controls (4 U/mL, range: 0-20). Increasing level of sCD30 was associated with a continuous worsening of FFS and OS, and patients with sCD30 >= 200 U/mL had a 5-year FFS of 39%. With multivariate analysis, sCD30, Ann Arbor stage, and lactic acid dehydrogenase were significant independent factors in terms of FFS. The association of the above-mentioned three independent prognostic variables could discriminate 22% of patients with 5-year FFS of 40%. Conclusions: Our data confirm the independent prognostic role of sCD30 in identifying the patients with high risk of treatment failure, and show that its association with other variables can recognize patients with FFS considerably lower than 50%.

2006 - Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) as salvage therapy in relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL): Results of a phase II study conducted by the Gruppo Italiano per lo Studio dei Linfomi [Articolo su rivista]
Di Renzo, N; Brugiatelli, M; Montanini, Antonella; Vigliotti, Ml; Cervetti, G; Liberati, Am; Luminari, Stefano; Spedini, P; Giglio, G; Federico, Massimo
abstract

Patients with aggressive NHL who fail initial treatment or subsequently relapse have a very poor outcome and less than 20-25% achieve a prolonged disease-free interval with salvage therapies. To improve the outcome of patients with refractory aggressive NHL not suitable for High Dose Therapy (HDT) and Autologous Stem Cell Transplant (ASCT), the efficacy of a combination of gemcitabine, vinorelbine, procarbazine and prednisone (ViGePP) were tested. Between November 1999 and September 2002, 69 patients with relapsed or refractory aggressive NHL were treated with ViGePP regimen, every 4 weeks up to six courses. At the end of planned chemotherapy patients could receive additional radiotherapy on residual masses or on sites of previously bulky disease. Sixty-six patients were available for evaluation of study end-points. Thirty patients were refractory to therapy and 36 patients had relapsed after remission obtained with previous therapy. At the end of therapy, complete remission (CR) rate was 23%, 3-year relapse free survival rate was 40% and 3-year overall survival rate was 25% for the whole series (29% and 20% for relapsed and refractory patients, respectively). Patients achieving CR with ViGePP had a significantly better survival as compared with the remaining ones (p =0.0003). ViGePP as used in the present setting has demonstrated a promising activity, comparable to other conventional dose regimens. Although CR was achieved only in a minority of patients, this was durable in a significant proportion of them. This regimen should be tested in less heavily pretreated patients and probably in combination with new active agents such Rituximab. Further developments of this combination are warranted.

2005 - A PROSPECTIVE, RANDOMIZED, PHASE II STUDY OFGISL COMPARING TWO MITOXANTRONE-BASED SALVAGEPROGRAM (MIPE VS MJMA) IN AGGRESSIVE NON-HODGKIN’SLYMPHOMA (ANHL) FAILING AN ANTHRACYCLINECONTAININGFRONT-LINE TREATMENT [Abstract in Rivista]
N., Di Renzo; Sacchi, Stefano; M., Broglia; M., Dell’Olio; A., La Sala; M., Brugiatelli; C., Stelitano; Federico, Massimo
abstract

Background: Patients (pts) never achieving or failing after initial completeresponse (CR) have a poor prognosis when treated with conventionalsalvage regimens. The Parma study has shown significantly better eventfree(EFS) and overall survival (OS) with high-dose therapy and stem-cellsupport in pts with first or subsequent chemosensitive relapsing aNHL.However, many pts prove to be ineligible because of age or associatedmorbidity for this potentially curing approach. Although, newer combinationsincluding agents with proven efficacy, without cross-resistance,and not included in the front-line regimens have been developed is notstill clear which of them is able to give higher response rates and longlastingCR. Aim of study was to compare in a prospective, randomizedstudy two mitoxantrone-based regimens in order to evaluate their efficacyand toxicity in patients with relapsed-refractory aNHL after anthracyclinecontainingup-front therapy.Patients and methods: Between April 1991 and October 1996, 87 ptsentered in the study; 44 pts were randomized to receive MJMA (mitoxantrone10 mg/m2 d1, carboplatin 100 mg/m2 d1-4, methyl-prednisolone500 mg td d1-4 and Ara-C 2000 mg/m2 d5) and 43 MIPE (mitoxantrone12 mg/m2 d1, ifosfamide 1660 mg/m2 d1-3, VP-16 120 mg/m2 d1-3, prednisone60 mg/m2 PO d1-5, MESNA 600 mg/m2 h 0, + 4, + 8 d1-3) every4 weeks for maximum six courses. To be eligible pts had to have histologicallyconfirmed aNHL, age older 15 years and at least one measurablelesion. There were no significant differences between the two arm ofstudy concerning the median age (51.9 vs 52.8 yr), B-symptoms (37 vs44%), bulky disease (27 vs 21%), bone marrow involvement (43 vs 44%),abnormal LDH level (50 vs 53%), and IPI score 0-1(34 vs30%) whilethere were more pts with advanced stage in the MIPE arm (82 vs 98%;P = 0.015). Thirty-seven pts (42.5%) had relapsed and 50 refractorydisease.Results: On intent to treat analysis, the ORR was 50% in the MJMA and42% in the MIPE arm including 38.6% and 27.9% of CRs respectively(P = 0.33). After a median observation time of 36 months (range: 1 to 85months), the actuarial 5-year RFS, EFS, and OS rates were 42.8% vs66.6% (P = 0.27), 14.6% vs 16.2%, and 31.8% vs 30.2% (P = 0.29) forMJMA and MIPE respectively. For CR pts the median TTF was 8 months(95% CI, 6 to 10), and 6 months (95% CI, 5 to 7)[P = 0.3], and the mediansurvival time 14 (range: 1 to 91; 95% CI, 1.93 to 26.07) and 7 months(range: 1 to 90; 95% CI, 3.26 to 10.74) [P = 0.4] for MJMA and MIPErespectively. In multivariate analysis pts with IPI score 0-1 had significantlybetter 5-yr OS than those with score 2-5 (57 vs 16.6%; p = 0.0002).The WHO grade III-IV hematologic toxicity was comparable in the twoarm (59 vs 67%) while the mucositis occurred more frequently in theMIPE arm (37 vs 7%; P = 0.0001). Twenty patients in the MJMA and 22in the MIPE arm died of progressive disease while 1 and 3 patientsrespectively died of treatment-related toxicity.Conclusion: the results of this randomized study show that both regimensare effective and safe in patients with refractory/relapsed aNHL; the5-year EFS and OS rates achieved in both arm are comparable with thosereported by other series in patients with only chemosensitive relapsed disease.In the future studies including monoclonal antibodies should be conducted.

2005 - ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: Final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi [Articolo su rivista]
Gobbi, Pg; Levis, A; Chisesi, T; Broglia, C; Vitolo, U; Stelitano, C; Pavone, V; Cavanna, L; Santini, G; Merli, F; Liberati, M; Baldini, L; Deliliers, Gl; Angelucci, E; Bordonaro, R; Federico, Massimo
abstract

Purpose: prospective, randomized clinical trial on advanced Hodgkin's lymphoma (HL), In this multicenter doxorubicin, vinblastine, mechloreththe efficacy and toxicity of two chemotherapy regimens, annine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to <= two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program). Patients and Methods: Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively. Results: The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses. Conclusion: When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with limited irradiation.

2005 - Aggressive non-Hodgkin's lymphoma in the elderly: A validated prognostic evaluation performed by the Gruppo Italiano per lo Studio dei Linfomi (GISL) [Articolo su rivista]
Mazza, P; Marcheselli, L; Specchia, M; Luminari, Stefano; Partesotti, G; Montanini, A; Fregoni, V; Federico, Massimo; Merli, F.
abstract

2005 - Centroblastic (CB) and immunoblastic (IB) subtypes of diffuse large B cell lymphomas (DLBCL) have such a different clinical outcome that should be considered as separate entities in the WHO classification of lymphomas. A GISL study [Articolo su rivista]
Federico, Massimo; Artusi, T; Luminari, Stefano; Brugiatelli, M; Ricciotti, M; Marcheselli, L; Molica, S; Lombardo, M; Angrilli, F; Polimeno, G; Gobbi, P.
abstract

2005 - Classic Kaposi's sarcoma in Italy [Articolo su rivista]
Dal Maso, L.; Polesel, J.; Ascoli, V.; Zambon, P.; Budroni, M.; Ferretti, S.; Tumino, R.; Tagliabue, G.; Patriarca, S.; Federico, Massimo; Vercelli, M.; Giacomin, A.; Vicario, G.; Bellù, F.; Falcini, F.; Crocetti, E.; De Lisi, V.; Vitarelli, S.; Piffer, S.; Stracci, F.; Serraino, D.; Rezza, G.; Franceschi, S.; for the, Cancer; AIDS Registry Linkage, Study
abstract

To evaluate incidence rates (IRs) of classic Kaposi's sarcoma (CKS) in Italy after the spread of AIDS, we distinguished CKS from AIDS-related KS (AKS) using an 'ad hoc' record linkage procedure between 15 Cancer Registries (CRs) (21% of the Italian population) and the national AIDS Registry. Between 1985 and 1998, 874 cases of CKS and 634 cases of AKS were diagnosed in the study areas. CKS accounted for 16 and 27% of KS cases below 55 years of age in men and women, respectively, but for 91 and 100% of those above age 55. The IRs for CKS were 1.0/ in men and 0.4/100,000 in women, but they varied between 0.3 in Umbria and 4.7 in Sassari in men, and between 0.1 in Parma and 1.7 in Sassari in women. IRs of CKS in both genders were stable between 1985-1987 and 1993-1998. In Northern and Central CRs the IR (adjusted for age and gender) for CKS was 0.5 in individuals born in the same area, but 1.6 in individuals born in Southern Italy or in the Islands (rate ratio = 3.2) suggesting that KS-associated herpesvirus, the cause of KS, is acquired early in life.

2005 - Comment on 'Cancer genetic counselling' by P. Mandich et al. [Articolo su rivista]
Contegiacomo, A; Pensabene, M; Capuano, I; Tauchmanova, L; Federico, Massimo; Turchetti, D; Cortesi, L; Marchetti, P; Ricevuto, E; Cianci, G; Barbieri, Viola; Venuta, S; Silingardi, Vittorio
abstract

no abstract

2005 - Fludarabine and cyclophosphamide combination in the treatment of patients with indolent non-follicular B-cell non-Hodgkin's lymphomas. Results of a phase II trial of the Gruppo Italiano per lo Studio dei Linfomi (GISL). [Articolo su rivista]
Federico, Massimo; Luminari, Stefano; Brugiatelli, M; Goldaniga, M; Sacchi, Stefano; Merli, F; Stelitano, C; Bagnulo, A; Rizzo, M; Baldini, L.
abstract

2005 - High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an Intergruppo Italiano Linfomi randomized trial [Articolo su rivista]
Vitolo, U; Liberati, Alessandro; Cabras, Mg; Federico, Massimo; Angelucci, E; Baldini, L; Boccomini, C; Brugiatelli, M; Calvi, R; Ciccone, G; Genua, A; Deliliers, Gl; Levis, A; Parvis, G; Pavone, E; Salvi, F; Sborgia, M; Gallo, E.
abstract

Background and Objectives. Poor prognosis diffuse large cell lymphoma (DLCL) responds poorly to standard chemotherapy. Randomized studies comparing high-dose chemotherapy with autologous stem-cell transplantation (ASCT) against standard chemotherapy have produced conflicting results. Dose-dense chemotherapy with granulocyte colony-stimulating factor (G-CSF) support seems to hold promise. The purpose of this multicenter, randomized trial was to compare failure-free and overall survival in patients with poor prognosis DLCL treated with high-dose sequential (HDS) chemotherapy followed by ASCT or an outpatient dose-dense chemotherapy regimen (MegaCEOP). Design and Methods. Between 1996 and 2001, 130 DLCL patients, aged <= 60 years, with intermediate-high or high-risk disease, according to the International Prognostic Index score, and/or bone marrow involvement were enrolled. Sixty were randomized to HDS chemotherapy plus high-dose mitoxantrone and melphalan with ASCT (arm A) and 66 to the MegaCEOP regimen (6-8 courses of an escalated dose of cyclophosphamide and epirubicin plus vincristine and prednisone with G-CSF every 2-weeks) (arm B); 4 patients were considered ineligible. Results. The complete remission rate was 59% in arm A and 70% in arm B (p=0.18). After a median follow-up of 78 months, the 6-year failure-free survival was 45% in arm A and 48% in arm B (hazard ratio=1.15, 95% confidence intervals =0.72-1.84, p=0.56). The 5-year overall survival was 49% in arm A and 63% in arm B (hazard ratio=1.67, 95% confidence interval=0.98-2.85, p=0.06). Two cases of secondary acute myeloid leukemia were observed after treatment in group A. Interpretations and Conclusions. HDS and ASCT as initial therapy for patients with poor-prognosis DLCL does not provide a benefit over that of outpatient dose-dense MegaCEOP chemotherapy.

2005 - I tumoti in provincia di Modena nel 2003 [Monografia/Trattato scientifico]
Federico, Massimo; Rashid, I.; Artioli, M. E.; Cirilli, C.; Fracca, A.; Vinceti, Marco; Maiorana, Antonino; De Girolamo, G.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

2005 - In situ breast cancer: Incidence trend and organised screening programmes in Italy [Articolo su rivista]
A., Barchielli; Federico, Massimo; V., DE LISI; L., Bucchi; S., Ferretti; E., Paci; A., Ponti; E., BUIATTI AND FOR THE SCREENREG WORKING GROUP
abstract

The effect of mammography screening programmes on the incidence of in situ breast cancer (CIS) is described by analysis of the CIS incidence trend in the 1990s and comparison of pre-screening and screening periods in six areas of Italy. All 1069 CIS arising in women aged 40-79 years between 1988 and 1999 were analysed through age-standardised rates and Poisson regression models. The results show that, for the whole series, ductal carcinoma in situ (DCIS) represented 89% and lobular carcinoma in situ (LCIS) 11% of CIS detected. For all six areas, the introduction of screening increased the incidence of DCIS (screening/pre-screening ratio, range 1.12-1.77). Overall, DCIS represented 11% (226/2022) of all screening-detected cancers. A significant increasing trend in DCIS incidence during the 1990s and a modification in pattern of age-specific incidence rates after the beginning of screening programmes were observed. This increase can largely be explained by screening programmes. The incidence observed during the screening period was a persistent 39% higher than during the pre-screening period, after adjustment for the "percentage of cases diagnosed by screening". The increase also involves women at an age not targeted by screening programmes. In conclusion, as the increasing trend in DCIS is not completely explained by the effect of the screening programmes, this supports the use of mammography as a "spontaneous" preventive practice during ongoing organised screening programmes, particularly among age groups not usually invited for screening. Therefore, the effect of mammography on stage-specific incidence of CIS may be more marked than expected on the basis of the effect of screening programmes.

2005 - MOPPEBVCAD CHEMOTHERAPY WITH LIMITED RADIOTHERAPYIN ADVANCED HODGKIN’S LYMPHOMA: 10-YEARRESULTS [Abstract in Rivista]
C., Broglia; P., Gobbi; A., Levis; Sacchi, Stefano; T., Chisesi; F., Valentino; E., Iannitto; M., Brugiatelli; L., Baldini; Federico, Massimo
abstract

Background: In 1987 the MOPPEBVCAD chemotherapy regimen wasone of the first attempts at reducing late toxicity and second tumor incidencewhile carrying out some basic concepts of the Goldie and Coldmantheory on cell growth to increase effectiveness. The new treatment programintensified and hybridized all the drugs of three previously alternatingregimens (CAD, MOPP and ABV), lowered the cumulative dose ofmechlorethamine and made irradiation optional, reducing it to no morethan 2 sites which responded uncertainly or partially to chemotherapy.Methods: The patients treated so far with MOPPEBVCAD were includedin one open and controlled GISL study and in two randomized trials(GISL and IIL) in which it represented one of the compared treatmentarms. Staging and treatment criteria were identical in the 3 trials. Drugdosages (mg/sm) were as follows: HN2 6 i.v. d 1 (cycles 1, 3 and 5),CCNU 100 p.o. d 1 (cycles 2, 4 and 6), VDZ 3 i.v. d 1, MPH 6 p.o.d 1–3, Pred p.o. 40 d 1–14, EPI 40 i.v. d 8, VCR i.v. d 8, PCZ 100 p.o.d 8–14, VBL 6 i.v. d 15 and Bleo i.v. 10 d 15 (q 28 day for 6 cycles).Radiotherapy doses ranged from 25 to 40 Gy.Results: A total of 307 treated patients were reviewed. With a median follow-up of 110 months, 10-year overall-, disease- and failure-free survivalwere 78%, 81%, 79%, respectively. Two hundred and ninety patients (94%) achieved complete remission, 12 (4%) obtained partial responsewhile 5 (2%) did not respond. Forty-two patients relapsed and 60 died.The causes of death were Hodgkin’s lymphoma in 36 patients, secondneoplasms in 12, cardiorespiratory diseases in 4, pulmonary diseases in 2,and unknown in 6. Sixteen second tumors were diagnosed, 9 myelodisplasiasand/or acute leukemias, 3 secondary non-Hodgkin’s and 4 solidtumors. Among these patients deaths due to second neoplasms were 8, 2and 2, respectively.Conclusions: Clinical response and long-term results are excellent, atleast as good as that from the best and most recent therapeutic combinations,and better than those attainable with MOPP or MOPP-like regimens.The second tumor incidence, however, is still too similar as thatrecorded with MOPP and MOPP variants and stimulates further effortstowards selected modifications of the schedule which can maintain effectivenesswhile reducing oncogeneity.

2005 - National estimates of cancer patients survival in Italy: a model-based method [Articolo su rivista]
Inghelmann, R.; Grande, E.; Francisci, S.; De Angelis, R.; Micheli, A.; Verdecchia, A.; Ferretti, S.; Vercelli, M.; Ramazzotti, V.; Pannelli, F.; Federico, Massimo; De Lisi, V.; Tumino, R.; Falcini, F.; Budroni, M.; Zanetti, R.; Paci, E.; Crosignani, P.; Zambon, P.; Capocaccia, R.
abstract

AIMS AND BACKGROUND: To provide model-based estimates of all cancers patient survival in Italy and in Italian large geographical areas (North-West, North-East, Center, South), where only partial coverage of cancer registries data is available, and to describe them in terms of time trends. Moreover, to measure the degree of representativeness of cancer patient survival obtained from Italian cancer registries data. METHODS: Relative survival in the four main Italian geographical areas was estimated by a parametric mixture model belonging to the class of "cure" survival models. Data used are from Italian cancer registries, stratified by sex, period of diagnosis and age. The Italian national survival was obtained as a weighted average of these area-specific estimates, with weights proportional to the number of estimated incident cases in every area. The model takes into account also differences in survival temporal trends between the areas. RESULTS: Relative survival for all cancers combined in Italian patients diagnosed in 1990-1994 was estimated to be higher in women (53%) than in men (38%) at 5 years from the diagnosis. The survival trend is increasing by period and decreasing by age, both for men and women. The greatest gain in terms of survival was obtained by the elderly, with annual mean growth rates in the period 1978-1994 equal to 3.5% and 3.2% for men and women, respectively. More than 50% of the youngest cancer patients were "cured", whereas for the elderly this proportion dropped to 15% and 25% for men and women, respectively. The South of Italy had the lowest survival and the North the most pronounced increase. CONCLUSIONS: The obtained national survival estimates are similar, but not identical, to previously published estimates, in which Italian registries' data were pooled without any adjustment for geographical representativeness. The four Italian areas have different survival levels and trends, showing variability within the country. The differences in survival between men and women may be explained by the different proportion of lethal cancers. Among males, most cases had a poor prognosis (lung and stomach cancers), whereas among females the largest proportion was made up of curable and less lethal cancers (breast cancer).

2005 - PDGFR expression in differential diagnosis between KIT-negative gastrointestinal stromal tumours and other primary soft-tissue tumours of the gastrointestinal tract [Articolo su rivista]
G., Rossi; R., Valli; F., Bertolini; A., Marchioni; A., Cavazza; C., Mucciarini; Migaldi, Mario; Federico, Massimo; G. P., Trentini; A., Sgambato
abstract

Aims: To investigate the value of platelet-derived growth factor receptors (PDGFRs) by immunohistochemistry in discriminating KIT-negative gastrointestinal stromal tumours (GISTs) from other soft-tissue neoplasms of the digestive tract. Methods and results: One-hundred and sixty-seven primary gastrointestinal mesenchymal tumours (125 GISTs, 15 intra-abdominal desmoids, 12 leiomyomas, eight leiomyosarcomas, three schwannomas, two solitary fibrous tumours, and one case each of inflammatory pseudotumour and fibroid polyp) were reclassified based on morphology and on the immunohistochemical panel recommended by the National Institutes of Health consensus on GIST. All cases were then tested with antibodies specific for PDGFR alpha and beta. Of 125 GISTs, 117 were KIT-positive (93.6%) and eight KIT-negative (6.4%). All the KIT-positive GISTs were negative for both PDGFRs, while all the eight KIT-negative GISTs expressed PDGFR-alpha, with two of them also coexpressing PDGFR-beta. Among the 42 non-GIST tumours, only a small percentage (26.6%) of desmoids immunostained for PDGFR-alpha, two of them coexpressing PDGFR-beta. Conclusions: Immunostaining with PDGFR-alpha is a helpful marker in discriminating between KIT-negative GISTs and other gastrointestinal mesenchymal lesions: all KIT-negative GISTs were positive for PDFGR-alpha, while none of the other gastrointestinal mesenchymal tumours analysed, except a small subset of desmoids, was reactive with anti-PDGFRs. These preliminary data demonstrate the suitability of commercially available antibodies to detect immunohistochemically the mutually exclusive expression of KIT and PDGFR-alpha previously reported in GISTs by molecular biological techniques. Since PDGFR exists in the form of a homodimer (alpha alpha, beta beta) or heterodimer (alpha beta) and two of the KIT-negative GISTs coexpressed both PDGFR isoforms, further investigations are required to elucidate the role of PDGFR-beta in GISTs.

2005 - Screen-detected vs clinical breast cancer: the advantage in the relative risk of lymph node metastases decreases with increasing tumour size [Articolo su rivista]
Bucchi, L.; Barchielli, A.; Ravaioli, A.; Federico, Massimo; De Lisi, V.; Ferretti, S.; Paci, E.; Vettorazzi, M.; Patriarca, S.; Frigerio, A.; Buiatti, E.; the SCREENREG Working, Group
abstract

Screen-detected (SD) breast cancers are smaller and biologically more indolent than clinically presenting cancers. An often debated question is: if left undiagnosed during their preclinical phase, would they become more aggressive or would they only increase in size? This study considered a registry-based series (1988-1999) of 3329 unifocal, pT1a-pT3 breast cancer cases aged 50-70 years, of which 994 were SD cases and 2335 clinical cases. The rationale was that (1) the average risk of lymph node involvement (N+) is lower for SD cases, (2) nodal status is the product of biological aggressiveness and chronological age of the disease, (3) for any breast cancer, tumour size is an indicator of chronological age, and (4) for SD cases, tumour size is specifically an indicator of the duration of the preclinical phase, that is, an inverse indicator of lead time. The hypothesis was that the relative protection of SD cases from the risk of N+ and, thus, their relative biological indolence decrease with increasing tumour size. The odds ratio (OR) estimate of the risk of N+ was obtained from a multiple logistic regression model that included terms for detection modality, tumour size category, patient age, histological type, and number of lymph nodes recovered. A term for the detection modality-by-tumour size category interaction was entered, and the OR for the main effect of detection by screening vs clinical diagnosis was calculated. This increased linearly from 0.05 (95% confidence interval: 0.01-0.39) in the 2-7 mm size category to 0.95 (0.64-1.40) in the 18-22 mm category. This trend is compatible with the view that biological aggressiveness of breast cancer increases during the preclinical phase.

2005 - The myocan phase II study of cyclophosphamide, oncovin, Myocet (TM) and prednisone plus rituximab (R-COMP) in elderly patients with diffuse large B-cell (DLBCL) non-Hodgkin lymphoma [Articolo su rivista]
Federico, Massimo; Caballero, M; Dyer, M; Luminari, Stefano; Thiel, E.
abstract

2005 - Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) regimen as salvage therapy in relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL): Results of a phase II study conducted by the Gruppo Italiano per lo Studio dei Linfomi (gisl) [Articolo su rivista]
Di Renzo, N; Brugiatelli, M; Montanini, A; Dell'Olio, M; Petrini, M; Stelitano, C; Liberati, Alessandro; Luminari, Stefano; Morandi, S; Giglio, G; Federico, Massimo
abstract

2004 - An oncologist-based model of cancer genetic counselling for hereditary breast and ovarian cancer [Articolo su rivista]
Contegiacomo, A; Pensabene, M; Capuano, I; Tauchmanova, L; Federico, Massimo; Turchetti, D; Cortesi, L; Marchetti, P; Ricevuto, E; Cianci, G; Venuta, S; Barbieri, Viola; Silingardi, Vittorio
abstract

Background: We describe a multistep model of cancer genetic counselling designed to promote awareness, and disease surveillance and preventive measures for hereditary and familial breast and ovarian cancer. Patients and methods: Step T0 of the model entails information giving; this is followed by pedigree analysis and risk estimation (T1), risk communication and genetic testing (T2), and genetic test result communication (T3). User consent was required to proceed from one step to the next. Surveillance and preventive measures are proposed to at-risk users. Of the 311 subjects who requested cancer genetic counselling, consent data to each counselling step were available for 295: 93 were disease-free, 187 had breast cancer, 12 had ovarian cancer and three had breast plus ovarian cancer. Results: Consent was high at T0 (98.39%), T1 (96.40%) and T2 (99.65%). Consent decreased at the crucial points of counselling: T2 (87.71%) and T3 [genetic test result communication (85.08%), and extension of counselling to and testing of relatives (65.36%)]. Conclusions: The model fosters the user's knowledge about cancer and favours identification of at-risk subjects. Furthermore, by promoting awareness about genetic testing and surveillance measures, the algorithm enables users to make a fully informed choice of action in case of predisposing or familial cancer risk.

2004 - Anthracycline-based chemotherapy as primary treatment for intravascular lymphoma [Articolo su rivista]
Ferreri, A. J. M.; Campo, E.; Ambrosetti, A.; Ilariucci, F.; Seymour, J. F.; Willemze, R.; Arrigoni, G.; Rossi, G.; Lopez Guillermo, A.; Berti, E.; Erikson, M.; Federico, Massimo; Cortelazzo, S.; Govi, S.; Frungillo, N.; Dell'Oro, S.; Lestani, M.; Asioli, S.; Pedrinis, E.; Ungari, M.; Motta, T.; Rossi, R.; Artusi, T.; Iuzzolino, P.; Zucca, E.; Cavalli, F.; Ponzoni, M.; on behalf of the International Extranodal Lymphoma Study, Group
abstract

BACKGROUND: Optimal therapeutic management of intravascular lymphoma (IVL) lacks precise guidelines. PATIENTS AND METHODS: The clinico-pathological features of 38 HIV-negative patients with IVL were reviewed to define efficacy of chemotherapy in these malignancies. Clinical characteristics of 22 patients treated with chemotherapy and of 16 untreated patients were compared in order to understand better the impact and causes of potential patient selection. RESULTS: Median age was 70 years (range 34-90), with a male/female ratio of 0.9; 23 (61%) patients had Eastern Cooperative Oncology Group performance status (ECOG-PS) > 1; 21 (55%) had systemic symptoms. Cutaneous lesions and anemia were significantly more common among patients treated with chemotherapy; central nervous system (CNS) and renal involvement were significantly more common among untreated patients. Chemotherapy was associated with a response rate of 59% and a 3-year overall survival of 33 +/- 11%. Five of six patients with CNS involvement received chemotherapy: four of them died early; only one patient, treated with adriamycin, cyclophosphamide, vincristine, methotrexate, bleomycin and prednisolone (MACOP-B) followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), was alive at 19 months. High-dose chemotherapy supported by ASCT was indicated at diagnosis in another patient (43 years of age, stage I), who was alive at 71 months, and at relapse after cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) in two patients who died early after transplantation. PS < or = 1, disease limited to the skin, stage I, and use of chemotherapy were independently associated with better outcome. CONCLUSIONS: Anthracycline-based chemotherapy is the standard treatment for IVL. However, survival is disappointing, with a relevant impact of diagnostic delay and lethal complications. More intensive combinations, containing drugs with higher CNS bioavailability, are needed in cases with brain involvement, and the role of high-dose chemotherapy supported by ASCT should be further investigated in younger patients with unfavorable features. Copyright 2004 European Society for Medical Oncology

2004 - Breast Carcinoma Survival in Europe and the United States: A Population-Based Study [Articolo su rivista]
Sant, M.; Allemani, C.; Berrino, F.; Coleman, M. P.; Aareleid, T.; Chaplain, G.; Coebergh, J. W.; Colonna, M.; Crosignani, P.; Danzon, A.; Federico, Massimo; Gafà, L.; Grosclaude, P.; Hédelin, G.; Macè Lesech, J.; Martinez Garcia, C.; Møller, H.; Paci, E.; Raverdy, N.; Tretarre, B.; Williams, E. M. I.; Kupp, A.; Exbrayat, C.; Mercier, M.; Artioli, E.; Barchielli, A.; Gatta, G.; Sant, M.; Allemani, C.; Speciale, D.; Ruzza, M. R.; Frassoldi, E.; Capocaccia, R.; Verdecchia, A.; Gafà, L.; Tumino, R.; La Rosa, M.; Voogd, A.; Bell, J.; Youngson, J.
abstract

BACKGROUND. Breast carcinoma survival rates were found to be higher in the U.S. than in Europe. METHODS. Multiple regression analysis of breast carcinoma survival rates among women diagnosed between 1990 and 1992 was performed using clinical data from population-based case series from the Surveillance, Epidemiogy, and End Results (SEER) program (13,172 women) and the European Concerted Action on survival and Care of Cancer Patients (EUROCARE) project (4478 women). RESULTS. Early-stage tumors (T1N0M0) were more frequent in the SEER data (41% of cases) than in the EUROCARE data (29%). In the SEER data, early tumors were more frequent in women age ≥ 65 years (43%) than in younger women (38%), whereas the reverse was true in the European data (25% vs. 31%). In both case series, &gt; 90% of women underwent surgery and 81-82% underwent lymphadenectomy, but the number of axillary lymph nodes evaluated was higher in the SEER data than in the EUROCARE data. The 5-year survival rate was higher in the U.S. case series (89%) than in the European series (79%). This differential was observed for each stage category evaluated: early (T1N0M0), large lymph node-negative (T2-3N0M0), lymph node-positive (T1-3N+M0), locally advanced (T4M0), and metastatic (M1) tumors. The overall relative excess risk (RER) of death was significantly higher (RER, 1.37; 95% confidence interval [95% CI], 1.25-1.50) among European women compared with U.S. women (referent group). Adjustment for stage, age, surgery, and the number of lymph nodes evaluated explained most of the excess risk (RER, 1.07; 95% CI, 0.98-1.17). CONCLUSIONS. Transatlantic differences in the 5-year survival rates for women diagnosed with breast carcinoma between 1990 and 1992 were attributable mainly to differences in stage of disease. Resources should be invested to achieve earlier diagnosis of breast carcinoma in Europe, especially for elderly women.

2004 - Clinical relevance of immunophenotype in a retrospective comparative study of 297 peripheral T-cell lymphomas, unspecified, and 496 diffuse large B-cell lymphomas: experience of the Intergruppo Italiano Linformi. [Articolo su rivista]
F., Morabito; A., Gallamini; C., Stelitano; V., Callea; C., Guglielmi; S., Neri; A., Lazzaro; L., Orsucci; F., Ilariucci; Sacchi, Stefano; U., Vitolo; Federico, Massimo
abstract

BACKGROUND. To assess the impact of T-cell/B-cell phenotype on clinical outcome, the authors retrospectively compared patients who had peripheral T-cell lymphoma, unspecified (PTCL-U), with patients who had diffuse large B-cell lymphoma (DLBCL). METHODS. Two hundred ninety-seven cases of PTCL-U and 496 cases of DLBCL that had been transferred from the files of the Intergruppo Italiano Linfomi or the Gruppo Italiano Linfomi were integrated into a unique working file and reviewed by the authors. RESULTS. The PTCL-U group and the DLBCL group had significantly different distribution patterns with respect to patient age, gender, disease stage, performance status (PS), the presence or absence of systemic B symptoms, the presence or absence of bulky disease, lactic acid dehydrogenase (LDH) levels, and number of extranodal sites (ENS). A significantly greater number of patients in the DLBCL group experienced complete remission (P < 0.0001). Multinomial logistic regression analysis confirmed that immunophenotype, PS, LDH concentration, and number of ENS were independent predictors of response. At a median follow-tip duration of 43 months, there was no observable difference in disease-free Survival (DFS) between patients with DLBCL and patients with PTCL-U; however, multivariate analysis did reveal that poorer PS and bone marrow involvement were significantly associated with shorter DFS. Furthermore, although the overall survival (OS) curves associated with the T-cell and B-cell ummunophenotypes were significantly different from each other at a median follow-up duration of 37 months (P = 0.0012), Cox multivariate analysis excluded immunophenotype from the final OS model. CONCLUSIONS. The findings made in the current study indicate that the natural history of PTCL-U may differ from that of DLBCL. Patients with PTCL-U tended to have less favorable clinical outcomes, although the observed difference in outcome was only partially attributable to immunophenotype, which was independently associated with response, but not with survival. Differences in prognostic factor distributions between patients with PTCL-U and patients with DLBCL may account for some portion of the expected phenotype-associated risk.

2004 - Erratum: Splenosis peritonei (British Journal of Heamatology 123:3 (378)) [Articolo su rivista]
Luminari, S.; De Santis, M.; Casolo, A.; Federico, M.
abstract

2004 - FLUDARABINE AND CYCLOPHOSPHAMIDE FOR THE TREATMENT OF PATIENTS WITH INDOLENT NON-FOLLICULAR (INFL) B-CELL NON-HODGKIN'S LYMPHOMAS. PRELIMINARY RESULTS OF A PHASE II TRIAL OF THE 'GRUPPO ITALIANO PER LO STUDIO DEI LINFOMI (GISL) [Abstract in Rivista]
Luminari, Stefano; L., Baldini; M., Brugiatelli; M., Goldaniga; Sacchi, Stefano; A., Bagnulo; F., Merli; C., Stelitano; G., Giglio; Federico, Massimo
abstract

Introduction: INFL comprises a rather heterogeneous subgroup of lymphomas,including small lymphocytic lymphoma (SLL), immunocytoma (IC) and marginalzone lymphomas (MZL). In April 2002, the GISL started a phase II trial to verifythe efficacy of fludarabine and cyclophosphamide (Flu–Cy) combination in this subsetof NHL, in terms of response, survival and toxicity.Patients and methods: Patients should have a diagnosis of SLL, IC, MZL or CD5negative mature B-cell leukemia (MBCL), supported by morphologic, phenotypicand molecular data; patients should also be untreated for lymphoma and have activedisease defined by the presence of anemia, thrombocytopenia, bulky disease, rapidlyincreasing lymphocytosis or enlarging masses. Treatment consisted of fludarabine25 mg/m2 i.v. day 1–3 and cyclophosphamide 250 mg/m2 i.v. days 1–3, to berepeated every 28 days for six cycles; an intermediate evaluation of response afterthree cycles was planned and an adequate anti-infective prophylaxis was mandatory.Results: As of March 2004, 44 patients were registered into the trial; one patientwas excluded from the study due to incorrect histology. Median age was 63 years(range 39–75), M/F ratio was 1.9. The diagnosis was SLL in 11 patients, IC in 7,MZL in 19 and MBCL in 5. All patients had stage IV disease. Anemia was presentin 32%, elevated b2 microglobulin in 56%, abnormal LDH in 32%. At the time ofthe present analysis, 24 patients completed the treatment program with 13 CR (52%)and 11 PRs (44%). Three patients died during treatment, one after the second cycledue to erosive pulmonary aspergillosis, the others due to bone marrow aplasiaoccurred after the 4th and 5th cycle, respectively. Overall, grade III or IV hematologicaltoxicity was observed in 44% of the patients. After a median follow-up of9 months, OS was 81%.Conclusion: The preliminary results of our study demonstrate that the Flu–Cycombination is effective in the treatment of patients with INFL but has also shown arelevant toxicity profile suggesting the need for extensive antimicrobial prophylaxis

2004 - Follicular lymphoma international prognostic index. [Articolo su rivista]
SOLAL CELIGNY, P; Roy, P; Colombat, P; White, J; Armitage, Jo; ARRANZ SAEZ, R; Au, Wy; Bellei, Monica; Brice, P; Caballero, D; Coiffier, B; CONDE GARCIA, E; Doyen, C; Federico, Massimo; Fisher, Ri; GARCIA CONDE, Jf; Guglielmi, C; Hagenbeek, A; Haioun, C; Leblanc, M; Lister, At; LOPEZ GUILLERMO, A; Mclaughlin, P; Milpied, N; Morel, P; Mounier, N; Proctor, Sj; Rohatiner, A; Smith, P; Soubeyran, P; Tilly, H; Vitolo, U; Zinzani, Pl; Zucca, E; Montserrat, E.
abstract

The prognosis of follicular lymphomas (FL) is heterogeneous and numerous treatments may be proposed. A validated prognostic index (PI) would help in evaluating and choosing these treatments. Characteristics at diagnosis were collected from 4167 patients with FL diagnosed between 1985 and 1992. Univariate and multivariate analyses were used to propose a PI. This index was then tested on 919 patients. Five adverse prognostic factors were selected: age (&gt; 60 years vs &lt; or = 60 years), Ann Arbor stage (III-IV vs I-II), hemoglobin level (&lt; 120 g/L vs &gt; or = 120 g/L), number of nodal areas (&gt; 4 vs &lt; or = 4), and serum LDH level (above normal vs normal or below). Three risk groups were defined: low risk (0-1 adverse factor, 36% of patients), intermediate risk (2 factors, 37% of patients, hazard ratio [HR] of 2.3), and poor risk (&gt; or = 3 adverse factors, 27% of patients, HR = 4.3). This Follicular Lymphoma International Prognostic Index (FLIPI) appeared more discriminant than the International Prognostic Index proposed for aggressive non-Hodgkin lymphomas. Results were very similar in the confirmation group. The FLIPI may be used for improving treatment choices, comparing clinical trials, and designing studies to evaluate new treatments.

2004 - Hodgkin's disease - A quantitative evaluation by computed tomography of tumor burden [Articolo su rivista]
Torricelli, Pietro; Grimaldi, Pl; Fiocchi, Federica; Federico, Massimo; Romagnoli, Renato
abstract

A direct method for the evaluation by computed tomography (CT) of the neoplastic mass (tumor burden [TB]) has been adopted in 34 patients diagnosed with Hodgkin´s disease in the early stage. Stressed are its prognostic value, and its correlation with the clinical and laboratory parameters usually adopted in the staging of the disease and in its follow-up. It is concluded that the CT-calculated TB is a reliable index showing good correlation with other commonly used prognostic parameters.

2004 - I tumor in provincia di Modena nel 2002 [Monografia/Trattato scientifico]
Federico, Massimo; Artioli, M. E.; Rashid, I.; Fracca, A.; Cortesi, L.; Luminari, Stefano; Maiorana, Antonino; De Girolamo, G.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

2004 - I tumori in provincia di Salerno nel 1998-1999 [Monografia/Trattato scientifico]
Donato, A.; Federico, Massimo; Apicella, A. M.; Ferrentino, A.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Salerno

2004 - Il linfoma mantellare [Capitolo/Saggio]
Federico, Massimo; Luminari, Stefano; Artusi, Tullio
abstract

Il linfoma mantellare (LM) è stato identificato per la prima volta come entità clinico-patologica distinta solo agli inizi degli anni 90 (1), con la scoperta della specifica traslocazione cromosomica t (11;14), ma era già stato ben descritto dal punto di vista morfologico nel 1982 da Denis Weisenburger che lo aveva definito com elinfoma della zona mantellare (2). L'esistenza di un linfoma costituito interamente da cellule clivate, con un comportamento clinico diverso dagli altri linfomi di origine centrofollicolare era stata postulata già negli anni 70 da Karl Lennert e dalla sua scuola di Kiel, che avevano coniato il termine di "linfoma centrocitico puro" (3). E' verosimile che casi di LM in passato siano stati classificati come linfomi linfocitici intermedi (4), a cellule clivate (5), centrocitici (6) o centrocitici diffusi a picocle cellule clivate (7).Il LM è stato riconosciuto definitivamente come una entità distinta nella recente classificazione dei linfomi della WHO ed ha una storia naturale ed una prognosi nettamente diversa dai linfomi di origine centrofollicolare e da quelli linfocitici che per molti anni sono stati inseriti nel gruppo ormai eterogeneo dei linfomi non-Hofgkin (LNH) indolenti.

2004 - Il linfoma mantellare. Linfomi non-Hodgkin [Monografia/Trattato scientifico]
Federico, Massimo; Luminari, Stefano; Artusi, Tullio
abstract

Monografia scientifica sul linfoma mantellare

2004 - Linfomi: linfomi di Hodgkin e linfomi non-Hodgkin [Articolo su rivista]
Federico, Massimo; Conti, E. M. S.
abstract

Vengono presentati i risultati dello studio degli andamenti temporali dei linfomi nella banca dati dell'Associazione Italiana Registri Tumori (pool AIRT) nel periodo 1986-1997. I linfomi di Hodgkin (2.959 casi e 911 decessi inclusi nell'analisi) presentano una riduzione dell'incidenza, statisticamente significativa fra i maschi. I tassi standardizzati di mortalità si sono ridotti significativamente, in entrambi i sessi, nel periodo 1986-1997 ad un ritmo medio di 7-9% all'anno.Per quanto riquarda i linfomi non-Hodgkin (16.470 casi incidenti e 7.193 decessi analizzati) è presente una significativa crescita, sia nei maschi che nelle femmine, sia dei tassi di incidenza (oltre il 3% all'anno) che di quelli di mortalità (circa il 2 %/anno)

2004 - Penetrances of breast and ovarian cancer in a large series of families tested for BRCA1/2 mutations [Articolo su rivista]
Marroni, F; Aretini, P; D'Andrea, E; Caligo, Ma; Cortesi, L; Viel, A; Ricevuto, E; Montagna, M; Cipollini, G; Federico, Massimo; Santarosa, M; Marchetti, P; Bailey Wilson, Je; Bevilacqua, G; Parmigiani, G; Presciuttini, S.
abstract

Accurate estimates of breast and ovarian cancer penetrance in BRCA1/2 mutation carriers are crucial in genetic counseling. Estimation is difficult because of the low frequency of mutated alleles and the often-uncertain mechanisms of family ascertainment. We estimated the penetrances of breast and ovarian cancers in carriers of BRCA1/2 mutations by maximizing the retrospective likelihood of the genetic model, given the observed test results, in 568 Italian families screened for germline mutations. The software BRCAPRO was used as a probability calculation tool in a Markov Chain Monte Carlo approach. Breast cancer penetrances were 27% (95% CI 20-34%) at age 50 years and 39% (27-52%) at age 70 in BRCA1 carriers, and 26% (0.18-0.34%) at age 50 and 44% (29-58%) at age 70 in BRCA2 carriers, and ovarian cancer penetrances were 14% (7-22%) at age 50 and 43% (21-66%) at age 70 in BRCA1 carriers and 3% (0-7%) at age 50 and 15% (4-26%) at age 70 in BRCA2 carriers. The new model gave a better fit than the current default in BRCAPRO, the likelihood being 70 log units greater; in addition, the observed numbers of mutations in families stratified by gene and by cancer profile were not significantly different from those expected. Our new penetrance functions are appropriate for predicting breast cancer risk, and for determining the probability of carrying BRCA1/2 mutations, in people who are presently referred to genetic counseling in Italy. Our approach could lead to country-customized versions of the BRCAPRO software by providing appropriate population-specific estimates.

2004 - Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study [Articolo su rivista]
A., Gallamini; C., Stelitano; R., Calvi; Bellei, Monica; D., Mattei; U., Vitolo; F., Morabito; M., Martelli; E., Brusamolino; E., Iannitto; F., Zaja; S., Cortelazzo; L., Rigacci; L., Devizzi; G., Todeschini; G., Santini; M., Brugiatelli; Federico, Massimo
abstract

To assess the prognosis of peripheral T-cell lymphoma unspecified, we retrospectively analyzed 385 cases fulfilling the criteria defined by the World Health Organization classification. Factors associated with a worse overall survival (OS) in a univariate analysis were age older than 60 years (P=.0002), equal to or more than 2 extranodal sites (P=.0002), lactic dehydrogenase (LDH) value at normal levels or above (P&lt;.0001), performance status (PS) equal to or more than 2 (Pless than or equal to.0001), stage III or higher (P=.0001), and bone marrow involvement (P=.0001). Multivariate analysis showed that age (relative risk, 1.732; 95% CI, 1.300-2.309; P&lt;.0001), PS (relative risk, 1.719; 95% CI, 1.269-2.327, P&lt;.0001), LDH level (relative risk, 1.905; 95% CI, 1.415-2.564; P&lt;.0001), and bone marrow involvement (relative risk, 1.454; 95% CI, 1.045-2.023; P=.026) were factors independently predictive for survival. Using these 4 variables we constructed a new prognostic model that singled out 4 groups at different risk: group 1, no adverse factors, with 5-year and 10-year OS of 62.3% and 54.9%, respectively; group 2, one factor, with a 5-year and 10-year OS of 52.9% and 38.8%, respectively; group 3, 2 factors, with 5-year and 10-year OS of 32.9% and 18.0%, respectively; group 4,3 or 4 factors, with a 5-year and 10-year OS of 18.3 and 12.6%, respectively (Pless than or equal to.0001; log-rank, 66.79).

2004 - Prognostic value of morphology and hormone receptor status in breast cancer - a population based study [Articolo su rivista]
Allemani, C.; Sant, M.; Berrino, F.; Aareleid, T.; Chaplain, G.; Coebergh, J. W.; Colonna, M.; Costiero, P.; Danzon, A.; Federico, Massimo; Gafà, L.; Grosclaude, P.; Hedelin, G.; Macè Lesech, J.; Garcia, C. M.; Paci, E.; Raverdy, N.; Tretarre, B.; Williaams, E.
abstract

We analysed the 5-year relative survival among 4473 breast cancer cases diagnosed in 1990-1992 from cancer registries in Estonia, France, Italy, Spain, the Netherlands and the UK. Among eight categories based on ICD-O codes (infiltrating ductal carcinoma, lobular plus mixed carcinoma, comedocarcinoma, 'special types', medullary carcinoma, not otherwise specified (NOS) carcinoma, other carcinoma and cancer without microscopic confirmation), the 5-year relative survival ranged from 66% (95% CI 61-71) for NOS carcinoma to 95% (95% CI 90-100) for special types (tubular, apocrine, cribriform, papillary, mucinous and signet ring cell); 27% (95% CI 18-36) for cases without microscopic confirmation. Differences in 5-year relative survival by tumor morphology and hormone receptor status were modelled using a multiple regression approach based on generalised linear models. Morphology and hormone receptor status were confirmed as significant survival predictors in this population-based study, even after adjusting for age and stage at diagnosis.

2004 - Quality of life assessment in elderly patients with aggressive non-Hodgkin's Lymphoma treated with anthracycline-containing regimens. Report of a prospective study by the Intergruppo Italiano Linfomi [Articolo su rivista]
Merli, F; Bertini, M; Luminari, Stefano; Mozzana, R; Berte, R; Trottini, M; Stelitano, C; Botto, B; Pizzuti, M; Quintana, G; De Paoli, A; Federico, Massimo
abstract

Background and Objectives. The aim of this study was to evaluate quality of life (QOL) in a group of elderly patients ( > 65 years) with aggressive non-Hodgkin's lymphoma (NHL) treated with chemotherapy regimens containing anthracyclines. Design and Methods. QOL was evaluated in a population of elderly patients with aggressive NHL enrolled in a phase III clinical trial run by the Intergruppo Italiano Linfomi (11L) from 1996 to 1999 to compare two different anthracycline-containing regimens (mini-CEOP vs P-VEBEC). The EORTC-QLQ-C30 questionnaire, which has already been validated in oncology, was used. The questionnaire was administered at the time of diagnosis, half way through the chemotherapy and at the time of restaging. Results. Ninety-one patients completed pre-therapy and post-therapy questionnaires and they are the subject of this report. Baseline QOL assessment showed a strong correlation of poor values of QOL with anemia and high risk according to the International Prognostic Index (IPI). At the end of treatment no functional scales showed worse values. A significant improvement was observed for pain (p = 0.003), appetite (p = 0.006), sleep (p = 0.015) and global health (p = 0.027). Considering only the 50 patients who achieved a complete remission (CR), an improvement was also recorded for emotional state (p = 0.10), role (P = 0.05), constipation (p = 0.04) and global QOL (p = 0.05). Interpretation and Conclusions. The EORTC-QLQ-C30 is feasible even in a population of elderly patients, in whom it had never been tested before. The improvement of QOL at the end of the treatment demonstrated that the symptoms of the disease have a greater negative influence on the patient's life than do the side effects of the therapy.

2003 - Childhood cancer survival in Europe [Articolo su rivista]
Gatta, G.; Corazziari, I.; Magnani, C.; Peris Bonet, R.; Roazzi, P.; Stiller, C.; Oberaigner, W.; Jechova, M.; Rousarova, M.; Storm, H. H.; Aareleid, T.; Hakulinen, T.; Hédelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Macé Lesech, I.; Faivre, I.; Chaplain, G.; Carli, P. M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, F.; Grosclaude, P.; Estève, I.; Kaatsch, P.; Tryggvadottir, L.; Berrino, F.; Allemani, C.; Baili, P.; Ciccolallo, L.; Gatta, G.; Micheli, A.; Sant, M.; Taussig, E.; Capocaccia, R.; Carrani, E.; De Angelis, R.; Hartley, S.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Ferretti, S.; Crosignani, P.; Tagliabue, G.; Conti, E.; Vercelli, M.; Pannelli, F.; Mosciatti, P.; Federico, Massimo; Artioli, M. E.; De Lisi, V.; Serventi, L.; Magnani, C.; Pastore, G.; Gafà, L.; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P.; Guzzinati, S.; Dalmas, M.; Langmark, F.; Andersen, A; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pleško, I.; Obsitníková, A.; Pompe Kirn, V.; Izarzugaza, I.; Martinez Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Peris Bonet, R.; Barlow, L.; Möller, T.; Lutz, J. M.; Usel, M.; Coebergh, J. W. W.; Van Der Does Van Den Berg, A.; Visser, O.; Coleman, M. P.; Stiller, C.; Black, R.; Brewster, D.
abstract

Background: EUROCARE-3 collected data from 45 population-based cancer registries in 20 countries on 24 620 European children aged from 0 to 14 years diagnosed with malignancy in the period 1990-1994. Methods: Five-year survival between countries was compared for all malignancies and for the major diagnostic categories, adjusting for age, and estimated average European survival weighting for differences in childhood populations. Results: For all cancers combined, survival variation was large (45% in Estonia to 90% in Iceland), and was generally low (60-70%) in eastern Europe and high (≥75%) in Switzerland, Germany and the Nordic countries (except Denmark). The Nordic countries had the highest survival for four of the seven major tumour types: nephroblastoma (92%), acute lymphoid leukaemia (85%), CNS tumours (73%) and acute non-lymphocytic leukaemia (62%). The eastern countries had lowest survival: 89% for Hodgkin's disease, 71% for nephroblastoma, 68% for acute lymphoid leukaemia, 61% for non-Hodgkin's lymphoma, 57% for central nervous system (CNS) tumours and 29% for acute non-lymphocytic leukaemia. Conclusions: The Nordic countries represent a survival gold standard to which other countries can aspire. Since most childhood cancers respond well to treatment, survival differences are attributable to differences in access (including referral and timely diagnosis) and use of modern treatments; however, the obstacles to access and application of standard treatments probably vary markedly with country.

2003 - Different expressivity of BRCA1 and BRCA2: analysis of 179 Italian pedigrees with identified mutation [Articolo su rivista]
Aretini, P; D'Andrea, E; Pasini, B; Viel, A; Costantini, Rm; Cortesi, L; Ricevuto, E; Agata, S; Bisegna, R; Boiocchi, M; Caligo, Ma; Chieco Bianchi, L; Cipollini, G; Crucianelli, R; D'Amico, C; Federico, Massimo; Ghimenti, C; De Giacomi, C; De Nicolo, A; Della Puppa, L; Ferrari, Stefano; Ficorella, C; Iandolo, D; Manoukian, S; Marchetti, P; Marroni, F; Menin, C; Montagna, M; Ottini, L; Pensotti, V; Pierotti, M; Radice, P; Santarosa, M; Silingardi, Vittorio; Turchetti, D; Bevilacqua, G; Presciuttini, S.
abstract

Mutations in BRCA1 and BRCA2 show different expressivity with respect to cancer risk, and allelic heterogeneity may be present in both genes. We collected 179 pedigrees with identified germline mutation ( 104 BRCA1 and 75 BRCA2), ascertained in six collaborating centers of the Italian Consortium for Hereditary Breast and Ovarian Cancer. Significant heterogeneity was detected for several variables, and a logistic regression model including age of diagnosis in the proband, presence of ovarian cancer in the family, presence of prostate or pancreatic cancer in the family, and presence of male breast cancer in the family proved to be effective in predicting the presence of a mutation in a gene rather than the other. Excess of familial aggregation of both breast and ovarian cancer was observed in both genes. Proportion of ovarian cancer was increased in the 5' portion of BRCA1, and presence of prostate or pancreatic cancer in a family was correlated with presence of ovarian cancer in BRCA2.

2003 - Do we need high-dose therapy for initial treatment of high-risk Hodgkin's disease? Venezia New isights in Hematology [Articolo su rivista]
Federico, Massimo; Luminari, Stefano
abstract

no abstract

2003 - Efficacy Controls and Long-Term Follow-Up of Patients (Pts) Treated with FC Plus Rituximab for Relapsed Follicular NHL. Session Type: Publication Only [Abstract in Rivista]
Sacchi, Stefano; Alessandra, Tucci; Francesco, Merli; Loretta, Orsucci; Giulia, Cervetti; Ubaldo, Occhini; Marina, Liberati; Giuseppe, Tarantini; Vuncenzo, Callea; Maura, Brugiatelli; Vito Michele, Lauta; Luca, Baldini; Marcheselli, Raffaella; Luminari, Stefano; Federico, Massimo
abstract

Although treatment of follicular lymphomas (FL) with standard chemotherapy regimens generally yields a high initial response rate, the clinical course consists of a pattern of repeated relapses.Subsequent responses after every new line of treatment are of progressively shorter duration and the patients eventually die of disease-related causes. The ability of Rituximab to sensitize cell lines to fludarabine, doxorubicine, vinblastine, and cisplatin together with the synergism of Rituximab with CHOP in the treatment of DLBCL, was recently reported .We have completed in April 2003 a multicenter Phase II clinical trial in 52 pts with relapsed FL. Patients received chemotherapy consistent of Fludarabine 25 mg/sqm/die and Cyclofosfamide 30 mg/sqm/die for 3 consecutive days every 3 weeks for 4 cycles. Rituximab was infused on day 1 of every cycles at a dose of 375 mg/sqm. Patient characteristic: median age 62 years (range: 44-80); disease stage: I -II B 21%, III 30%, IV 49%; number of prior chemotherapy regimens:1- 43%, 2-43%, 3-12%, 4-3%. The response rates in the intent to treat analysis is: CR 75 % (39 pts), PR 19% (10 pts) and dropouts 6% (3 pts).Of note, 58% of the pts initially bcl-2 positive in the bone marrow became bcl-2 negative following treatment.At a median follow-up of 20 months, the restricted media duration of response in the 49 pts who have obtained a response was 26 months (95% CI, 22-29). Included in the group of this 49 pts assessed for duration of response were 6 pts who had achieved a PR and a CR but whose bone marrow remained bcl-2 positive. These pts were treated with a subsequent course of 4 doses of Rituximab plus IFN-a 3 MU t.i.w for 6 weeks.Approximately 93% experienced treatment-related toxicity; however, the majority of side effects were grade 1 / 2. The most common severe adverse events were hematologic, and included 20 cases of grade 3/ 4 neutropenia, 1 case of thrombocytopenia, and 3 cases of anemia as well as infection. Five patients died during the treatment period and follow-up: 1 of myelodysplastic syndrome, 2 of disease progression, 1 of progressive carcinoma, and 1 of pneumonitis.Treatment delays of 1-3 weeks were necessary in 12 pts. Treatment interruptions were necessary in 3 pts, 1 following cycle 2 and 2 following cycle 3.The results of our trial demonstrate that this regimen is active and relatively well tollerate although significant cytopenia with delay of subsequent treatment administration was observed in several pts.Finally, a DR of 26 months after a median follow-up of 20 months compare favorably with the results obtained in other trial in similar subset of pts and support the evidence for Rituximab plus chemotherapy as a new standard for treating relapsed FL

2003 - EUROCARE-3 summary: Cancer survival in Europe at the end of the 20th century [Articolo su rivista]
Coleman, M. P.; Gatta, G.; Verdecchia, A.; Estève, J.; Sant, M.; Storm, H.; Allemani, C.; Ciccolallo, L.; Santaquilani, M.; Berrino, F.; Oberaigner, W.; Jechova, M.; Rousarova, M.; Storm, H. H.; Aareleid, T.; Hakulinen, T.; Hédelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Macé Lesec'h, J.; Faivre, J.; Chaplain, G.; Carl, P. M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, F.; Grosclaude, P.; Estèv, Z; Kaatsch, P.; Ziegler, H.; Hölzel, D.; Schubert Fritschle, G.; Tryggvadottir, L.; Berrino, F.; Allemani, C.; Baili, P.; Ciccolallo, L.; Gatta, G.; Micheli, A.; Sant, M.; Taussig, E.; Capocaccia, R.; Carrani, E.; De Angelis, R.; Hartley, S.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Ferretti, S.; Crosignani, P.; Contiero, P.; Conti, E.; Vercelli, M.; Pannelli, F.; Vitarelli, S.; Pannelli, F.; Mosciatti, P.; Federico, Massimo; Artioli, M. E.; PONZ DE LEON, Maurizio; Benatti, Piero; De Lisi, V.; Serventi, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafà, L.; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P. Guzzinati S.; Dalmas, M.; Langmark, F.; Andersen, A.; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pinheiro, P. S.; Pleško, I.; Obsitníková, A.; Pompe Kirn, V.; Izarzugaza, I.; Martinez Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Peris Bonet, R.; Barlow, L.; Möller, T.; Jundt, G. Lutz J. M.; Usel, M.; Coebergh, J. W. W.; Van Der Does Van Den Berg, A.; Visser, O.; Godward, S.; Coleman, M. P.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, C.; Verne, J.; Møller, H.; Bell, J.; Botha, J. L.; Lawrence, G.; Black, R.; Brewster, D.; Steward, J. A.
abstract

No abstract available

2003 - EUROCARE-3: survival of cancer patients diagnosed 1990–94—results and commentary [Articolo su rivista]
Sant, M.; Aareleid, T.; Berrino, F.; Bielska Lasota, M.; Carli, P. M.; Faivre, J.; Grosclaude, P.; Hédelin, G.; Matsuda, T.; Møller, H.; Möller, T.; Verdecchia, A.; Capocaccia, R.; Gatta, G.; Micheli, A.; Santaquilani, M.; Roazzi, P.; Lisi, D.; Oberaigner, W.; Jechova, M.; Rousarova, M.; Storm, H. H.; Aareleid, T.; Hakulinen, T.; Hédelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Macé Lesech, J.; Faivre, J.; Chaplain, G.; Carli, P. M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, F.; Grosclaude, P.; Estève, J.; Kaatsch, P.; Ziegler, H.; Hölzel, D.; Schubert Fritschle, G.; Tryggvadottir, L.; Berrino, F.; Allemani, C.; Baili, P.; Ciccolallo, L.; Gatta, G.; Micheli, A.; Sant, M.; Taussig, E.; Capocaccia, R.; Carrani, E.; De Angelis, R.; Hartley, S.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Ferretti, S.; Crosignani, P.; Contiero, P.; Conti, E.; Vercelli, M.; Pannelli, F.; Vitarelli, S.; Pannelli, F.; Mosciatti, P.; Federico, Massimo; Artioli, M. E.; PONZ DE LEON, Maurizio; Benatti, Piero; De Lisi, V.; Serventi, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafà, ; L., Aw; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P.; Guzzinati, S.; Dalmas, M.; Langmak, F.; Andersen, A.; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pinheiro, P. S.; Pleško, I.; Obsitníková, A.; Pompe Kirn, V.; Izarzugaza, I.; Martinez Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Peris Bonet, R.; Barlow, L.; Möller, T.; Jundt, G.; Lutz, J. M.; Usel, M.; Coebergr, J. W. W.; Van Der Does Van Den Berg, A.; Visser, O.; Godward, S.; Coleman, M. P.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, C.; Verne, J.; Møller, H.; Bell, J.; Botha, J. L.; Lawrence, G.; Black, R.; Brewster, D.; Steward, J. A.
abstract

EUROCARE-3 analysed the survival of 1 815584 adult cancer patients diagnosed from 1990 to 1994 in 22 European countries. The results are reported in tables, one per cancer site, coded according to the International Classification of Diseases (ICD)-9 classification. The main findings of the tables are summarised and commented on in this article. For most solid cancers, wide differences in survival between different European populations were found, as also reported by EUROCARE-1 and EUROCARE-2, despite a remarkable (10%) overall increase in cancer survival from 1985 to 1994. Survival was highest in northern Europe (Sweden, Norway, Finland and Iceland), and fairly good in central-southern Europe (France, Switzerland, Austria and Spain). Survival was particularly low in eastern Europe, low in Denmark and the UK, and fairly low in Portugal and Malta. The mix of tumour stage at diagnosis explains much of the survival differences for cancers of the digestive tract, female reproductive system, breast, thyroid, and also skin melanoma. For tumours of the urinary tract and prostate, the differences were explained mainly by differences in diagnostic criteria and procedures. The case mix by anatomic subsite largely explains differences in survival for head and neck cancers. For oesophagus, pancreas, liver and brain cancer, with poor prognoses, survival differences were limited. Tumours, for which highly effective treatments are available, such as testicular cancer, Hodgkin's lymphoma and some haematological malignancies, had fairly uniform survival across Europe. Survival for all tumours combined (an indicator of the overall cancer care performance of a nation's health system) was better in young than old patients, and better in women than men. The affluence of countries influenced overall cancer survival through the availability of adequate diagnostic and treatment procedures, and screening programmes. © 2003 European Society for Medical Oncology.

2003 - Follicular lymphoma: experience of the italian cooperative groups [Articolo su rivista]
Brugiatelli, M.; Mannina, D.; Neri, S.; Tarella, C.; Federico, Massimo
abstract

No abstract

2003 - High-dose sequential chemotherapy and peripheral blood progenitor cell autografting in patients with refractory and/or recurrent Hodgkin lymphoma - A multicenter study of the Intergruppo Italiano Linfomi showing prolonged disease free survival in patients [Articolo su rivista]
Tarella, C; Cuttica, A; Vitolo, U; Liberati, M; Di Nicola, M; Cortelazzo, S; Rosato, R; Rosanelli, C; Di Renzo, N; Musso, M; Pavone, E; Santini, G; Pescarollo, A; De Crescenzo, A; Federico, Massimo; Gallamini, A; Pregno, P; Romano, R; Coser, P; Gallo, E; Boccadoro, M; Barbui, T; Pileri, A; Gianni, Am; Levis, A.
abstract

BACKGROUND. The objective of the current study was to evaluate in a multicenter setting the feasibility and efficacy of a high-dose sequential (HDS) chemotherapy regimen that combined intensive debulking and high-dose therapy (HDT) with peripheral blood progenitor cell (PBPC) autografting in patients with refractory or recurrent Hodgkin lymphoma (HL). METHODS. Data were collected from 102 patients with HL who were treated with the HDS regimen at 14 centers associated with the Intergruppo Italiano Linfomi. Twenty-four patients had primary refractory HL, 59 patients had their first recurrence of HL (within I year in 32 patients and &gt; 1 year in 27 patients), and 19 patients had multiple disease recurrences. The HDS regimen included the sequential delivery of high-dose (hd) cyclophosphamide with PBPC harvesting, methotrexate, etoposide, then HDT (usually hd mitoxantrone plus L-phenylalanine mustard) with PBPC autografting. In addition, radiotherapy was delivered to 36 patients at sites of bulky or persistent disease. RESULTS. Ninety-two patients (90%) completed the HDS program. There were five toxic deaths (treatment-related mortality rate, 4.9%) and six secondary malignancies (five patients developed myelodysplastic syndrome/acute myelogenous leukemia, and one patient developed colorectal carcinoma). At a median follow-up of 5 years, the 5-year overall survival (OS) and event-free survival (EFS) projections were 64% (95% confidence interval [95% Cl], 54-74%) and 53% (95% Cl, 43-63%), respectively. Patients with their first recurrence had the most favorable outcome, with 5-year OS and EFS projections of 77% (95% CI, 66-88%) and 63% (95% CI, 50-76%), respectively. There were no significant differences between patients with early first recurrence and late first recurrence. The poorest outcome was observed in patients with refractory HL, with 5-year OS and EFS projections of 36% (95% Cl, 16-55%) and 33% (95% Cl, 14-52%), respectively. Patients who received HDS chemotherapy after multiple recurrences had an intermediate outcome. Multivariate analysis showed that refractory disease and systemic symptoms at the time of initial presentation were associated significantly associated with poor OS and EFS. CONCLUSIONS. The use of HDS chemotherapy for patients with refractory and/or recurrent HL is feasible at the multicenter level. The combination of intensive debulking and HDT with PBPC autografting offers a good chance of prolonged disease free survival for patients with their first recurrence of HL.

2003 - High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy [Articolo su rivista]
Federico, Massimo; Bellei, Monica; Brice, P; Brugiatelli, M; Nagler, A; Gisselbrecht, C; Moretti, L; Colombat, P; Luminari, Stefano; Fabbiano, F; Di Renzo, N; Goldstone, A; Carella, Am
abstract

To determine whether high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT) should be included in the initial consolidative treatment of patients with advanced, unfavorable Hodgkin's lymphoma (HL). Patients and Methods: One hundred sixty-three patients achieving complete remission (CR) or partial remission (PR) with four initial courses of doxorubicin, bleomycin, vinblastine, and dacarbazine, or other doxorubicin-containing regimens, were randomly assigned to receive HDT plus ASCT (83 patients) versus four courses of conventional chemotherapy (80 patients). Unfavorable HL was defined as the presence of at least two of the following poor prognostic factors: high lactate dehydrogenase level, large mediastinal mass (greater then at least 33%. of the thoracic diameter), more than one extranodal site, low hematocrit level, and inguinal involvement. Results. At the end of the treatment program, 92% of patients in arm A and 89% in arm 8 achieved a CR (P = .6). After a median follow-up of 48 months, the 5-year failure-free survival rates were 75% (95% confidence interval [CI], 65 to 85) in arm A and 82% (95% CI, 73 to 90) in arm B (P = .4). The 5-year overall survival rates were 89% (95% CI, 90 to 96) in arm A and 88%. (95% CI, 79 to 96) in arm B (P = .99). The 5-year relapse-free survival rates were 88% in arm A (95% CI, 80 to 96) and 94% in arm 6 (95% CI, 88 to 100), and the difference was not significant (P = .3). Conclusion: Patients with advanced unfavorable HL achieving CR or PR after four courses of doxorubicin-containing regimens have a favorable outcome with conventional chemotherapy. No benefit from an early intensification with HDT and ASCT was shown.

2003 - I tumori in Provincia di Modena nel 2000. [Monografia/Trattato scientifico]
Federico, Massimo; Artioli, M. E.; Rashid, I.; Cirilli, C.; Maiorana, Antonino; De Girolamo, G.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

2003 - I tumori in provincia di Salerno nel 1996-1997 [Monografia/Trattato scientifico]
Donato, A.; Federico, Massimo; Apicella, A. M.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Salerno

2003 - Incidence of AIDS-Defining cancers after AIDS diagnosis among people with AIDS in Italy, 1986-1998 [Articolo su rivista]
Franceschi, S.; Dal Maso, L.; Pezzotti, P.; Polesel, J.; Braga, C.; Piselli, P.; Serraino, D.; Tagliabue, G.; Federico, Massimo; Ferretti, S.; De Lisi, V.; La Rosa, F.; Conti, E.; Budroni, M.; Vicario, G.; Piffer, S.; Pannelli, F.; Giacomin, A.; Bellù, F.; Tumino, R.; Fusco, M.; Rezza, G.; for the, Cancer; AIDS Registry Linkage, Study
abstract

A record linkage was carried out between the Italian National Registry of AIDS and 19 cancer registries. The aim was to evaluate the 1986 through 1998 trends in incidence rate (IR) of AIDS-defining cancers (ADCs) among persons with AIDS (PWA) in Italy overall and according to various characteristics. A steady decrease in IRs was found for Kaposi sarcoma (KS) in men between 1986-1992 (2.5 per 100 person-years [py]) and 1997-1998 (1.0 per 100 py). Conversely, the first decrease in IRs of KS in women (from 0.9 to 0.6 per 100 py) and of non-Hodgkin lymphoma in both genders (from 1.7 to 0.7 per 100 py) was seen between 1993-1996 and 1997-1998, thus pointing to a favorable impact of highly active antiretroviral therapies. The decline was consistent across different age and HIV transmission groups, but it was more marked in PWA with a CD4 count &gt;50 cells/microL than in PWA with more severe immune suppression. As a proportion of AIDS cases, invasive cervical cancer increased from 1.5% in 1993-1996 to 2.4% in 1997-1998, but IRs after AIDS could not be evaluated. On account of the marked decline of KS in men in 1997-1998, the overall burden of ADCs in Italy became similar in both genders.

2003 - Italian family with two independent mutations:3358T/A in BRCA1 and 8756delA in BRCA2 genes. [Articolo su rivista]
Cortesi, L.; Turchetti, D.; Bertoni, Carlo Maria; ZANOCCO MARANI, Tommaso; Silvestri, C.; Vinceti, Marco; Federico, Massimo; Silingardi, Vittorio; Ferrari, Sergio
abstract

Hereditary breast/ovarian cancer is a well-characterized clinical entity, largely attributed to the inheritance of BRCA1 or BRCA2 mutations. Among general population, the mutation's frequency of these genes is very low; therefore, the identification of two independent mutations in the same family is a rare event. This study reports the presence of two mutations, one in the BRCA1 and the second in the BRCA2 gene in an Italian Caucasian kindred. This family is composed of more than 250 individuals, spanning through five generations, among which endogamy was a common phenomenon. Considering the tumor spectrum, this family is characterized by a high incidence of different types of cancer. In our study, we considered only three out of seven family units for BRCA1 and BRCA2 analysis. In one of the family units, we found independent mutations of both BRCA genes. The BRCA1 mutation on exon 11 (3358TA) was identified originally in the index case and subsequently in 18 members of this family, whereas the same mutation was not detected in a related family member with male breast cancer. The male breast cancer patient led to the identification, through mutational analysis, of a new BRCA2 mutation (8756delA). This BRCA2 mutation was also found in the male breast cancer patient's daughter. The discovery of the BRCA2 mutation allowed us to alert the patient's daughter who, otherwise, could be falsely reassured since she had a negative BRCA1 test.

2003 - Mitoxantrone, prednisone, pentostatin and bleomycin for patients with indolent non-Hodgkin's lymphoma relapsed or unresponsive to previous treatments. Results of a phase II study conducted by the Gruppo Italiano per lo Studio dei Linfomi (GISL) [Articolo su rivista]
Federico, Massimo; Callea, V.; Danesi, R.; Montanini, Antonella; Di Renzo, N.; Petrini, M.; Del Tacca, M.; Sirotti, Maria Angela; Santacroce, G.; Bagnulo, A.; Dell'Olio, M.; Brugiatelli, M.
abstract

Background. Taking into account the promising results achieved with purine analogs in combination regimens in patients with indolent NHL, we designed a phase II study aimed at assessing the efficacy of Pentostatin in combination with Mitoxantrone, Prednisone and Bleomycin (MiPPeB). Patients and Methods. Thirty patients (18 males and 12 females) with relapsed or unresponsive indolent NHL were treated with MiPPeB. The treatment consisted of Pentostatin 5 mg/m2, on day 1 and 8, Mitoxantrone 10 mg/m2, on day 1, Bleomycin 8 mg/m2, on day 8, Prednisone 100 mg, on day 1 and 8; cycles were administered at 3 week intervals for a maximum of 6 cycles. In 5 patients we investigated the pharmacokinetics of Pentostatin and 2’-deoxyadenosine. Results. A median of 5 cycles (range 2-6) was administered. Ten Complete Remissions (CRs) and 8 Partial Remissions (PRs) were observed, with an overall (CR+PR) response rate of 60%. The median response duration was 38 months (95% CI: 28 to 48 months). The actuarial 3-year relapse free survival for 10 patients in CR was 57%. The 3-year overall and failure free survival rates were 71% and 23%, respectively. Toxicity was mainly hematological with grade 3-4 neutropenia in 37% and grade 3 thrombocytopenia in 7% of the cases. Conclusion. MiPPeB, as used in the present study, showed a promising activity with acceptable toxicity in patients with relapsed or unresponsive indolent NHL and resulted in durable remission.

2003 - Prevalence and prognostic significance of sMUC-1 levels in plasma cell dyscrasias [Articolo su rivista]
Luminari, Stefano; Goldaniga, M; Ceccherelli, F; Guffanti, A; Bombardieri, E; Marcheselli, R; Cro, L; Colombi, M; Federico, Massimo; Baldini, L.
abstract

High serum Mucin-1 (sMUC-1) levels have been shown in patients with adenocarcinoma and multiple myeloma (MM). We evaluated sMUC-1 levels in 76 patients with MM, 6 with plasma cells leukaemia (PCL) and 89 with monoclonal gammopathy of undetermined significance, to establish prevalence data and verify its possible prognostic role. Of the 171 patients, 27 [16%; 95% confidence interval (CI): 10-21%] had high sMUC-1 levels compared with healthy subjects (1.5%; 95% CI: 0-4%). Elevated sMUC-1 levels in MM and PCL patients correlated with anaemia and elevated serum lactate dehydrogenase levels; these patients showed a shorter survival than those with normal sMUC-1 levels (median overall survival: 25 vs. 49 months, P = 0.003).

2003 - Serum MUC-1 as a marker of disease status in multiple myeloma patients receiving thalidomide - Response to Mileshkin et al. [Articolo su rivista]
Luminari, Stefano; Federico, Massimo; Baldini, L.
abstract

no abstract

2003 - Splenosis peritonei. [Articolo su rivista]
Luminari, Stefano; M. D., Santis; A., Casolo; Federico, Massimo
abstract

this article does not have an abstract

2003 - Stage at diagnosis is a key explanation of differences in breast cancer survival across Europe [Articolo su rivista]
Sant, M.; Allemani, C.; Capocaccia, R.; Hakulinen, T.; Aareleid, T.; Coebergh, J. W.; Coleman, M. P.; Grosclaude, P.; Martinez, C.; Bell, J.; Youngson, J.; Berrino, F.; Kupp, A.; Hedelin, G.; Chaplain, G.; Exbrayat, C.; Tretarre, B.; Mace Lesech, J.; Danzon, A.; Mercier, M.; Raverdy, N.; Artioli, E.; Federico, Massimo; Barchielli, A.; Paci, E.; Gatta, G.; Crosignani, P.; Speciale, D.; Ruzza, M. R.; Frassoldi, E.; Verdecchia, A.; Gafa, L.; Tumino, R.; La Rosa, M.; Voogd, A.; Williams, E. M. I.
abstract

We used multiple regression models to assess the influence of disease stage at diagnosis on the 5-year relative survival of 4,478 patients diagnosed with breast cancer in 1990-1992. The cases were representative samples from 17 population-based cancer registries in 6 European countries (Estonia, France, Italy, Netherlands, Spain and UK) that were combined into 9 regional groups based on similar survival. Five-year relative survival was 79% overall, varying from 98% for early, node-negative (T1N0M0) tumours; 87% for large, node-negative (T2-3N0M0) tumours; 76% for node-positive (T1-3N+M0) tumours and 55% for locally advanced (T4NxM0) tumours to 18% for metastatic (M1) tumours and 69% for tumours of unspecified stage. There was considerable variation across Europe in relative survival within each disease stage, but this was least marked for early nodenegative tumours. Overall 5-year relative survival was highest in the French group of Bas-Rhin, Côte d'Or, Hérault and Isère (86%), and lowest in Estonia (66%). These geographic groups were characterised by the highest and lowest percentages of women with early stage disease (T1N0M0: 39% and 9%, respectively). The French, Dutch and Italian groups had the highest percentage of operated cases. The number of axillary nodes examined, a factor influencing nodal status, was highest in Italy and Spain. After adjusting for TNM stage and the number of nodes examined, survival differences were greatly reduced, indicating that for these women, diagnosed with breast cancer in Europe during 1990-1992, the survival differences were mainly due to differences in stage at diagnosis. However, in 3 regional groups, the relative risks of death remained high even after these adjustments, suggesting less than optimal treatment. Screening for breast cancer did not seem to affect the survival patterns once stage had been taken into account.

2003 - The EUROCARE-3 database: Methodology of data collection, standardisation, quality control and statistical analysis [Articolo su rivista]
Capocaccia, R.; Gatta, G.; Roazzi, P.; Carrani, E.; Santaquilani, M.; De Angelis, R.; Tavilla, A.; Oberaigner, W.; Jechova, M.; Rousarova, M.; Storm, H. H.; Aareleid, T.; Hakulinen, T.; Hédelin, G.; Tron, I.; Le Gall, E.; Launoy, G.; Macé Lesech, J.; Faivre, J. n. Chaplain G.; Carli, P. M.; Danzon, A.; Tretarre, B.; Colonna, M.; Lacour, B.; Raverdy, N.; Berger, C.; Freycon, F.; Grosclaude, P.; Estève, J.; Kaatch, P.; Ziegler, H.; Hölzel, D.; Fritschle, G. S.; Tryggvadottir, L.; Berrino, F.; Allemani, C.; Baili, P.; Ciccolallo, L.; Gatta, G.; Micheli, A.; Sant, M.; Taussig, E.; Capocaccia, R.; Carrani, E.; De Angelis, R.; Hartley, S.; Roazzi, P.; Santaquilani, M.; Tavilla, A.; Valente, F.; Verdecchia, A.; Ferretti, S.; Crosignani, P.; Tagliabue, G.; Conti, E.; Vercelli, M.; Pannelli, F.; Vitarelli, S.; Pannelli, F.; Mosciatti, P.; Federico, Massimo; Artioli, M. E.; PONZ DE LEON, Maurizio; Benatti, Piero; De Lisi, V.; Serventi, L.; Zanetti, R.; Patriarca, S.; Magnani, C.; Pastore, G.; Gafà, L.; Tumino, R.; Falcini, F.; Budroni, M.; Paci, E.; Crocetti, E.; Zambon, P.; Guzzinati, S.; Dalmas, M.; Langmark, F.; Andersen, A.; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Zwierko, M.; Pinheiro, P. S.; Pleško, I.; Obsitníková, A.; Pompe Kim, V.; Izarzugaza, I.; Martinez Garcia, C.; Garau, I.; Navarro, C.; Chirlaque, M. D.; Ardanaz, E.; Moreno, C.; Galceran, J.; Torrella, A.; Perisbonet, R.; Barlow, L.; Möller, T.; Jundt, G.; Lutz, J. M.; Usel, M.; Coebergh, J. W. W.; Van Der Does Van Den, A.; Visser, O.; Godward, S.; Coleman, M. P.; Williams, E. M. I.; Forman, D.; Quinn, M. J.; Roche, M.; Edwards, S.; Stiller, C.; Verne, J.; Møller, H.; Bell, J.; Botha, J. L.; Lawrence, G.; Black, R.; Brewster, D.; Steward, J. A.
abstract

The EUROCARE database contains data on 6.5 million cancer patients diagnosed from 1978 to 1994 in populations covered by 67 cancer registries in 22 European countries. The quality-checked entries specify age, sex, diagnosis date, cancer site, morphology, microscopic confirmation and vital status, as well as containing broad indicators of stage. For EUROCARE-3, which refers to diagnoses from 1990 to 1994, 3389 cases with major data problems and 142 525 second or subsequent cancers were removed, leaving more than 2 million cases for analysis. From these data, observed and relative survival for each cancer site and country were calculated at 1, 3 and 5 years from diagnosis. Overall European survival for each cancer site and for all cancers combined were calculated combining country-specific survival figures. Overall, 1.1% of cases were lost to follow-up, 4.2% were known from death certificates only and 1.2% were known at autopsy only. The percentage of microscopically confirmed cases varied with cancer site and country, and was always higher in northern European countries. Comparison of quality indicators for the EUROCARE-3 database with earlier EUROCARE databases indicates that data quality and standardisation have improved.

2003 - The impact of organised Screening programmes on the stage-specific incidence of breast cancer in some Italian areas. [Articolo su rivista]
E., Buiatti; A., Barchielli; S., Bartolacci; Federico, Massimo; V., De Lisi; L., Bucchi; S., Ferretti; E., Paci; N., Segnan; R., Tumino
abstract

The aim of this study was to examine the effects of mammographic screening programmes on stage-specific incidence of breast cancer. The study compared prescreening and screening periods in seven areas in Italy, primarily evaluating the first screening round. All 17617 breast cancers (16554 invasive, 1063 in situ) registered in women aged 40-79 years between 1988 and 1999 were analysed through age-standardised rates and Poisson regression models. For all areas, independent of the baseline rates, the introduction of screening increased incidence for invasive cancers overall and, more markedly, for early cancers (screening/prescreening ratio: range 1.07-1.47 and 1.23-1.82, respectively), modifying the pattern of age-specific rates. The multiple regression analysis showed that the percentage of cases diagnosed at screening explained most of the increase; a residual effect of diagnosis period (screening versus prescreening) suggested a role for 'spontaneous' early detection in ages outside of the screening programme. Advanced cases did not show consistent variations across the registries for those aged 40-79 years (range: 0.91-1.21), whereas a more coherent picture was observed for those aged 50-69 years. In one area, a moderate reduction in the number of 'advanced' cases in the second screening period was observed. For all stages, the age-specific incidence rates of cases diagnosed outside of the screening programme for the age groups 50-69 years were lower than the corresponding rates in the prescreening period, suggesting a shift from the usual clinical services to the screening programme. Our results confirmed the increase in early-stage cancers occurring at the start of screening, and substantially explained the rise in breast cancer incidence. In addition, our study confirms the importance of cancer registries in monitoring the effect of breast cancer screening and the validity, for this purpose, of the linkage between cancer registries and screening programme databases.

2003 - The Length of Treatment of Aggressive Non Hodgkin’s Lymphomas According to the International Prognostic Index Score. Some Lessons from the GISL LA03 Study. [Abstract in Rivista]
Matteo, Dell'Olio; Caterina, Mammi; Monica, Bellei; Nicola Di, Renzo; Maura, Brugiatelli; Sacchi, Stefano; Marco, Lombardo; Francesco, Merli; Daniele, Vallisa; Luca, Baldini; Francesco, Caracciolo; Paolo, Gobbi; A. M., Carella; Federico, Massimo
abstract

In 1993 the Gruppo Italiano per lo Studio dei Linfomi (GISL) started a randomized 2x2 factorial study comparing a flexible versus fixed dosing schedule of two different antracycline-containing ProMACE-CytaBOM regimens, where the length of the treatment was modulated according to the IPI. Patients were randomly assigned to receive one of the following treatments: fixed ProME(Epidoxorubicin)CE-CytaBOM (PE-C); fixed ProMI(Idarubicin)CE-CytaBOM (PI-C); flexible PE-C; flexible PI-C. Epidoxorubicin (EPI) was used at the dose of 40 mg/sm IV and Idarubicin (IDA) at 8 mg/sm IV. In the flexible arms the doses of EPI or IDA were modified according to the following criteria: in absence of haematologic toxicity (i.e.WBC>4,000 and platelets>150,000) during the previous cycle increase the dose by 20%, in case of grade 1 toxicity, was increased the dose by 10%, in case of grade 2 toxicity administer the same dose, in case of grade 3-4 toxicity decrease the dose by 10%.After four courses of ProMACE-CytaBOM, remitters patients with low or low-intermediate IPI (low risk) were planned to receive 2 additional courses whereas those with intermediate-high or high IPI(high risk)were planned to receive 4 additional courses of chemotherapy. Between July 1993 and June 1997, 356 patients with advanced aggressive NHL were registered for the study. After randomization 11 patients were excluded for lacking inclusion criteria. Five out of remaining 345 patients withdrawn from the study before the first assessment of response. The remaining 340 patients, 246 at low and 94 at high risk, were assessed for response. The relative dose intensity of EPI and IDA was 0.91 and 0.88 in the fixed and 1.00 and 1.01 in flexible arms, respectively. At the end of induction chemotherapy 208 patients(61%)achieved a CR, and 59(17%)a PR. The CR rate was 70% and 48% for patients at low and high risk(P = 0.000), whereas no differences emerged between patients treated with fixed or flexible PC(P = 0.894) and EPI or IDA containing PC(P = 0.144). With radiotherapy(10 patients) or other different salvage treatments(11 patients), 21 additional patients reached a CR. In conclusion 229 patients (65% of all eligible and 67% of assessable patients) enrolled in the trial achieved a CR.During follow-up 77 relapses(34%) were recorded, with a 5-year relapse-free survival rate of 65%. The relapse rate was similar in patients treated with fixed or flexible PC(P=0.339), EPI or IDA containing PC(P=0.335), and in patients at low or high risk (P=0.507). After a median follow-up of 57 months (84 months for patients alive), 59% patients were estimated to be alive at 5 years. The 5-year estimated survival rates were 60% and 58% for flexible and fixed P-C (P=0.915), 61% and 57% for EPI and IDA (P=0,325), and 66% and 40% for patients at low and high risk (P = 0.000) respectively.The mature results of our study suggest that 6 courses of fixed or flexible PE-C or PI-C can determine a promising success rate in patients with advanced aggressive NHL and low or low intermediate IPI, whereas the same regimens are less effective in patients with intermediate or high IPI, even if 2 additional courses are delivered. Moreover, given that in the latter group of patients most failures were observed during the first 4 courses of therapy, we suggest that innovative approaches should be considered up-front.

2003 - The role of anthracyclines in combination chemotherapy for the treatment of follicular lymphoma: Retrospective study of the Intergruppo Italiano Linfomi on 761 cases [Articolo su rivista]
Rigacci, L; Federico, Massimo; Martelli, M; Zinzani, Pl; Cavanna, L; Bellesi, G; Merli, F; Alterini, R; Petrucci, Mt; Tani, M; Liberati, Alessandro; Vitolo, U; Pavone, V; Cuneo, A; Chisesi, T; Brugiatelli, M.
abstract

In order to elucidate the role of anthracycline based combination chemotherapy regimens for the treatment of follicular lymphoma we conducted a retrospective study on a large series of patients with a histologically confirmed diagnosis of follicular lymphoma. The Italian lymphoma intergroup (ILI) promoted a retrospective study of patients with follicular lymphoma treated in cooperative trials between 1985 and 1996. Six hundred and thirty three cases were treated with an anthracycline-containing regimen and 128 patients were treated without anthracyclines. The two groups were prognostically comparable; in particular, no difference was observed according to both IPI and ILI prognostic index. Results showed a complete remission (CR) rate for patients treated with anthracyclines was 69.2% and overall response rate was 92.5%. After a median follow-up of 51 months (54 months for patients still alive), the 5- and 10-year overall survival (OS) rates were 80 and 66%, respectively. Disease-free survival (DFS) and failure-free survival (FFS) rates at 5 years were 61 and 49%, respectively. In the group of patients treated with combination chemotherapy not including anthracyclines, the CR rate was 67.5% and the overall response rate was 85.4%. A longer OS (80% at 5 years) was observed in patients treated with anthracyclines compared to 67% OS rate in patients treated without anthracyclines (p=0.0004). FFS was significantly longer in patients treated with anthracyclines (49 vs. 34% p=0.006 ). Patients treated with anthracyclines with low or intermediate risk according to ILI prognostic index showed a significantly longer OS (p=0.0001 and p=0.0009, respectively); those in the high-risk group showed a trend for a longer survival. In conclusion, this retrospective study shows that patients with follicular lymphoma treated with an anthracycline containing regimen had a better outcome compared to patients treated with other combination regimens non including anthracyclines in terms of CRs, OS and FFS. On the basis of these results anthracycline-containing regimens (ACR) should be considered as the standard treatment of patients with advanced follicular lymphoma.

2003 - Treatment of indolent B-Cell nonfollicular lymphomas: final results of the LL01 randomized trial of the Gruppo Italiano per lo Studio dei Linfomi. [Articolo su rivista]
L., Baldini; M., Brugiatelli; Luminari, Stefano; M., Lombardo; F., Merli; Sacchi, Stefano; S. P., Gobbi; M., Liberati; L., Cavanna; M., Colombi; C., Stelitano; M., Goldaniga; F., Morabito; Federico, Massimo; V., Silingardi
abstract

Purpose: To evaluate the effect of epirubicin on therapeutic response and survival in patients with indolent nonfollicular B-cell lymphomas (INFL) treated with pulsed high-dose chlorambucil. Patients and Methods: A total of 170 untreated patients with advanced/active INFL were randomly assigned to receive either eight cycles of high-dose chlorambucil (15 mg/m2/d) plus prednisone (100 mg/d) for 5 days (HD-CHL-P; arm A) or eight cycles of HD-CHL-P plus epirubicin 60 mg/m2 intravenous on day 1 (arm B). The responding patients were randomly assigned to either maintenance therapy with interferon alfa (IFN-2a; 3 MU, three times weekly) for 12 months or observation. Results: There were 160 assessable patients (82 males, 78 females; median age, 63 years; range, 33 to 77 years); 77 patients were assigned to arm A, and 83 were assigned to arm B. Induction therapy led to 47 complete responses (CRs; 29.4%) and 68 partial responses (PRs; 42.5%), with no significant difference between the two arms (60 CR + PR in arm A [77.9%] and 55 CR + PR in arm B [66.3%]; P = .07). After a median follow-up of 38 months (range, 2 to 103 months), there was no between-group difference in overall survival (OS; P = .45), failure-free survival (P = .07), or progression-free survival (PFS; P = .5). Eighty-eight patients were randomly assigned to either IFN-2a (n = 43) or observation (n = 45), without any difference in 3-year PFS (44% and 42%, respectively). Univariate analysis showed that OS was influenced by age, anemia, serum lactate dehydrogenase levels, and International Prognostic Index distribution; multivariate analysis identified age and anemia as having influence on OS. Conclusion: HD-CHL-P treatment outcome in INFL patients was good (50% 3-year PFS, minimal toxicity, and low costs); epirubicin did not add any advantage. One-year IFN maintenance treatment did not prolong response duration. Supported by a grant (Ricerca Corrente) from the Italian Ministry of Health to Ospedale Maggiore Istituto Ricovero Cura Carattere Scientifico, Milan, Italy, and a grant from Associazione Angela Serra, Modena, Italy.

2003 - Vinblastine, bleomycin, and methotrexate chemotherapy plus irradiation for patients with early-stage, favorable Hodgkin lymphoma - The experience of the gruppo italiano studio linfomi [Articolo su rivista]
Gobbi, Pg; Broglia, C; Merli, F; Dell'Olio, M; Stelitano, C; Iannitto, E; Federico, Massimo; Berte, R; Luisi, D; Molica, S; Cavalli, C; Dezza, L; Ascari, E.
abstract

BACKGROUND. The acknowledged effectiveness of vinblastine, bleomycin, and methotrexate (VBM) chemotherapy in patients with early-stage Hodgkin lymphoma has been associated with conflicting toxicity reports. METHODS. One hundred forty-three patients were evaluated clinically and had favorable Stage IA or IIA Hodgkin lymphoma. Ninety-three patients were treated with the standard VBM schedule combined with extended-field radiotherapy (EFRT), leaving the choice of the therapeutic sequence free. Fifty subsequent patients were treated with a slightly modified VBM schedule (VbMp) combined with RT limited to involved fields (IF-RT) and delivered only after the end of chemotherapy. In the VbMp schedule, intervals between cycles were 21 days instead of 28 days, bleomycin doses were reduced, small doses of prednisone were given orally, and the interval before RT was prolonged. RESULTS. Clinical response was complete in 96% of patients who were treated with VBM plus EF-RT and in 94% of patients who were treated with VbMp plus IF-RT. Recurrence rates were nearly identical (12% and 11%, respectively) over necessarily different follow-up (91 months and 33 months, respectively). Hematologic toxicity was tolerable in both trials, and pulmonary side effects were moderate in the first trial and negligible in the second. On the whole, treatment was tolerated better when RT followed chemotherapy. CONCLUSIONS. The VBM regimen was confirmed to be effective in patients with early-stage Hodgkin lymphoma. Administration of all cycles before RT improved tolerance; pulmonary toxicity probably is mitigated further by reduced bleomycin doses, mild prednisone therapy, and a more prolonged resting interval before RT. A slightly higher recurrence rate was expectable in the VBM plus IF-RT trial despite the actual intensification of vinblastine and methotrexate.

2002 - ABVD versus Stanford V versus MEC in unfavourable Hodgkin's lymphoma: results of a randomised trial [Articolo su rivista]
Chisesi, T; Federico, Massimo; Levis, A; Deliliers, Gl; Gobbi, Pg; Santini, G; Luminari, Stefano; Brugiatelli, M.
abstract

Background: Between January 1996 and April 2000, 355 patients with advanced Hodgkin's disease (HD) (stage II bulky disease, III and IV) were enrolled in a prospective, multicentre, randomised trial aimed at comparing the efficacy of two new promising regimens: Stanford V and MEC hybrid. ABVD was chosen as the control arm. Radiotherapy was planned at the end of induction therapy on residual masses or on sites of previous bulky lesions. One hundred and seventeen, 123 and 115 patients were treated with Stanford V, MEC and ABVD, respectively. The records of 275 enrolled patients (89 Stanford V, 88 MEC, 98 ABVD) have been reviewed and are the subject of this report. Results: After induction therapy a complete response (CR) was observed in 93, 89 and 74% of patients treated with MEC, ABVD and Stanford V, respectively, with a statistically significant difference (P = 0.013) between the arms. After a median follow-up of 24 months, 16 relapses have been recorded among 196 patients who achieved a CR. Relapse rates are 16, 6 and 4% for Stanford V, ABVD and MEC, respectively (P = 0.042). The 3-year survival was 93%, without any significant difference among the arms. However, a significant difference emerged in terms of failure free survival (FFS). Patients treated with Stanford V did the worst compared with those treated with ABVD or MEC (P = 0.001). Toxicity was comparable in the three treatment arms. Conclusion: For this randomised study, both ABVD and MEC gave superior results to Stanford V in term of response and FFS; MEC seems to be the best regimen in terms of relapse-free survival, even if a significant difference has not yet been achieved. Notwithstanding the short follow-up, these results seem to be very impressive in defining the best standard treatment for HD for this subset of patients.

2002 - Bleomycin, epidoxorubicin, cyclophosphamide, vincristine and prednisone (BACOP) in patients with follicular non-Hodgkin's lymphoma: Results of a prospective, multicenter study of the Gruppo Italiano per lo Studio dei Linfomi (GISL) [Articolo su rivista]
M., Lombardo; F., Morabito; F., Merli; S., Molica; L., Cavanna; Sacchi, Stefano; C., Broglia; F., Angrilli; F., Ilariucci; C., Stelitano; D., Luisi; R., Berte; Luminari, Stefano; Federico, Massimo; M., Brugiatelli
abstract

At present we report the results of a prospective, non-randomized open trial, conducted on follicular lymphoma (FL) patients by the Gruppo Italiano per lo Studio dei Linfomi (GISL), after a median follow-up of 62.6 months. Seventy-three patients with FL were registered to the study and treated with combination chemotherapy consisting of cyclophosphamide, epidoxorubicin, vincristine, bleomycin and prednisone, weekly administered every 4 weeks. After chemotherapy, involved-field radiotherapy was delivered in case of either localized, bulky and extranodal disease at presentation or limited residual disease at the end of chemotherapy. Patient received four or eight chemotherapy courses in case of localized or advanced disease, respectively. The overall response rate at the end of the treatment program was 97.3%, with 78.1% CR and 19.2% PR. CR rate was 94.3 and 63.1% in stage I-II and III-IV, respectively (p = 0.006). Beside the stage, response rate was significantly influenced by bone mar-row involvement, and the number of extranodal sites. Relapse free survival was 60.8% at 5 years in the whole series; in localized disease it was 70.3 vs. 44.8% in advanced disease (p = 0.044). Relapse free survival was significantly influenced by stage, bone marrow involvement, number of extranodal sites and International Prognostic Index (IPI) score. The overall 5-year survival rate was 90.2%; being 95.6% for patients with stage I-II and 85.1% for those III-IV (p = 0, 0133). In addition, both IPI and Italian Lymphoma Intergroup (ILI) score had a significant impact on survival. The toxicity profile of the treatment was acceptable. From the results of this prospective study it is possible to conclude that this regimen and the whole treatment program is effective as first line therapy for the general population of FL. In particular the BACOP schedule is a valid anthracycline-containing regimen, and in this respect suitable to be considered as a treatment option.

2002 - Changes in breast cancer incidence and stage distribution in Modena, Italy: the effect of mammographic screening program. [Articolo su rivista]
D., Turchetti; L., Mangone; R., Negri; G., Rossi; L., Cortesi; Vinceti, Marco; Maiorana, Antonino; E., Gallo; Federico, Massimo
abstract

Objective: Assessing changes in breast cancer (BC) incidence and stage distribution in the District of Modena, Italy, during the period 1992-1998, and their relationship to a mammographic screening program launched in 1995. Methods: Demographic, clinical, and pathological data of all BC cases reported to the population-based Modena Cancer Registry between 1992 and 1998 were collected and linked to the screening database. Results: A total of 3429 women were diagnosed with BC in the District of Modena between 1992 and 1998. In this period the incidence rate increased by 15.7% (from 134.3 in 1992 to 155.4 per 100,000 in 1998). The increase began in 1995 and exclusively included women aged 50-69; the incidence rose by 30.4%. Moreover, the rise was confined to early tumors, with more than half (54%) of all cases reported in 1998 diagnosed as stage 0 or I disease, compared with 42% in 1992. Screen-detected tumors were significantly smaller (13.2 mm) than other tumors diagnosed in women aged 50-69 (18.5 mm), with 46% of screen-detected tumors smaller than 10 mm. Overall, a decline in the average tumor diameter was shown (from 20.2 mm in 1992-1994 to 18 mm in 1996-1998). Conclusions: Our data confirm that mammographic screening leads to an increase in the incidence of early-stage BC cancers.

2002 - Follicular lymphomas: is there a chance for cure? [Articolo su rivista]
Federico, Massimo; Sacchi, Stefano; Bellei, Monica; Luminari, Stefano; Baldini, L.; Vitolo, U.; Rigacci, L.; Brugiatelli, M.
abstract

no abstract

2002 - Hereditary risk of breast cancer: not only brca [Articolo su rivista]
D., Turchetti; L., Cortesi; Federico, Massimo; Romagnoli, Renato; Silingardi, Vittorio
abstract

The BRCA1 and BRCA2 genes are involved in genetic susceptibility to breast cancer (BC). Nevertheless, in a relevant number of families displaying a disease pattern suggesting an inherited susceptibility to BC, mutational analysis fails to detect any defect in the BRCA genes. Therefore, women belonging to such families should be considered eligible for programs aimed at BC control in individuals at hereditary risk. A clinico-mammographic surveillance program for women at high genetic risk, as defined on the basis of pedigree, has been carried out at our centre for ten years, leading to the diagnosis of 19 new BC cases. Only in 13% of the families analysed, the underlying genetic defect was evidenced in BRCA1 or 2. Here we describe two BC prone families where, although no mutations were detected in BRCA genes, follow-up confirmed an increased BC incidence. In three women belonging to these families clinico-mammographic surveillance resulted to be successful in detecting early-stage BC, supporting the usefulness of screening women from high-risk families, irrespective of whether a mutation was found.

2002 - I tumori in Provincia di Modena nel biennio 1998-1999. [Monografia/Trattato scientifico]
Federico, Massimo; Artioli, M. E.; Maiorana, Antonino; De Girolamo, G.
abstract

Monografi a sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

2002 - I Tumori in Provincia di Salerno nel 1996. [Monografia/Trattato scientifico]
Donato, A.; Federico, Massimo; Mangone, L.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Salerno

2002 - Induction chemotherapy stategies for primary mediastinal large B-cell lymphoma with sclerosis: a retrospective multinational study on 426 previously untreated patients. [Articolo su rivista]
Zinzani, P. L.; Martelli, M.; Bertini, M.; Gianni, A. M.; Devizzi, L.; Federico, Massimo; Pangalis, G.; Michels, J.; Zucca, E.; Cantonetti, M.; Cortelazzo, S.; Wotherspoon, A.; Ferreri, A. J. M.; Zaja, F.; Lauria, F.; De Renzo, A.; Liberati, M. A.; Falini, B.; Balzarotti, M.; Ca,
abstract

BACKGROUND AND OBJECTIVES: This multinational retrospective study compares the outcomes of patients with primary mediastinal large B-cell lymphoma (PMLBCL) with sclerosis after first-generation (dose-intensive regimens), third-generation (alternating regimens) and high-dose chemotherapy strategies, frequently with adjuvant radiation therapy. DESIGN AND METHODS: Between August 1981 and December 1999, a total of 426 previously untreated patients with confirmed diagnosis were enrolled in 20 institutions to receive combination chemotherapy with either first generation (CHOP or CHOP-like) regimens, third generation (MACOP-B, VACOP-B, ProMACE CytaBOM) regimens or high-dose chemotherapy (HDS/ABMT). RESULTS: With chemotherapy, complete response (CR) rates were 49% (50/105), 51% (142/277) and 53% (23/44) with first generation, third generation and high-dose chemotherapy strategies, respectively; partial response (PR) rates were 32%, 36% and 35%, respectively. All patients who achieved CR and 124/142 (84%) with PR had radiation therapy on the mediastinum. The final CR rates became 61% for CHOP/CHOP-like regimens, 79% for MACOP-B and other regimens, and 75% for HDS/ABMT. After median follow-ups from attaining CR of 48.5 months for CHOP/CHOP-like regimens, 51.7 months for MACOP-B type regimens and 32.4 months for HDS/ABMT, relapses occurred in 15/64 (23%), 27/218 (12%) and 0/33 (0%) patients, respectively. Projected 10-year progression-free survival rates were 35%, 67% and 78%, respectively (p=0.0000). Projected 10-year overall survival rates were 44%, 71% and 77%, respectively (p=0.0000), after median follow-ups from diagnosis of 52.3 months, 54.9 months and 35.8 months, respectively. INTERPRETATION AND CONCLUSIONS: In patients with PMLBCL with sclerosis, MACOP-B plus radiation therapy may be a better strategy than other treatments; these retrospective data need to be confirmed by prospective studies. The encouraging survival results after high dose chemotherapy require confirmation in selected high-risk patients.

2002 - Phase II Study with Fludarabine and Cyclophosphamide Plus Rituximab (FC+R) in Relapsed Follicular Lymphoma Patients. [Abstract in Rivista]
Sacchi, Stefano; Alessandra, Tucci; Francesco, Merli; Loretta, Orsucci; Giulia, Cervetti; Ubaldo, Occhini; Marina, Liberati; Giuseppe, Tarantini; Vicenzo, Callea; Maura, Brugiatelli; Vito Michele, Lauta; Luca, Baldini; Luminari, Stefano; Federico, Massimo
abstract

Both Cyclophsphamide (C) and Fludarabine (F) have individual anti-lymphoma activity and the combination Rituximab (R) + F has been shown to have a synergistic activity against resistant lymphoma cell lines in vitro. In march 2000, we started a Phase II multicenter clinical trial to test safety and efficacy of FC+R combination in patients with relapsed follicular lymphoma. We have recently completed the enrollment of 48 pts in the trial. Patients received 4 doses of R (375 mg/sqm/d) in combination with 4 cycles of F (30 mg/sqm/d for 3 days) and C (300mg/sqm/d for 3 days) every 28 days. Patients characteristic: 45% males, 55% females; median age: 62 years (range 44-71); stage IV 47% pts; Systemic Symptoms 8,5% pts; elevated LDH 15% pts. Rearrangement of BCL2 gene was evaluated with PCR in 38pts (79%) on bone marrow or peripheral blood mononucleated cells; 22 patients showed BCL2 rearrangement (58%). Medium number of previous chemotherapy regimens was 1,7 (range 1-4); median duration of last remission before registration into the trial was 12 months (range 1-68). Thirty-nine patients were available for evaluation at the time of current analysis. One patient did not complete therapy due to severe cytopenia. The response rate in the intent-to-treat analysis was 97%, with 74%, Complete Responses (CR) and 23% Partial Responses (PR). Out of 18 patients with molecular monitoring of disease before and after chemotherapy, 15 patients (83%) obtained molecular remission in the bone marrow (BM) .After a median follow-up of 12 months (1-25), median duration of remission was 13 months; twenty percent of patients were only recently registered into the trial and had a short follow-up (less than 4 months). Overall, 8 patients relapsed (21%). One patient died due to severe neutropenia occurred during chemoterapy; two patients died due to lymphoma progression. Complete responses are ongoing in 28 patients. As far as toxicity is concerned WHO grade III-IV leukopenia was observed in 10 patients, with 4 patients presentig a WHO grade IV granulocytopenia. WHO grade IV infections were observed in only one patient who had a pulmonary infection after third cycle. Non-ematologic toxicity was minimal. During follow up, one patient had a renal cell tumor and one patient had myelodisplasia, 3 and 6 months after the end of treatment, respectively. In conclusion the combination FC+R is associated with acceptable toxicity and with an excellent response rate in this group of heavily pre-treated patients with relapsed follicular lymphoma. Furhter follow-up is required to evaluate response duration and survival in the whole group of patients.

2002 - Prospective study of indolent non-follicular non-Hodgkin's lymphoma: validation of Gruppo Italiano per lo studio dei linfomi (GISL) prognostic criteria for watch and wait policy. [Articolo su rivista]
F., Morabito; L., Baldini; C., Stelitano; Luminari, Stefano; A., Frassoldati; F., Merli; M., Colombi; R., Sabbatini; M., Brugiatelli; Federico, Massimo; G. I., per lo studio dei linfomi
abstract

Only recently both the Revised European American Lymphoma (REAL) and World Health Organization (WHO) classifications clearly identified indolent non-follicular non-Hodgkin's lymphoma (NHL) as a distinct group of precise histological entities. Therefore, prognostic models, specifically designed for this NHL subset, are still lacking. In this study, we prospectically evaluated the prognostic criteria proposed by the Gruppo Italiano per lo studio dei linfomi (GISL) to identify patients with an indolent non-progressive clinical course, eligible for a watch and wait policy within this histological subset defined according to stringent criteria of histomorphology and immunophenotype. Fifty-three patients affected with small lymphocytic, marginal zone, lymphoplasmacytic lymphoma and lacking at presentation the following: B symptoms, bulky disease, anemia, thrombocytopenia, diffuse pattern of bone marrow infiltration and short tumor doubling time, were registered in a prospective therapeutic GISL trial and addressed to a watch and wait program. After 41.3 months of median follow-up, the median progression free survival (PFS) was not reached and 73% of cases did not progress. When additional variables were considered, in order to improve the prognostic model, it was evident that LDH level and the number of extranodal sites were of statistical significance in the multivariate analysis. Based on this finding, a prognostic score was devised which was able to further identify a small group of patients more likely to undergo early progression, and thus suitable for immediate treatment. In conclusion, the GISL definition of indolent disease is a reliable tool to design the appropriate therapeutic strategy in this histological setting.

2002 - Risk of second cancer in patients with hairy cell leukemia: Long-term follow-up [Articolo su rivista]
Federico, Massimo; Pl, Zinzani; A., Frassoldati; Vinceti, Marco; A., Mode; L., Annino; T., Chisesi; G., Pagnucco; R., Invernizzi; M., Spriano; L., Resegotti; M., Bendandi; Ee, Damasio
abstract

Purpose : The purpose of the present study was to assess the risk of second cancers in patients with hairy cell leukemia (HCL). Patients and Methods: We investigated the incidence of additional cancers in those patients registered in the nationwide registry of the Italian Cooperative Group for the Study of HCL, asking the cooperating centers for additional information on initial and subsequent therapies and on time and type of second malignancies, if they developed. Here we report the final results of this survey, consisting of 54 cases of second malignancies (excluding nine cases of epithelial skin cancer) which developed in 54 patients of 1,022 with adequate follow-up. Results: The cumulative risk of development of a second cancer was 5%, 10%, and 14% at 5, 10, and 15 years, respectively. The incidence of second malignancies was not significantly higher than the expected rate (standardized incidence ratio [SIR], 1.01; 95% confidence interval [CI], 0.74 to 1.33; P = 1.0). However, the SIR of non-Hodgkin´s lymphoma in the entire cohort was 5.3 (95% Cl, 1.9 to 11.5). Second malignancies occurred in eight (4.7%) of 386 patients who never received interferon (IFN), nine (5.9%) of 495 patients treated with IFN at the time of diagnosis, and seven (6.9%) of 102 patients who received IFN as second-line therapy. These differences were not statistically significant. Analysis of the separate calendar periods did not reveal any particular trends with respect to variations in SIR. Conclusion: The present study does not support the suspicion that patients with HCL are at increased risk of additional second malignancies, although the incidence of lymphoid neoplasms was significantly higher than expected. In addition, our data indicate that IFN therapy did not exert an oncogenic effect in such patients.

2002 - Stage-specific incidence of breast cancer before the beginning of organized screening programs in Italy [Articolo su rivista]
Buiatti, E.; Barchielli, A.; Bartolacci, S.; Bucchi, L.; De Lisi, V.; Federico, Massimo; Ferretti, S.; Paci, E.; Vettorazzi, M.; Zanetti, R.
abstract

OBJECTIVE: To measure stage-specific geographic and time variability of breast cancer in seven Italian areas before the onset of organized screening programs. METHODS: All invasive cancers (8689 cases) arising in women aged 40-79 years during the pre-screening period 1985-1997, were considered. Multiple Poisson regression analysis was performed. RESULTS: About 39% of the cases were classified as "early," 52% as "advanced," and 9% as "unspecified" stage. Age-adjusted incidence rates showed a significant geographic variation for early but not for advanced cancers (range: 58-103 cases/100,000 and 104-125 cases/100,000, respectively). The result was confirmed in the multiple regression analysis after adjustment for year of diagnosis and age. Early breast cancer risk adjusted for age and registry showed a significant increase over time (+3.9% per year for all ages, and +6.2% per year for age category 50-79). In contrast, a decreasing time trend was observed for advanced cancer of 3 cm or over in women aged less than 60. CONCLUSIONS: In our study, early breast cancer incidence varied both by geographic area and time before the commencement of screening. The differences in early-stage incidence may well be related to differences in availability of "spontaneous" mammography. Late-stage incidence decreased over time in younger women and for very advanced cases, but not in the older ones, nor for cancers less than 3 cm. Early detection outside organized screening was only partially efficient in reducing advanced breast cancer incidence. The trend of incidence of advanced disease, as previously proposed, is confirmed to be a valid early indicator of effectiveness of screening.

2002 - The italian multi-center project on evaluation of MRI and other imaging modalities in early detection of breast cancer in subjects at high genetic risk [Articolo su rivista]
Podo, F.; Sardanelli, F.; Canese, R.; D'Agnolo, G.; Natali, P. G.; Crecco, M.; Grandinetti, M. L.; Musumeci, R.; Trecate, G.; Bergonzi, S.; De Simone, T.; Costa, C.; Pasini, B.; Manuokian, S.; Spatti, G. B.; Vergnaghi, D.; Morassut, S.; Boiocchi, M.; Dolcetti, R.; Viel, A.; De Giacomi, C.; Veronesi, A.; Coran, F.; Silingardi, Vittorio; Turchetti, D.; Cortesi, L.; De Santis, M.; Federico, Massimo; Romagnoli, Renato; Ferrari, S.; Bevilacqua, G.; Bartolozzi, C.; Caligo, M. A.; Cilotti, A.; Marini, C.; Cirillo, S.; Marra, V.; Martincich, L.; Contegiacomo, A.; Pensabene, M.; Capuano, I.; Burgazzi, G. B.; Petrillo, A.; Bonomo, L.; Carriero, A.; Mariani Costantini, R.; Battista, P.; Cama, A.; Palca, G.; Di Maggio, C.; D'Andrea, E.; Bazzocchi, M.; Francescutti, G. E.; Zuiani, C.; Londero, V.; Zunnui, I.; Gustavino, C.; Centurioni, M. G.; Iozzelli, A.; Panizza, P.; Del Maschio, A.
abstract

This report presents the preliminary results of the first phase (21 months) of a multi-centre, non-randomised, prospective study, aimed at evaluating the effectiveness of contrast-enhanced magnetic resonance imaging (MRI), X-ray mammography (XM) and ultrasound (US) in early diagnosis of breast cancer (BC) in subjects at high genetic risk. This Italian national trial (coordinated by the Istituto Superiore di Sanità, Rome) so far recruited 105 women (mean age 46.0 years; median age 51.0; age range 25-77 years), who were either proven BRCA1 or BRCA2 mutation carriers or had a 1 in 2 probability of being carriers (40/105 with a previous personal history of BC). Eight cases of breast carcinomas were detected in the trial (mean age 55.3 years, median age 52.5; age range 35-70 years; five with previous personal history of BC). All trial-detected BC cases (8/8) were identified by MRI, while XM and US correctly classified only one. MRI had one false positive case, XM and US none. Seven "MRI-only" detected cancers (4 invasive, 3 in situ) occurred in both pre- (n = 2) and post-menopausal (n = 5) women. With respect to the current XM screening programmes addressed to women in the age range 50-69 years, the global incidence of BC in the trial (7.6%) was over ten-fold higher. The cost per "MRI-only" detected cancer in this particular category of subjects at high genetic risk was substantially lower than that of an XM-detected cancer in the general women population. These preliminary results confirmed that MRI is a very useful tool to screen subjects at high genetic risk for breast carcinoma, not only in pre-, but also in post-menopausal age, with a low probability of false positive cases.

2002 - The role of molecular monitoring in autotransplantation for non-Hodgkin's lymphoma [Articolo su rivista]
S., Galimberti; Marasca, Roberto; F., Caracciolo; R., Fazzi; F., Papineschi; E., Benedetti; F., Guerrini; F., Morabito; E., Oliva; N., Di Renzo; Federico, Massimo; M., Petrini; Torelli, Giuseppe
abstract

Seventy-two patients with non-Hodgkin's lymphoma were evaluated for the presence of molecular markers (IgH, bcl-1, bcl-2 rearrangement) on bone marrow, at diagnosis and after PBSCT, and on harvests in order to find a possible predictive role of minimal residual disease on treatment outcome. At diagnosis, 41 (59%) out of 69 available bone marrows showed molecular involvement. Fifty-six percent of leukaphereses were involved, mainly indolent lymphoma (P = 0.001) or advanced disease (P = 0.01). Ex vivo purging cleared only one stem collection out of 31 PCR-positive leukaphereses. Aggressive lymphomas showed both a longer overall survival (OS) (P = 0.03) and relapse-free survival RFS (P = 0.02) when transplanted with unpurged stem cells, whereas indolent NHL survival was not influenced by ex vivo purging. Twenty out of 26 samples taken during follow-up had bone marrow involvement at diagnosis. Of these, 15 cleared their bone marrow; both OS and RFS were significantly longer in the PCR-negative cases (P = 0.05 and P = 0.005). At 1 year after PBSCT, 75% of patients were PCR negative, with 50% molecular remissions; the relapse rate was 55% for patients still PCR positive vs 29% for those who were PCR negative. Thus, after high-dose chemotherapy, close molecular monitoring of MRD using qualitative PCR techniques seems to represent a reliable prognostic indicator.

2002 - Usefulness of breast MRI in a patient with genetic risk [Articolo su rivista]
L., Cortesi; B., Canossi; M., De Santis; P., Panizza; G., Rossi; D., Turchetti; A., Del Maschio; Ferrari, Sergio; Romagnoli, Renato; Federico, Massimo; Silingardi, Vittorio
abstract

We describe an interesting case-report represented by a patient carrying BRCA1 mutation, recruited for the study Multicenter evaluation of Magnetic Resonance Imaging (MRI) in early diagnosis and prevention of breast cancer in high risk population, diagnosed with breast cancer on the basis of MRI findings but not with conventional mammography and ultrasound (US). She was already affected at 53 years of age by a multifocal Ductal Infiltrating Carcinoma (DIC) in the left breast; then, she had an axillary and sovraclavear nodal recurrence of the disease, three years after the initial diagnosis. Since other relatives were affected by breast cancer (mother, sister and niece) and two arose at early age (<40 years), BRCA1 mutational analysis was offered to the patient, identifying a nonsense mutation on the exon 13. Furthermore, this patient was recruited to study contralateral breast and at the second round, two little foci, suspicious of malignancy, were identified only with MRI, but not with mammography and ultrasonography. The final diagnosis was multifocal Ductal Carcinoma in situ (DCIS); the major focus measured 3 mm. In our patient MRI has shown a major sensitivity with respect to conventional radiology and US and has provided a very early diagnosis in this woman at genetic risk.

2001 - Clinical activity and safety of combination immunotherapy with interferon-(2a and rituximab in patients with relapsed low grade non-Hodgkin's lymphoma. [Articolo su rivista]
Sacchi, Stefano; Federico, Massimo; Vitolo, U.; Boccomini, C.; Vallisa, D.; Baldini, L.; Petrini, M.; Rupoli, S.; Di Raimondo, F.; Merli, F.; Liso, V.; Tabilio, A.; Saglio, G.; Vinci, G.; Brugiatelli, M.; Dastoli, G.
abstract

BACKGROUND AND OBJECTIVES: To determine the clinical activity and safety of the combination immunotherapy of the chimeric anti-CD20 antibody, Rituximab, and Interferon (IFN)- alpha 2a DESIGN AND METHODS: Sixty-four patients with relapsed low-grade or follicular B-cell non Hodgkin's lymphoma received 4 infusion of Rituximab (375 mg/m(2) x dose) after priming and simultaneous treatment with IFN- alpha 2a. RESULTS: The overall response rate was 70% with 33% complete responses. Median for duration of response is 19 months, after a median follow-up of 22 months. By univariate analysis none of the most common prognostic factors predicted for response to therapy. After treatment 10 patients become bcl-2 negative in the bone marrow, but no correlation between molecular and clinical response was found. Fifty-three patients (83%) had drug related or unknown origin adverse events. The number of adverse events per patient varied from 1 to 21. Considering all 272 events, 231 (85%) were grade 1 or 2, 36 (13%) grade 3 and 5 (2%) grade 4. Twenty-three patients required reduction in the dose and/or short discontinuation of IFN treatment, either during priming or subsequent treatment. The most frequent adverse events were leukopenia, fever, neutropenia, hypotension and thrombocytopenia. INTERPRETATION AND CONCLUSIONS: this report shows that combination immunotherapy Rituximab + IFN- alpha 2a is active and relatively well tolerated. The overall response rate of 70% and the median duration remission of 19 months compare favorable with the results obtained with Rituximab alone in similar subset of patients. Randomized trials, investigating Rituximab versus combination immunotherapy are needed.

2001 - Comparison of prognostic models in patients with advanced Hodgkin disease - Promising results from integration of the best three systems [Articolo su rivista]
Gobbi, Pg; Zinzani, Pl; Broglia, C; Comelli, M; Magagnoli, M; Federico, Massimo; Merli, F; Iannitto, E; Tura, S; Ascari, E.
abstract

BACKGROUND, Several prognostic systems have been elaborated for patients with Hodgkin disease (HD) over the last 12 years, but early identification of a reasonably large group of both low and high risk, advanced stage patients remains unsatisfactory. METHODS. Seven well known models were applied to 516 patients with advanced HD, with 315 patients used for the study sample and 201 patients used for the test sample. Individual performances as well as joint performances were analyzed univariately and multivariately in relation to overall survival, recurrence free survival, and time to treatment failure by means of a proportional hazards model. RESULTS, None of the models identified a group containing > 10% of patients from the total population who had a failure risk of either less than or equal to 10% or greater than or equal to 50%. The systems of the International Database on Hodgkin Disease, the Memorial Sloan-Kettering Cancer Center, and the International Prognostic Factor Project showed the best prognostic power; only these three, when analyzed together, predicted clinical outcome with a statistically significant fit to the clinical data. Integration of the three systems in a linear model dramatically improved their individual discriminatory capacity by identifying patients with 10% and 50% failure risks, respectively, in 23% and 24% of the study patient population and in 19% and 25% of the test population, respectively. CONCLUSIONS, As powerful and simple new prognostic factors are awaited that may improve our predictive ability, this integrated index is probably the best way to exploit the significance of those presently available. The program required for the calculations can be downloaded from the Internet at the web site http://www.unimo.it/gis1/default.htm. Cancer 2001;91:1467-78.

2001 - I tumori in Provincia di Modena nel biennio 1996-1997. [Monografia/Trattato scientifico]
Federico, Massimo; L., Mangone; Maiorana, Antonino; G., De Girolamo
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

2001 - Is an antiemetic prophylactic treatment needed for patients submitted to consecutive days of 5-fluorouracil? An observational study [Articolo su rivista]
De Angelis, V; Roila, F; Tonato, M; Ballatori, E; Tumolo, S; Meneghetti, L; Negri, D; Gaspera, Sd; Presot, C; Muran, G; Lucenti, A; Ciccarese, G; Palladino, Ma; Porrozzi, S; Sabbatini, R; Depenni, Roberta; Federico, Massimo; Silingardi, Vittorio
abstract

Aims and Background. The necessity of an antiemetic prophylaxis in patients treated with chemotherapy of low emetogenic potential, such as 5-fluorouracil +/- folinic acid fractionated over several consecutive days, is controversial. The aim of the study was to evaluate the therapeutic behavior of oncologists on this issue. Methods. All consecutive in and out patients who started chemotherapy in 33 Italian oncological departments from June 24 to July 6, 1996, were studied. The antiemetic prescription pattern and its effectiveness, in patients submitted to 5-fluorouracil +/- folinic acid were evaluated. Results. Of the 1956 patients submitted to cancer chemotherapy, 259 patients received 5-fluorouracil +/- folinic acid. Of these, 186 patients were treated for 5 consecutive days, 47 for 4 days, 20 for 3 days and 6 for 2 days. A total of 219 (84.5%) received an antiemetic prophylaxis: 43.4% a 5-HT3 antagonist +/- steroids, 37.5% an antidopaminergic drug, 10.9% a steroid +/- antidopaminergic drug, and 8.2% other drugs. Only 40 patients (15.5%) did not receive an antiemetic prophylaxis. Overall complete protection from vomiting/nausea was 225/259 (86.9%)/163/259 (62.9%). The complete protection from vomiting/nausea during the 5 days in the 186 patients was not significantly different among patients receiving or not an antiemetic prophylaxis (88.1%/64.9% vs 88.9%/55.6%). At unifactorial analysis, the previous experience of vomiting/nausea caused by chemotherapy was found to be a significant prognostic factor. In fact, overall complete protection from vomiting/nausea was significantly inferior in patients who had previous experience of vomiting/nausea (65.1%/35.0%) with respect to those who did not (91.2%/75.4%, P < 0.001/ > 0.001, respectively). Conclusions. The study showed that in clinical practice patients submitted to 5-fluorouracil +/- folinic acid obtained a similar high protection from vomiting and nausea regardless of whether or not antiemetic prophylaxis was given. It would be therefore reasonable not to treat patients undergoing such chemotherapy, whereas patients with previous experience of vomiting/nausea caused by chemotherapy should be given an antiemetic prophylaxis.

2001 - Problemi di confrontabilità dei dati di sopravvivenza. [Articolo su rivista]
Ferretti, S.; Federico, Massimo; Contiero, P.; Stracci, F.
abstract

Il presente studio ha esaminato l'omogeneità dei criteri di registrazione e follow up adottati dai diversi registri partecipanti, per consentire una corretta valutazione dei dati e delle differenze osservate tra le diverse aree geografiche italiane. Il controllo sui dati ha riguardato la corrispondenza alle regole internazionali di registrazione, la loro correttezza e la metodologia adottata per il follow up. Per le differenze osservate nella gestione di alcune neoplasie a più incerto inquadramento clinico e biologico, secondo quanto emerso anche a livello internazionale (codifica tumori in situ, neoplasie vescicali), l'analisi è stata integrata da un questionario somministrato a tutti i registri. Sono emerse alcune differenze nei metodi di registrazione seguiti. I problemi più rilevanti sono stati riscontrati nella registrazione dei tumori vescicali, principalmente nella valutazione dei tumori in situ e a comportamento incerto, e nella proporzione dei pazienti a breve sopravvivenza per alcune aree geografiche. Buoni livelli di qualità e omogeneità sono stati osservato globalmente per i principali indici di valutazione della registrazione (verifiche microscopiche, gestione del follow up). In conclusione i livelli qualitativi osservati nelle procedure di registrazione appaiono sostanzialmente in grado di assicurare una corretta confrontabilità dei dati. Solo per alcune sedi tumorali (in particolare la vescica) si sono evidenziati problemi significativi che suggeriscono maggiore cautela nell'interpretazione della sopravvivenza e delle differenze territoriali osservate.

2001 - Protocolli sperimentali e orientamenti terapeutici per il trattamento delle più freqenti neoplasie. [Monografia/Trattato scientifico]
Folloni, S.; Palumbo, R.; Federico, Massimo
abstract

Monografia contenete informazioni sul trattamento delle principali neoplasie

2001 - Risk assessment in diffuse large cell lymphoma at first relapse. A study by the Italian Intergroup for Lymphomas. [Articolo su rivista]
Guglielmi, C.; Martelli, M.; Federico, Massimo; Zinzani, P. L.; Vitolo, U.; Bellesi, G.; Santini, G.; Tarella, C.; Zallio, F.; Pregno, P.; Di Renzo, N.; Resegotti, L.
abstract

BACKGROUND AND OBJECTIVES: Our aim was to identify risk factors in adults with diffuse large cell lymphoma at first relapse. DESIGN AND METHODS: We studied 474 patients observed at 45 centers in Italy. Median time from diagnosis to relapse was 395 days, median age at relapse was 55 years and median follow-up from relapse was 3.3 years. Salvage therapy consisted of polychemotherapy in 79% of patients, monochemotherapy and/or radiotherapy and/or surgery alone in 16%, and palliative therapy in 5%. Salvage treatment was intensified with high-dose chemotherapy + stem cell transplant in 20% of patients. OS and PFS were compared by sex, International Prognostic Index at diagnosis, histology, B/T phenotype, initial treatment, salvage therapy, and features at relapse: time from diagnosis, LDH, stage, performance status and bone marrow involvement. Cox models, adjusted for salvage therapy, were performed with factors related to overall survival (OS) and progression-free survival (PFS). RESULTS: Overall response (complete + partial) was 63%, OS at 3 years 35% and PFS at 3 years 26%. Relapse within 12 months from diagnosis, elevated serum lactic dehydrogenase (LDH), advanced stage and poor performance status were independent adverse factors for OS and PFS. The cumulative number of adverse factors is proposed as prognostic index for DLCL at first relapse since it identifies risk groups (p<0.0001) and has been validated (p=0.01). Moreover, it predicts OS and PFS in the selected group of patients with a responsive relapse (p<0.0001). INTERPRETATION AND CONCLUSION: Delay from initial diagnosis, LDH, stage and performance status at relapse should be balanced in comparative studies of salvage therapy of adults with DLCL. Patients with more than 2 adverse factors are one third of all cases and deserve more effective salvage treatments.

2001 - Treatment of B-cell low-grade non-Hodgkin's lymphoma with anti CD 20 monoclonal antibody Rituximab. [Articolo su rivista]
Sacchi, Stefano; Federico, Massimo; G., Dastoli; C., Fiorani; G., Vinci; V., Clò; B., Casolari
abstract

Rituximab is a chimeric anti CD-20 monoclonal antibody containing human IgG1 kappa constant regions, with murine variable regions. The anti-lymphoma effects of Rituximab are probably due to complement and antibody-dependent cell-mediated cytotoxicity, and induction of apoptosis. Phase II trials have demonstrated a strong activity of rituximab alone in indolent B non-Hodgkin lymphoma, especially in patients with follicular lymphoma. The most utilized dose-schedule is 375 mg/m2 weekly×4. The association with chemotherapy or with interferon-alpha increases Rituximab efficacy. More recently, Rituximab have showed activity also in diffuse large cell lymphoma, mantle cell lymphoma and in other B-malignancies. Good results have also been obtained utilizing Rituximab for in vivo purging. However, we are still far from having found a definite position for Rituximab in the treatment of lymphoproliferative disorders. The aim of future studies should be to develop new strategies that will hopefully produce the most effective Rituximab-based regimens in order to find the Rituximab key position in the treatment of B-malignancies

2000 - BRCA1 mutations and clinico-pathological features in a sample of italian women with early-onset breast cancer [Articolo su rivista]
Turchetti, D.; Cortesi, L.; Federico, Massimo; Bertoni, Carlo Maria; Mangone, L.; Ferrari, Stefano; Silingardi, V.
abstract

Breast cancer in young women is uncommon and often presents with unfavourable biopathological features. Although early age at onset could suggest a genetic susceptibility to cancer, the appropriateness of BRCA1 testing for women with early-onset breast cancer and modest family history (FH) is controversial. 40 Women diagnosed with breast cancer at the age of 35 years or less, unselected for FH, were screened for germ line BRCA1 mutations by automated sequencing of exons 2, 5, 6, 11, 13 and 20. Overall, deleterious mutations were evidenced in 6 (15%) patients. With regard to FH, mutations were detected in 14%, 11% and 29% of women with none, weak and strong FH, respectively. Large tumour size, grade 3, lack of oestrogen receptors and high proliferation rate were significantly more common in mutation carriers (MC). Our data support both the appropriateness of testing young breast cancer patients and the frequency of unfavourable features in BRCA1-related breast cancer. It is hypothesised that BRCA1 mutations partially justify the high rate of aggressive breast cancer in young patients and that combining age and breast cancer phenotype could help to identify probable MC.

2000 - Comparison between genotype and phenotype identifies a high-risk population carryingBRCA1 mutations [Articolo su rivista]
Laura, Cortesi; Daniela, Turchetti; Chiara, Bertoni; Roberta, Bellei; Lucia, Mangone; Vinceti, Marco; Federico, Massimo; Vittorio, Silingardi; Ferrari, Sergio
abstract

Hereditary breast carcinomas constitute about 10% of all malignant mammary tumors, but the selection criteria to identify a high-risk population carrying BRCAI mutations are not yet well-defined. We have collected $1 pedigrees of familial breast cancer, 16 pedigrees of familial breast and ovarian cancer, and 30 cases of early-onset breast cancer (<35 years of age) without any family history of breast cancer. The index cases of the 97 selected families were further subdivided into three groups based on histopathological parameters: group A (n = 19) was characterized by tumor grade III, negative estrogen and progesterone receptors, and high proliferative rate; group B (n = 20) was characterized by grade I-II tumors, positive hormonal receptors, and low proliferative rate; and group C (n = 58) was not homogeneous for the histopathological criteria. The aim of our study was to evaluate, in patients with a family history of breast cancer or with early diagnosis of breast cancer, the incidence of BRCAI mutation on the basis of tumor phenotype. We found the highest rate of BRCAI mutations in group A (53%), and low frequencies in groups B (5%) and C (0%). Our data strongly indicate that an aggressive tumor phenotype in patients with a positive family history or early diagnosis identifies a population with high probability of carrying BRCAI mutations.

2000 - Detection of circulating tumor cells by reverse transcriptase polymerase chain reaction of maspin in patients with breast cancer undergoing conventional-dose chemotherapy [Articolo su rivista]
R., Sabbatini; Federico, Massimo; M., Morselli; Depenni, Roberta; K., Cagossi; Luppi, Mario; Torelli, Giuseppe; Silingardi, Vittorio
abstract

Purpose: To establish, in patients with breast cancer subjected to primary conventional chemotherapy and enrolled in a prospective study, the mobilizing effect of therapy on potentially neoplastic cells by means of a reverse transcriptase polymerase chain reaction (RT-PCR) assay for mRNA of maspin, a protein related to the serpin family of protease inhibitors. Patients and Methods: Peripheral-blood samples were collected from 30 patients with histologically proven breast cancer before and 4 and 8 days after conventional chemotherapy for three consecutive courses. A total of 216 samples were screened for the presence of maspin mRNA by RT-PCR. Results: Before therapy, all samples but one were negative. After chemotherapy, 11 patients (38%) had positive samples. No difference in the rate of positivity was observed between groups defined according to initial stage, type of chemotherapy, Ki-67-related proliferative activity, or CA 15.3 expression. Conclusion: Our results confirm that RT-PCR for maspin mRNA is a sensitive assay for the study of circulating potentially neoplastic mammary cells in patients with breast cancer. Moreover, our findings indicate a marked effect of conventional-dose chemotherapy on the mobilization of these cells in breast tumors, In our series of patients, this phenomenon does not seem to be associated with other known risk factors. Finally, the data suggest, without proving, an association between the presence of circulating maspin positive cells and a higher risk of disease progression, If this association could be confirmed, then the assay could have prognostic significance. However, larger confir- matory studies are necessary.

2000 - I tumori in Provincia di Modena nel biennio 1994-1995. [Monografia/Trattato scientifico]
Mangone, L.; Carrozzi, G.; Maiorana, Antonino; Fontana, G.; Federico, Massimo
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

2000 - La mortalità per cause in provincia di Salerno nel 1994. [Monografia/Trattato scientifico]
De Girolamo, G.; Donato, A.; Mangone, L.; Feola, G.; Federico, Massimo
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Salerno

2000 - Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases [Articolo su rivista]
Federico, Massimo; U., Vitolo; Pl, Zinzani; T., Chisesi; V., Clo; G., Bellesi; M., Magagnoli; M., Liberati; C., Boccomini; P., Niscola; V., Pavone; A., Cuneo; G., Santini; M., Brugiatelli; L., Baldini; L., Rigacci; L., Resegotti
abstract

Patients (n-987) with a histologically confirmed diagnosis of follicular lymphoma were studied with the aim of developing a prognostic model specifically devised for this type of lymphoma. We collected information on age, sex, Ann Arbor stage, number of extranodal disease sites, bone marrow (BM) involvement, bulky disease, B symptom criteria (fever, night sweats, and weight loss), performance status (PS), serum lactate dehydrogenase (LDH) level, serum albumin level, hemoglobin level, and erythrocyte sedimentation rate (ESR). In the training sample of 429 patients with complete data, multivariate analysis showed that age, sex, number of extranodal sites, B symptoms, serum LDH level, and ESR were factors predictive for overall survival. Using these 6 variables, a prognostic model was devised to identify 3 groups at different risk. The 5- and 10-year survival rate was 90% and 65% for patients at low risk, respectively; 75% and 54% for patients at intermediate risk; and 38% and 11% for those at high risk (log-rank test, 86.62; P < .0001). The model was also predictive (P = .0001) in the validation sample of 265 patients with complete data only for the 6 variables used in the development of the model and even in the group of 210 patients from the validation sample uniformly treated with doxorubicin-containing regimens (P = .0001). The prognostic model appears to be very useful in identifying patients with follicular lymphoma at low, intermediate, or high risk.

2000 - Protocolli e Linee Guida attivi presso il Dipartimento di Scienze Mediche, Oncologiche e Radiologiche. [Monografia/Trattato scientifico]
Federico, Massimo; Longo, G.; Folloni, S.
abstract

Monografia contenente informazioni sul trattamento delle principali neoplasie

2000 - Validation of the international prognostic index in working formulation group a low-grade non-Hodgkin's lymphoma: retrospective analysis of 137 patients from the Gruppo Italiano per lo studio dei linfomi registry. [Articolo su rivista]
Stelitano, C.; Baldini, L.; Pieresca, C.; Callea, V.; Angrilli, F.; Clo, V.; Partesotti, G.; Merli, F.; Cavanna, L.; Morabito, F.; Federico, Massimo; Brugiatelli, M.; Silingardi, Vittorio
abstract

BACKGROUND AND OBJECTIVE: The subset of non-follicular non-Hodgkin's lymphoma (NHL) includes patients with varied prognoses, thus suitable for different therapeutic approaches. The International Prognostic Index (IPI), originally proposed for aggressive NHL, has been demonstrated to be of prognostic relevance also in follicular NHL. The main aim of the study was to validate the IPI in this histologic category; in addition, the specific prognostic classification, currently employed in the Gruppo Italiano per lo Studio dei Linfomi (GISL) prospective therapeutic trials and based on different features, more similar to those applied to chronic lymphocytic leukemia, was analyzed. DESIGN AND METHODS: The present series consists of 137 evaluable patients affected by Working Formulation group A NHL out of 256 cases referred to the GISL Registry. The retrospective prognostic study included the evaluation by both univariate and multivariate analyses of overall survival, response to therapy and response duration. The IPI was applied as originally proposed. The GISL definition of indolent and aggressive disease at diagnosis was based on the presence of B symptoms, bulky disease, anemia and thrombocytopenia. RESULTS: The distribution of patients in IPI risk groups was rather unbalanced with 18%, 47%, 28% and 7% of cases classified as low (L), intermediate-low (IL), intermediate-high (IH) and high (H) risk, respectively. The median overall survival was not reached in either L or IL risk groups, and was 84.1 and 7.4 months for IH and H risk groups, respectively (p=0. 0005). A simplified IPI model was designed merging patients in both intermediate risk groups and the statistical difference of survival retained its significance. GISL prognostic stratification was demonstrated to have a significant association with survival, with a median survival of 71.3 months in aggressive disease and a median survival not reached at 152 months in indolent disease. Both the simplified IPI model and the GISL risk definition retained their significance in multivariate analysis for overall survival, while for response to therapy only the simplified IPI model resulted to be of statistical significance. In addition, the GISL prognostic stratification identified patients with different outcomes within the IPI intermediate risk group, with a median survival of 70.2 months for patients with aggressive disease wheras the median survival for those with indolent disease was not reached. Finally, a prognostic score resulting from the integration of the simplified IPI and the GISL system was statistically validated. INTERPRETATION AND CONCLUSIONS: The retrospective analysis of this series demonstrates the validity of the IPI in non-follicular indolent NHL and the usefulness of integrating the IPI parameters with disease specific prognostic variables.

1999 - Cancer prevalence in Italian cancer registry areas: The ITAPREVAL study [Articolo su rivista]
Micheli, A.; Francisci, S.; Krogh, V.; Giorgi Rossi, A.; Crosignani, P.; Micheli, A.; Gatta, G.; Sant, M.; Giorgi Rossi, A.; Francisci, S.; Saltarelli, S.; Dell'Era, L.; Gasparre, N.; Verdecchia, A.; Capocaccia, R.; Mariotto, A.; Dally, L.; Corazziari, I.; Conti, E.; Ramazzotti, V.; Caperle, M.; Vercelli, M.; Caselli, C.; Parodi, S.; Crosignani, P.; Tagliabue, G.; Berrino, F.; Federico, Massimo; Mangone, L.; Santacroce, M.; PONZ DE LEON, Maurizio; Roncucci, Luca; Benatti, Piero; Zanetti, R.; Rosso, S.; Patriarca, S.; Falchi, F.; Milandri, C.; Vattiato, R.; De Lisi, V.; Serventi, L.; Barili, A.; Gafà, L.; Tumino, R.; La Rosa, E.; Barchielli, A.; Balzi, D.; Crocetti, E.; Paci, E.; Guzzinati, S.; Simonato, L.; Bovo, E.
abstract

Aim: To present data on cancer prevalence for the areas covered by Italian cancer registries, by using a standardized set of data collection and elaboration criteria, and a single method of data analysis. Subjects and Methods: Data on over 250,000 patients with cancer, diagnosed between 1978 and 1992, from 11 Italian cancer registries covering about 12% of the Italian population were collected, validated and analyzed according to the unified protocol of the ITAPREVAL project. The method implemented in the PREVAL computer program was used to provide prevalence estimates for the period covered by cancer registration. The total prevalence for each registry and for the pool of all registries was then estimated by correcting for incomplete observations due to the period in which the registration was not yet activated. All prevalence estimates were for 1992. Results: Prevalence figures are presented by cancer site, age, sex, years from diagnosis and registry area. For all malignancies combined, total prevalence ranged from 1,350 per 100,000 inhabitants in Ragusa to 3,650 per 100,000 inhabitants in Romagna, the ratio between these two extremes being 2.7. For the pool of the areas covered by registration cancer prevalence was 3,100 per 100,000 females and 2,250 per 100,000 males. About a third of the total female cases and about half the male cases were diagnosed in the previous five years. Among those aged over 75 years, total prevalence was higher for males than for females: 11,300 versus 8,900 per 100,000 respectively. Conclusions: This is the first large-scale estimate of the burden of cancer in Italy. It is also one of the first studies in the world which was aimed to study cancer prevalence in detail. These data are necessary for predicting health service needs and help in the evaluation of differences in health service demand by sex, age and Italian regions.

1999 - Clinical characteristics, treatment outcome and survival of 36 adult patients with primary anaplastic large cell lymphoma. Gruppo Italiano per lo Studio dei Linfomi (GISL). [Articolo su rivista]
G., Longo; C., Fiorani; Sacchi, Stefano; V., Callea; M., Lombardo; Federico, Massimo; C., Stelitano; F., Angrilli; D., Vallisa; P. G., Gobbi; F., Ilariucci; A., Frassoldati; M., Petrini; V., Silingardi
abstract

Background and Objective. Although in recent years anaplastic large-cell lymphoma (ALCL) has emerged as a distinct clinlco-pathological entity, a gold standard for treatment has still not been defined. Goals of our histologic, phenotypic and clinical study were to present clinical findings, treatment outcome and survival rates of a small, but highly homogeneously treat ed, series of patients. Design and Methods. From April 1991, 36 newly diagnosed adult patients with systemic ALCL CD30(+), entered a prospective non-randomized trial in one of the institutions participating in a GISL (Gruppo Italiano per lo studio dei Linfomi) study and were treated with a MOPP/EBV/CAD hybrid scheme. Chemotherapy (CHT) was administered every 28 days, for a total of 6 cycles. After CHT, 19 patients received radiation therapy (RT) to the site of previously involved fields. Kaplan and Meier and log-rank tests were used for statistical analysis. Results. The overall complete remission rate was 78%, the partial remission rate was 6%. The overall survival rate at 74 months was 69%. No statistically significant differences in response or survival rates were noted comparing ALCL-HL and -CT subgroups, T+ Null- and B- subtypes, or ALCL-HL and -CT, with different phenotypes. In the analysis of patients with T+ Null phenotype treated with CHT+RT in comparison with B-ALCL patients who had the same treatment, we observed statistically significant differences in the survival rate (p=0.048). No prognostic factors predictive of response or survival were identified. Interpretation and Conclusions. Our results show that using MOPP/ABV/CAD the results, in terms of remission rate and survival, are similar to those obtained with 3(rd) generation CHT regimens. The diagnosis of T and Null ALCL is the mast important prognostic factor, because it Is associated with a very good survival, even in patients with a high prognostic index. Finally, we believe that longer follow-ups are needed to evaluate long-term survival and toxicity with different treatments. (C)1999, Ferrata Storti Foundation.

1999 - Identification of families with hereditary breast and ovarian cancer for clinical and mammographic surveillance: the Modena Study Group proposal [Articolo su rivista]
Federico, Massimo; Maiorana, Antonino; L., Mangone; D., Turchetti; B., Canossi; L., Cortesi; Romagnoli, Renato; Silingardi, Vittorio
abstract

Hereditary factors play a fundamental role in the pathogenesis of breast cancer (BC). Approximately 15-20% of all BCs have been reported to show familial clustering. In spite of the recent demonstration and chromosomal localization of BC predisposing genes, clinical clues and careful inspection of pedigree still remain major instruments in HBC diagnosis. The aim of the present study was to develop minimum operational criteria for the selection of family groups at high risk of developing BC. Following a stepwise procedure, families were stratified into four clusters with increasing probability of genetic involvement. So far, 317 BC-prone families have been identified and distributed in the four groups, and 151 high risk women underwent our clinical and mammographic surveillance program. Among these, after a mean follow-up of 24 months, six BCs and one OC were diagnosed (one BC and one OC occurred in the same woman) and one 'interval' BC was observed. Since the prevalence rate so far detected is dramatically higher than that seen at the first round of Italian population-screening programs, our preliminary data support the usefulness of the proposed procedure in selecting high risk individuals.

1999 - La chemioprevenzione del carcinoma mammario [Articolo su rivista]
Turchetti, D.; Federico, Massimo; Silingardi, Vittorio
abstract

Col termine chemioprevenzione si indica la somministrazione di sosotanze chimiche (farmaci o costituenti della dieta) in grado di impedire lo sviluppo di unaneoplasia invasiva. Poichè un simile approccio potrebbe contribuire alla riduzione dell'incidenza del carcinoma della mammella, sono state intraprese ricerche volte ad accertarne la applicabilità. Gli interventi dietetici proposti per ridurre il rischio di carcinoma della mammella, a tutt'oggi in fase di valutazione, prevedono soprattutto la restrizione dell'apporto di grassi, mentre, per qwuanto riguarda i farmaci, quelli che hanno finora raggiunto la fase clinica di sperimentazione sono tamoxifen, fenretinide (somministrati singolarmente o in associazione) e raloxifene. L'efficacia del tamoxifen nel prevenire il carcinoma mammario, evidenziata dai risultati preliminari di un grandi trial americano, non ha finora trovato conferma nei primi dati relativi a due studi analoghi condotti in Europa. Complessivamente, la chemioprevenzione del carcinoma mammario, pur non essendo ancora un'opzione disponibile nella pratica medica quotidiana, costituisce un'area di ricerca estremamente promettente, che merita di ricevere attenzione e sforzi crescenti.

1999 - La prevenzione. Strategia intramontabile contro il cancro [Monografia/Trattato scientifico]
Federico, Massimo; Donato, A.; Di Grazia, M.; Iannelli, A.; Mangone, L.; Pistolese, G.
abstract

Monografia contenete suggerimenti sulle strategie di prevenzione contro il cancro.

1999 - Malattia celiaca e linfoma [Articolo su rivista]
Balli, Fiorella; Di Biase, A. R.; Bertolani, P.; Morinello, V.; Clo, V.; Federico, Massimo
abstract

Celiac disease (CD) has been acknowledge as being responsible for numerous secondary pathologies, in particular autoimmune and neoplastic diseases. Whether CD is more prevalent in patients with non-Hodgkin's lymphoma (NHL) than in the normal population is not known. Accordingly, we carried out a study of 86 patients hospitalized in the Section of Oncology, Haematology and Internal Medicine of the Department of Medical, Oncological and Radiological Sciences of the University of Modena and Reggio Emilia and who, between 1988 and 1995 had been diagnosed as affected by NHL. On diagnosis, and before the beginning of antitumour therapy, all the patients were tested for antigliadin (AGA IgA and IgG) and antiendomysium (EMA) antibodies together with total class IgA antibody levels. Our findings showed that none of the 86 patients had an IgA deficit, while one tested positive for AGA IgA (43.9% v.n. < 7.5). The same patient also tested positive for EMA. The extremely high sensitivity and specificity of the AGA IgA and EMA led us to conclude that the patient was affected by CD, although his early death precluded confirmation by biopsy. The presence of one celiac patient among 86 NHL patients examined at the onset of the disease would suggest that CD is not infrequent in NHL. The numbers involved in our study are insufficient for statistical purposes, and we are therefore awaiting the results of a SIGEP multi-centre study into the connection between CD and lymphomas.

1999 - Phase II study of rituximab after priming with IFN in patients with relapsed LG/F B-cell lymphoma [Abstract in Rivista]
Sacchi, Stefano; Federico, Massimo; U., Vitolo; C., Boccomini; G., Vallisa; L., Baldini; M., Petrini; S., Rupoli; F., Di Raimondo; F., Merli; V., Liso; A., Tabilio; G., Saglio; N., Di Renzo; P., Gobbi; G., Pitini; G., Quarta; M., Brugiatelli; G., Vinci; G., Dastoli
abstract

Rituximab mechanism of action includes CDC, ADCC and induction of apoptosis. The administration of IFN-a before and during Rituximab treatment could be effective in increasing antigen surface expression; further the immuno modulators effect of IFN-a, including stimulation of T-cell cytotoxicity and natural killer cell activity, might sinergize with the mechenism of action of Rituximab in inducing neoplastic clone suppression. In an ongoing open, non comparative, multicenter, Phase II Italian study, 63 relapsed LG/F NHL patiens, enrolled between May 97 and June 99, were treated with IFN+Rituximab. Treatment started with IFN-a, 1.5MU/day sc for the first week and then at 3 MU during second week. At day 15 patients received the first Rituximab injection at 375mg/sq, that was repeated at day 22, 29 an 36. IFN-a dose was maintained at 3 MU during the third week and than increased to 6 MU during fourth and fifth week. Patient characteristics included: median age 52 years (range 31-70 yr); male 30%; IWF: A 11%, B 27%, C 45%, D 17%; 80% stages III an IV; 53%, 29%, 18% of patients in 1st, 2nd and 3rd relapses, respectively. All patients had progressive disease, requiring therapy. By intent to treat analysis, the 58 patients evaluable for response obtained: CR 29%, PR 43% SD 14%, PD 4%, and dropouts 10%. Six out of the 17 patients who obtained CR are relapsed after 5, 12, 13, 15 and 16 months, respectively. The other 11 are still in CR after 2+ ® 24+ months of observation. Of the 25 PR patients, 4 were immediately treated with radiotherapy and/or chemotherapy and they are not evaluable for duration remission. Five out of the remaining 21 patients are relapsed after 1, 5, 8, 9, 12 months, respectively. The other 16 patients are still in PR after 2+ ® 22+ months. AEs, occurred in the 47 patients evaluable for toxicity, were primarily grade I and II, occurring with first Rituximab infusion. Nineteen patients required dose reduction of IFN. The most frequent treatment related AEs were: fever, neutropenia, transaminases increase, nausea, chills, hypertension, thrombocytopenia and vomiting. Ten patients (21%) had grade III and 3 (6%) grade IV AEs. This interim analysis suggests that combination immunotherapy with IFN-a and Rituximab is more effective than Rituximab alone, but the AEs rate increases (72% ORR versus 48% and 27% grade III and IV AEs versus 15%, observed in the pivotal study).

1999 - Protocolli e Linee Guida attivi presso il Dipartimento di Scienze Mediche, Oncologiche e Radiologiche [Monografia/Trattato scientifico]
Federico, Massimo; Clò, V.; Folloni, S.
abstract

Monografia contenete informazioni sul trattamento delle principali neoplasie

1998 - Efficacy of two different ProMACE-CytaBOM derived regimens in advanced aggressive non-Hodgkin's lymphoma. Final report of a multicenter trial conducted by GISL [Articolo su rivista]
Federico, Massimo; V., Clo; M., Burgiatelli; M., Carotenuto; Pg, Gobbi; D., Vallisa; M., Lombardo; P., Avanzini; N., Di Renzo; D., Dini; L., Baldini; Ginaldi, L.; V., Silingardi; Mauri, C.
abstract

Background and Objective. To compare the efficacy of ProME(Epidoxorubicin)CE-CytaBOM (PE-C) and ProMI(Idarubicin)CE-CytaBOM (PIG) in the treatment of adult patients with aggressive non Hodgkin's lymphoma in a multicenter randomized controlled trial performed by 18 centers of the Italian Lymphoma Study Group (GISL). Design and Methods. One hundred and twenty-eight and 122 patients were randomly assigned to receive either 6 courses of PE-C or PI-C, respectively. Some patients achieving complete remission with induction therapy participated in another randomized study comparing no further therapy versus maintenance therapy consisting of four blocks of two drugs. Results. The rate of CRs was 62% and 64% for patients treated with PE-C and PI-C, respectively (p=0.51). The 5-year relapse-free survival was 60% for PE-C and 53% for PI-C (p=0.29). The estimated relapse-free disease survival rates at 4 years were 75% for patients in the consolidation group and 57% for those in the observation group (p=0.11). Patients alive In first complete remission 4 years after study entry were estimated to be 39% in the PE-C arm and 38% in the PI-C arm (p=0.90). The 3-year and 5-year estimated survival rates were 61% and 55% for the PE-C group and 56% and 47% for the PI-C group (p=0.26). Fatal toxicities occurred in 7 patients (2.9%) with active disease and in 4 patients (1.7%) in complete remission. Stage (p=0.04), bulky disease (p=0.02), serum LDH (p=0.0006), serum albumin (p=0.0051), hemoglobin (p=0.0011), performance status (p=0.0001), International prognostic index (p<0.0001) and the index proposed by the French group G.E.L.A. (p<0.0001) were of prognostic value. In a multivariate analysis (Cox regression model) alternatively IPI alone or G.E.L.A, index plus performance status emerged as independent prognostic factors. Interpretation and Conclusions. The present study indicates that epirubicin and idarubicin in a combined chemotherapy regimen, have similar activities. The toxic profile also indicates the safety of both anthracyclines at the dosages employed, suggesting their possible dose escalation in a combined chemotherapy setting. PE-C and PI-C were both effective and feasible regimens in an outpatient setting, with acceptable cardiovascular toxicity. The trend toward a better outcome in patients undergoing consolidation therapy after the achievement of a complete remission, warrants further investigation. (C)1998, Ferrata Storti Foundation.

1998 - Elevata frequenza della infezioneda virus dell'epatite C (HCV) nei pazienti con linfoma non-Hodgkin all'esordio [Articolo su rivista]
Catassi, C.; Fabiani, E.; Coppa, G. V.; Gabrielli, A.; Centurioni, R.; Leoni, P.; Barbato, M.; Viola, F.; Martelli, M.; De Renzo, A.; Rotoli, B.; Bertolani, P.; Federico, Massimo; Carroccio, A.; Iannitto, E.; Baldassarre, M.; Guarini, A.; Guariso, G.; Favaretto, G.; Caramaschi, P.; Ambrosetti, A.
abstract

Tra le infezioni che sembrano favorire l’insorgenza del linfoma non-Hodgkin (LnH), è stato di recente segnalato il virus dell’epatite C. E stata indagata la prevalenza di infezione da HCV in un gruppo di 143 pazienti affetti da LnH all’esordio. La diagnosi è stata posta sulla base della ricerca su siero degli anticorpi anti-HCV e dell’HCV-RNA. Una mfezione da HCV è stata segnalata in 16 dei 143 casi di LnH indagati (11,2%; 95% CI 6,5 - 17,5), 11 maschi e 5 femmine [età media 59,9 anni] con malattia disseminata (13/16) o localizzata (3/16)1.11 grado di malignità era basso in 6 casi, intermedio in 2 e elevato mS. La derivazione linfocitaria era B in 15 casi e mista (B e T) in un caso. In 6 dei 16 casi il riscontro di HCV positività era contemporaneo alla diagnosi di LnH, in 10 era precedente. In questi 10 soggetti la durata mediana dell’intervallo di tempo intercorso tra il riscontro 4el- la infezione da HCV e l’esordio del tumore era di 3,6 anni (range 1-14,5). Il presente studio conferma che in Italia l’infezione da HCV presenta una maggiore prevalenza nei soggetti con LnH di origine B all’esordio, rispetto alla popolazione generale. Il ruolo dell’HCV nel processo di linfomagenesi sarebbe avvalorato dal riscontro che nella maggior parte dei casi la diagnosi di infezione da HCV era stata posta prima dell’esordio del tumore.

1998 - Fatti e cifre dei tumori in Italia [Monografia/Trattato scientifico]
Zanetti, R.; Buiatti, E.; Federico, Massimo; Micheli, A.
abstract

Monografia sui dati di incidenza, mortalità, sopravvivenza e prevalenza dei tumori in Italia.

1998 - Introduction: The EUROCARE II Study ( Editorial ) [Articolo su rivista]
Berrino, F.; Gatta, G.; Chessa, E.; Valente, F.; Capocaccia, R.; Oberaigner, W.; Storm, H.; Aareleid, T.; Hakulinen, T.; Pottier, D.; Mace Lesec'h, J.; Faivre, J.; Chaplain, G.; Carli, P. M.; Arveux, P.; Esteve, J.; Exbrayat, C.; Raverdy, N.; Kaatsch, P.; Michaelis, J.; Ziegler, H.; Tryggvadottir, L.; Tulinius, H.; Crosignani, P.; Micheli, A.; Sant, M.; Conti, E.; Vercelli, M.; Federico, Massimo; Mangone, L.; PONZ DE LEON, Maurizio; De Lisi, V.; Zanetti, R.; Magnani, C.; Gaf, L.; Tumino, R.; Falcini, F.; Barchielli, A.; De Angelis, G.; Verdecchia, A.; Pawlega, J.; Rachtan, J.; Bielska Lasota, M.; Wronkowski, Z.; Obsitnikova, A.; Plesko, I.; Pompe Kirn, V.; Izarzugaza, I.; Viladiu, P.; Martinez Garcia, C.; Garau, I.; Ardanaz, E.; Moreno, C.; Galceran, J.; Moller, T.; Torhorst, J.; Bouchardy, C.; Raymond, L.; Coebergh, J. W. W.; Damhuis, R. A. M.; Gould, A.; Davies, T. W.; Stockton, D.; Coleman, M. P.; Williams, E. M. I.; Littler, J.; Forman, D.; Quinn, M. J.; Roch, M.; Smith, J.; Bell, J.; Lawrence, G.
abstract

This introduction provides a general overview of the aims, methods and procedures used in the EUROCARE II study and the types of analyses presented in each article of this Special Issue of the European Journal of Cancer. The main aims of the EUROCARE II project are the updating of the survival database of the European Cancer Registries, the study of recent trends in relative survival rates and the interpretation of the survival differences observed both in time and across populations. Once having completed the preliminary stage of data checking, a total of 3 473 659 individual records from patients of all cancer sitess diagnosed between 1978 and 1989 and provided by 45 cancer registries in 17 European countries were accepted to build up the EUROCARE database. The quality of these data, in terms of the accuracy of the diagnosis and the validity of vital status assessment, was checked by indirect indicators, based on cross-validation analysis of consistency of the relevant variables. Statistical analysis was based on age- specific relative survival rates, computed for each cancer sites as the ratio of observed survival to the expected survival of the general population of the same area, gender and age, according to the Hakulinen method. An estimate of the European survival was computed as a weighted mean of the corresponding survival of the different countries, using as weights the expected yearly number of incident cases in each country. For comparison purposes, age- standardised survival was also calculated for Europe and for each country involved in the study.

1998 - La mortalità per cause in provincia di Lecce nel 1994 [Monografia/Trattato scientifico]
De Girolamo, G.; Feola, G.; Piccinno, G.; Quarta, F.; De Giorgi, A.; Mangone, L.; Federico, Massimo
abstract

Monografia sui dati di incidenza e sopravvivenza delle malatie neoplastiche in provincia di Lecce

1998 - La predisposizione genetica al cancro dell'ovaio. Individuazione e sorveglianza delle donne a rischio [Articolo su rivista]
Turchetti, D.; Mangone, L.; Cortesi, L.; Pifferi, M.; Silingardi, Vittorio; Federico, Massimo
abstract

Il carcinoma ovarico CO) rappresenta la principale causa di morte per neoplasia ginecologica nei Paesi Occidentali. Nell’arco della vita quasi il 2% delle donne occidentali contrae la malattia; la incidenza del CO aumenta con l’età, ed è massima intorno alla VI VII decade di vita, essendo rari i casi che esordiscono prima dei 30 anni d’età. Negli Stati Uniti si verificano ogni anno circa 26.000 nuovi casi e 14.000 decessi (Parker, 1997). In Emilia Romagna si registrano ogni anno circa 350 nuovi casi, con un tasso grezzo d’incidenza di oltre 16 casi per 100.000 abitanti (Federico, 1997). In provincia di Modena, nel 1993, l’incidenza di CO è stata di 16 casi per 100.000 abitanti, la mortalità di 11.9 casi per 100.000, con un rapporto mortalità/incidenza dello 0,66 (Mangone, 1997). Sempre negli Stati Uniti la sopravvivenza a 5 anni è risultata del 46% nelle donne bianche e del 40% nelle donne nere (Parker, 1997): a Modena la sopravvivenza a 5 anni è stimata intorno al 37% (Mangone, 1996).La prognosi della malattia è strettamente dipendente dall’estensione del processo neo- plastico al momento della diagnosi. La soprax’vivenza a cinque anni è superiore al 90% nei casi diagnosticati in stadio I o Il, ma è interiore al 20% in quelli diagnosticati in stadio IV. Le neoplasie dell’ovaio sono difficili da trattare perché’ le pazienti spesso si rivolgono al medico quando la malattia è già molto avanzata. Infatti. nonostante i notevoli progressi compiuti in questi ultimi decenni nei campo della diagnostica, il 70% circa dei tumori dell’ovaio sono diagnosticati già in stadio III o IV

1998 - Long-term results from MOPPEBVCAD chemotherapy with optional limited radiotherapy in advanced Hodgkin's disease [Articolo su rivista]
Pg, Gobbi; C., Pieresca; Ml, Ghirardelli; N., Di Renzo; Federico, Massimo; F., Merli; E., Iannitto; V., Pitini; G., Grignani; A., Donelli; M., Carotenuto; Silingardi, Vittorio
abstract

The purpose was to verify the 5-year results of the MOPPEBVCAD chemotherapy regimen with limited radiotherapy in relation to the promising preliminary data. Mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, melphalan, and vindesine were delivered according to a schedule derived through hybridization, intensification, and shortening of the corresponding alternating CAD/MOPP/ABV regimen. Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. This multicenter, controlled, nonrandomized trial involved 145 eligible patients. Radiotherapy was administered to 47 patients, 46 of whom were in complete remission after chemotherapy. Remissions were complete in 137 patients (94%), partial in 4 (3%), and null in the remaining 4. Tumor-specific, overall, relapse-free, and failure-free survival at 5 years were 0.89, 0.86, 0.82, and 0.78, respectively. Hematologic toxicity was considerable, whereas nonhematologic side effects were fully acceptable. Most of the unfavorable prognostic factors lost their clinical weight. Only age and lymphocyte depletion histologic type were statistically correlated with major follow up endpoints; performance status and bone marrow involvement were subordinate to age. Seven patients developed a second cancer (including 3 myelodysplasias). MOPPEBVCAD with selected radiotherapy is a highly effective regimen in advanced Hodgkin´s disease. Early and late toxicity are no more severe than what would be expected with other alternating or hybrid regimens. A comparison with ABVD, which is currently considered the standard regimen for advanced Hodgkin´s disease, is needed.

1998 - Protocoli e Linee Guida attivi presso il Dipartimento di Scienze Mediche, Oncologiche e Radiologiche [Monografia/Trattato scientifico]
Federico, Massimo
abstract

Monografia contenete informazioni sul trattamento delle principali neoplasie

1998 - Transferability to clinical practice of the results of controlled clinical trials: The case of antiemetic prophylactic treatment for cancer chemotherapy-induced nausea and vomiting [Articolo su rivista]
Del Favero, A; Roila, F; De Angelis, V; Tonato, M; Ballatori, E; Tumolo, S; Meneghetti, L; Negri, D; Della Gaspera, S; Presot, C; Muran, G; Lucenti, A; Ciccarese, G; Palladino, Ma; Porrozzi, S; Sabbatini, R; Depenni, Roberta; Federico, Massimo; Silingardi, Vittorio; Sansoni, E.
abstract

Background: There is convincing evidence from randomized clinical trials that the use of 5-HT3 antagonists has brought about a substantial improvement in the control of chemotherapy-induced nausea and vomiting. However, no data exist to indicate how this new research evidence can be applied to the individual patient. Patients and methods. We carried out a prospective, observational study on the use and effectiveness of antiemetic drugs in patients undergoing cancer chemotherapy in 33 Italian oncology departments. Results: A total of 1,956 consecutive patients entered the study; 1,238 of them underwent a one-day chemotherapy and 718 a chemotherapy fractionated over several consecutive days. The 5-HT3 antagonists, used either alone or in combination with a corticosteroid, have almost completely supplanted all other types of antiemetic regimens for preventing cancer chemotherapy-induced emesis. In fact, 80% of patients, irrespective of whether their emesis was acute or delayed, or of the emetogenic potential of the cancer chemotherapy they received, have been treated with these compounds. However, the practice of participating oncologists with respect to prescriptions has been far from consistent with the evidence provided by randomized controlled trials. Both overtreatment and undertreatment have occurred in many patients, creating unjustified costs and placing the patients at greater risk for emesis. However, when antiemetics are properly used their effectiveness is similar to that seen in randomized controlled trials. Conclusions: Powerful barriers exist between the evidence provided by sound research and clinical practice, and this issue hampers progress toward the optimal use of antiemetic drugs.

1998 - Treatment of B cell grow grade non Hodgkin's lymphoma (NHL) with anti CD20 monoclonal antibody Rituximab. Cancer in the ederly. [Abstract in Rivista]
Federico, Massimo; Clo, V; Vinci, G; Sacchi, Stefano
abstract

no abstract

1998 - Weekly administration of vincristine, cyclophosphamide, mitoxantrone and bleomycin (VEMB) in the treatment of elderly aggressive non Hodgkin's lymphoma [Articolo su rivista]
Merli, F; Federico, Massimo; Avanzini, P; Ilariucci, F; Stelitano, C; Iannitto, E; Colombi, M; Vallisa, D; Santagati, G; Piccinini, Lino
abstract

Background and Objective. Aim of the study was to assess the efficacy of VEMB, a short-lasting therapeutic regimen (50 days) which alternates two myelotoxic drugs (cyclophosphamide and mitoxantrone) every week with two less hematologically toxic drugs (vincristine and bleomycin) in the treatment of aggressive NHL in the elderly (over 70). Design and Methods. Between November 1994 and March 1996, 37 patients aged more than 70 years, with highly or moderately malignant NHL (according to the Working Formulation) have been enrolled into the study. The stage of the disease ranged between II and IV according to Ann Arbor. Mean age was 77 years; 14 patients (38%) had stage IV; 19 patients (51%) had LDH higher than normal; 26 patients (70%) had extranodal and 9 patients (24%) had bulky disease at time of diagnosis. Results. Sixty-two percent of patients achieved a complete and 22% a partial remission. Non-responders amounted to 5%. Four patients (11%) died during the therapy; Nine patients (24%) experienced grade III-IV neutropenia. The most frequently observed event was mild neurotoxicity (43% of cases). The overall survival rate at 30 months was 55%. DFS at 24 months was 66%. Interpretation and Conclusions. VEMB is a therapeutic regimen whose efficacy is comparable to that of the other derived MACOP-B therapeutic regimens used in the elderly NHL. It has proved to have a good feasibility, though the number of toxic deaths should not be neglected.

1997 - A pilot study on the use of the ProMACE CytaBOM regimen as a first-line treatment of advanced follicular non-Hodgkin's lymphoma [Articolo su rivista]
L., Baldini; A., Guffanti; P., Gobbi; M., Colombi; Federico, Massimo; P., Avanzini; L., Cavanna; C., Pieresca; Silingardi, Vittorio; At, Maiolo
abstract

BACKGROUND. The role of intensive conventional dose chemotherapy in advanced low grade non-Hodgkin´s lymphomas is a matter of debate, The Gruppo Italiano per lo Studio dei Linfomi conducted a study to evaluate the efficacy and toxicity of a third-generation polychemotherapeutic regimen, ProMACE-CytaBOM, as a first-line therapy in a selected group of patients with advanced follicular non-Hodgkin´s lymphoma (Fo-NHL) who were younger than 60 years. METHODS. Thirty-nine patients were included in the study (14 males, 25 females; median age, 44 years; age range, 22-60 years). Their WF histotypes were B (9 patients), C (23 patients), and D (7 patients), All of the patients had disease in an advanced clinical stage (Stage III, 15 patients; Stage IV, 24 patients), and 9 patients had B symptoms. According to the age-adjusted international Prognostic Index (IPI), 20 patients exhibited low-intermediate risk, 14 high-intermediate risk, and 5 high risk Three of the patients were not considered evaluable because they withdrew their consent after three (one patient) and four (two patients) cycles of therapy (one of these patients was in complete remission [CR], and two were in partial remission [PR]). Of the 36 evaluable patients, 4 received IF-PT after the 6 planned cycles of therapy. RESULTS. CR was achieved in 20 patients (55.5%) and PR in 14 (38.8%), One patient (2.7%) experienced disease progression during the treatment program, Eight of the 20 patients with CR (40%) relapsed. Eight patients (22.2%) died: 6 died of disease progression, 1 died of therapy consequences, and 1 died of an unrelated cause. With a median follow-up of 49 months (range, 28-79 months), the disease free survival rate was 60%. The overall survival rate was 80% after a median follow-up of 44 months (range, 3-79 months). The IPI stratification of patients shelved a borderline statistical difference in terms of time to treatment failure and overall survival. The main hematologic toxicity was neutropenia (Grade 3 in approximately 10% of patients). One patient died of sepsis. Cotrimoxazole prophylaxis was always given. Cardiac toxicity (Grade 3) was observed in 1 patient at the end of rile planned therapy. The average relative dose intensity of the drugs was 89% of the projected dose, without the regular use of growth factors. CONCLUSIONS. This study indicates that ProMACE-CytaBOM could be a suitable regimen for adult patients with advanced Fo-NHL, allowing a good CR rate and very good disease free survival rate. However, the occurrence of severe, albeit limited, adverse effects suggests that this regimen should first be used in controlled therapeutic protocols to verify its efficacy with respect to less intensive approaches.

1997 - Cancer Incidence in the Province of Modena. Cancer Incidence in Five Continents Vol.VII [Monografia/Trattato scientifico]
Federico, Massimo; Mangone, L.; Silingardi, Vittorio
abstract

Lavoro scientifico sull'incidenza dei tumori nella provincia di Modena

1997 - Hodgkin's disease presenting below the diaphragm. The experience of the Gruppo Italiano Studio Linfomi (GISL) [Articolo su rivista]
Iannitto, E; Accurso, V; Federico, Massimo; Vallisa, D; Pieresca, C; Gravina, Sf; Di Costanzo, F; Di Trapani, R; Silingardi, Vittorio; Mariani, G.
abstract

Background and Objective. Infradiaphragmatic Hodgkin´s disease is rare, making up 5-12% of cases in clinical stages I and II; consequently, several questions concerning prognosis and treatment strategy remain to be answered. The aim of this study was to analyze the clinical and prognostic characteristics and outcome of his condition. Methods. A series of 282 patients with CS I-II Hodgkin´s disease (HD) was investigated. In 31 patients the disease was confined below the diaphragm (BDHD), and in the remaining above the diaphragm (ADHD). The presenting features and outcomes were compared in the two groups. Results. The BDHD group was older (p < 0.0002), had a higher frequency of males (p < 0.08) and a different histological subtype group distribution (p < 0.0001). Stage II BDHD patients had a worse overall survival rate (OS) than stage II ADHD patients (68.8% vs 86.6% at 8 years, p < 0.01) if age is not considered; patients with more than 40 years of age, in fact, had the same survival rates as those with ADHD. BDHD patients with intra-abdominal disease alone had worse prognostic factors and OS (p = 0.12) than patients with inguinal-femoral nodes. Interpretation and Conclusions. Although BDHD patients present distinct features, they have the same OS and relapse-free survival rate as age-adjusted ADHD patients. According to our experience patients with stage I peripheral BDHD respond well to radiotherapy-based regimens. Those with stage II and or intra-abdominal disease are more challenging; chemotherapy or a combined therapy seem to be more suitable approaches for these patients.

1997 - I tumori in Emilia-Romagna. Prevenzione nei luoghi di vita e di lavoro. [Monografia/Trattato scientifico]
Federico, Massimo; Mangone, L.; Borrini, A.; Bucchi, L.; Carrozzi, G.; Cervino, D.; De Lisi, V.; Falcini, F.; Ferrari, C.; Ferretti, S.; Finarelli, A. C.; Garaffoni, G.; Luppi, G.; Nanni, O.; Picci, P.; PONZ DE LEON, Maurizio; Santacroce, M.
abstract

Monografia sui dati di incidenza e sopravvivenza delle malattie neoplastiche in Emilia-Romagna

1997 - I tumori in provincia di Modena nel 1993 [Monografia/Trattato scientifico]
Mangone, L.; De Girolamo, G.; Carrozzi, G.; Federico, Massimo
abstract

Monografia sui dati di incidenza e sopravvivenza dele neoplasie nella provincia di Modena

1997 - La strategia terapeutica del GISL nei linfomi non-Hodgkin [Articolo su rivista]
Clò, V.; Palmieri, S.; Molica, S.; Quarta, G.; Broglia, C.; Dezza, L.; Cavalli, C.; Cavanna, L.; Federico, Massimo; Silingardi, Vittorio
abstract

Le attuali strategie terapeutiche a disposizione per i linfomi non-Hodgkin hanno determinato un profondo cambiamento della storia naturale di queste malattie, che in un numero rilevante di casi possono guarire e comunque, nella maggior parte dei casi, possono raggiungere lunghe sopravvivenze, con una soddisfacente qualità della vita. I farmaci citostatici rappresentano oggi la risorsa terapeutica più importante per il controlo della malattia. Altri utili presidi terapeutici sono rappresentati da radioterapia, chirurgia e modificatori della risposta biologica, quasi sempre usati in associazione con la chemioterapia. Il Gruppo Italiano per lo Studio dei Linfomi (GISL) è nato alla fine del 1987 con lo scopo di approfondire lo studio biologico e clinico dei linfomi, di razionalizzare la programmazione terapeutica, di valutare l'importanza di nuovi metodi di indagine e di approccio clinico e di nuovi schemi di trattamento; a tale gruppo attualmente aderiscono oltre 20 centri italiani. L'attività del GISL è soprattutto rivolta allo sviluppo di linee guida per il disego e la conduzione di studi clinici controllati multicentrici. Dal 1987 il GISL ha raccolto informazioni su più di 4000 casi di linfoma maligno, dei quali oltre 2000 arruolati in studi clinici controllati e i restanti segnalati al Registro Linfomi.

1997 - Screening clinico, mammografico e genetico del carcinoma mammario ereditario [Articolo su rivista]
Mangone, L.; Cortessi, L.; Canossi, B.; Mauri, C.; Ferrari, S.; Romagnoli, Renato; Federico, Massimo; Silingardi, Vittorio
abstract

Nel 1990 è iniziato a Modena uno studio rivolto alla individuazione delle forme familiari e francamente ereditarie di Carcinoma mammario (CM). Non essendovi in letteratura criteri univoci che identificassero tali forme, sono stati messi a punto dei criteri originali per definire le forme ereditarie, le forme sospette ereditarie e quelle familiari di CM.In questi anni sono stati compilati 492 alberi genealogici allargati in donne con storia familiare per CM e le donne a rischio individuate sono state o saranno invitate a partecipare ad un programma di sorveglianza. Nel 1995 è iniziato anche lo studio genetico delle donne con CM ereditario, attraverso la ricerca di mutazioni del gene BrCa1, tale studio è stato condotto dapprima con la tecnica del PTT (Protein Troncation Test) e successivamente con la tecnica DAS (Sequenziamento Diretto Automatizzato).A tutte le donne che eseguono il test genetico, viene offerta una consulenza pre-test ed una post-test. Vengono discusse le problematiche dello screening del CM ereditario.

1997 - Terapia ormonale sostitutiva in menopausa e carcinoma mammario [Articolo su rivista]
Zironi, S.; Federico, Massimo
abstract

Nel presente lavoro viene analizzato il rapporto tra terapia ormonale sostitutiva in menopausa e neoplasia mammaria. E' stata fatta una revisione della letteratura più recente: anche se è difficile per diverse ragioni giungere a conclusioni certe, alcune puntualizzazioni risultano utili. Nelle donne sane bisogna valutare attentamente i rischi e i benefici di tale trattamento, specialmente se protratto per 5 anni o più e se l'età è superiore a 55 anni.Nelle donne già trattate per carcinoma mammario sono in corso alcuni studi prospettici sull'impiego della terapia ormonale sostitutiva in sottogruppi selezionati di pazienti a basso rischio di ricaduta. In attesa che siano disponibili i risultati di questi studi, l'impiego degli estrogeni è ancora controindicato e vengono consigliati farmaci alternativi.

1997 - Variations in the survival adult cancer patients in Italy [Articolo su rivista]
Gatta, G.; Buiatti, E.; Conti, E.; De Lisi, V.; Falcini, F.; Federico, Massimo; Gafà, L.; PONZ DE LEON, Maurizio; Vercelli, M.; Zanetti, R.
abstract

AIMS: As part of the ITACARE project, the present study analyzed and compared population-based data on the survival of adult cancer patients in Italy, according to sex, age, period of diagnosis and geographical area. METHODS: Nine Italian population-based cancer registries provided data on all their cancer patients (total 90,431 cases) followed for at least 5 years and diagnosed during the period 1978-1989. About 10% of the Italian population is covered by these registries. The data was analyzed by means of a multivariate model. RESULTS: The major findings were that there was a general improvement in 5-year relative survival over the study period (from 33% to 39%) and that there were significant differences in survival between different areas of the country, particularly for cancer sites which respond well to treatment. In general, the area covered by the Ragusa (Sicily) registry was characterized by significantly worse survival than other registry populations. Other important findings were that for all malignant cancer sites 5-year relative survival decreased with age from 50% for the youngest age class (15-44 years) to 27% for the oldest age class (75+ years) and that women have a better prognosis for most cancer sites (overall 5-year relative survival in women 48% vs 32% in men). CONCLUSIONS: The significant regional differences in survival may reflect unequal provision of care, particularly between northern-central Italy and the south. The reasons for the general survival improvement with time are not completely understood, whereas the marked overall sex difference is related to the fact that the commonest cancer in women (breast cancer) is eminently more treatable than the commonest malignancy in men (lung cancer). The unfavorable trend with increasing age may be due to increasing difficulty in applying complete therapy protocols as general health declines, sometimes in relation to an advanced cancer stage at diagnosis.

1996 - Cancer incidence and mortality in the province of Modena in 1992 [Monografia/Trattato scientifico]
Mangone, L.; De Girolamo, G.; Carrozzi, G.; Barbieri, F.; Maiorana, Antonino; Federico, Massimo
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

1996 - CCNU, vinblastine, procarbazine and prednisone (CVPP) with extended-field radiotherapy in the treatment of early unfavorable Hodgkin's disease - A prospective study on behalf of the Gruppo Italiano per lo Studio dei Linfomi (GISL) [Articolo su rivista]
Gobbi, Pg; Pieresca, C; Cavanna, L; Corbella, F; Vallisa, D; Federico, Massimo; Formisano, R; Carotenuto, M; Merli, F; Callea, V; Angrilli, F; Silingardi, Vittorio
abstract

Purpose. To test the adequacy of the CVPP four-drug regimen as ancillary chemotherapy associated with extended-field radiotherapy in the treatment of early, unfavorable, clinically staged Hodgkin's disease. Patients and Methods. The population of this prospective, multicenter study consisted of 49 patients with stage I-II disease, associated with bulky involvement or unfavorable histology (lymphocyte-depleted nodular sclerosis or lymphocyte depletion), systemic symptoms or extranodal involvement, or presenting with stage III A favorable-histology disease, with or without extranodal involvement. Results. Complete remission was achieved in 39 patients, partial remission in 2, while 8 patients did not respond. Four patients have relapsed so far (median follow-up: 43 months), all of whom were subsequently rescued with different salvage treatments. Dose intensity (mean+/-SD: 0.83+/-0.12) and hematological toxicity (including 2 deaths from infection) were higher when RT followed CT than when it was interposed in the middle of the 6 cycles. No growth factors were used. Nonhematological toxicity was very low and fully tolerable. Conclusions. Results confirmed the mild neurological and gastroenteric side effects of CVPP that make it an interesting MOPP-variant regimen. This combination seems most indicated when a regimen devoid of cardiac and pulmonary toxicity is required for association with full-dosage mediastinal radiotherapy, as is often the case in early, unfavorable Hodgkin's disease. The optimal sequence consists of radiotherapy administered after completion of the chemotherapy program. The use of growth factors for correction (or prevention) of marked leukopenia seems appropriate.

1996 - High-dose therapy and autologous stem cell transplantation vs conventional therapy for patients with advanced Hodgkin's disease responding to first-line therapy. Analysis of clinical characteristics of 51 patients enrolled in the HD01 protocol [Articolo su rivista]
Federico, Massimo; Clo, V; Carella, Am
abstract

Whether high-dose therapy (HDT) plus autologous stem cell transplantation (ASCT) ought to be included in the initial treatment plan for those patients with unfavourable Hodgkin's disease, a wide cooperative study (HD01 protocol) was approved, comparing HDT followed by ASCT vs conventional chemotherapy (CT). Patients were eligible for the study if they had at least two of the following adverse prognostic factors: high serum LDH levels, mediastinal mass >0.45, more than one extranodal involved site, low hematocrit (<34% for women and <38% for men), and inguinal involvement. Those patients achieving complete or partial remission with four courses of ABVD or ABVD-containing chemotherapy were randomized to receive either HDT plus ASCT or four additional courses of chemotherapy, followed by ASCT in second remission, if appropriate. Between April 1993 and September 1995, 55 patients from 14 different centers have been enrolled into the trial. Twenty patients (45%) were in stage IV, and 37 patients (84%) had systemic symptoms. Twenty-seven patients (61%) had two adverse prognostic factors, and 17 patients (39%) had three or more risk factors. After four cycles of ABVD-containing CT, 44 patients were assessable for response. Overall 12 patients achieved CR (27%), 25 obtained a PR (57%) and seven patients failed to respond (16%). Thirty-six patients were randomized between ASCT (20 patients) or four additional cycles of conventional CT (16 patients). With a median follow-up after ASCT of 13 months (range 1-23 months), no major ASCT-related toxicity has been reported to the trial office. In conclusion, the first 44 patients registered in the HD01 trial and assessable for response, had a very aggressive disease and responded poorly to conventional CT, thus warranting a more aggressive approach, such as HDT followed by ASCT.

1996 - Sensitive detection of circulating breast cancer cells by reverse-transcriptase polymerase chain reaction of maspin gene [Articolo su rivista]
Luppi, Mario; Morselli, M; Bandieri, E; Federico, Massimo; Marasca, Roberto; Barozzi, P; Ferrari, Mg; Savarino, M; Frassoldati, A; Torelli, Giuseppe
abstract

Background: Maspin, a recently identified protein related to the family of serpins, is believed to play a role in human breast cancer. In an effort to improve the present methods of detection, we have developed a reverse-transcriptase polymerase chain reaction (RT-PCR) assay for maspin transcript to identify small numbers of mammary carcinoma cells in the peripheral blood and bone marrow of patients with breast cancer. Patients and methods: Five non-neoplastic mammary tissue samples, 13 breast cancer specimens as well as 17 peripheral blood and 4 bone marrow samples from normal subjects were screened for the presence of maspin mRNA by RT-PCR. The same assay was applied to peripheral blood or bone marrow samples obtained from 29 patients with stages I to IV breast cancer. Results: By RT-PCR it was possible to amplify maspin mRNA in all of the primary and metastatic breast cancer specimens, but in none of the normal hemopoietic samples from healthy donors. Thus, detection of maspin transcript in the peripheral blood or marrow of a patient known to have breast cancer is indicative of the presence of mammary carcinoma cells. In reconstitution experiments, maspin RT-PCR reliably detected 10 mammary carcinoma cells in 1 million normal peripheral-blood mononuclear cells (PBMCs). None of the 9 patients with stages I, II, or III breast cancer had maspin transcript in peripheral blood. Of note, 3 of 9 patients with stage TV breast cancer receiving systemic therapy at the time of sample collection, but only I of 11 patients with stage IV not receiving therapy, had detectable maspin transcript in peripheral blood. Moreover, 3 marrow specimens from stage TV patients tested positive by this assay. Conclusions: This pilot study suggests that maspin RT-PCR assay is a sensitive, specific and sufficiently rapid method for detection of small numbers of circulating cells and marrow micrometastases in breast cancer patients. The possibility of applying this assay in the detection of tumor cell contamination of both marrow and stem-cell apheresis harvests of breast cancer patients merits further investigation.

1996 - Twelve years experience with high dose therapy and autologous stem cell transplantation for high risk Hodgkin's disease patients in first remission after MOPP/ABVD [Articolo su rivista]
Carella, A. M.; Prencipe, E.; Pungolino, E.; Lerma, E.; Frassoni, F.; Rossi, E.; Giordano, D.; Occhini, D.; Gatti, A. M.; Bruni, R.; Spriano, M.; Nati, S.; Pierluigi, D.; Congiu, M.; Vimercati, R.; Rovatti, J. L.; Federico, Massimo
abstract

High-dose therapy followed by autografting can cure patients with aggressive Hodgkin's disease (HD) refractory or with early relapse to first-line combination chemotherapy. On the other hand, the eradication of the disease is rarely achieved in heavily pretreated patients. It has been suggested that patients with HD with very high risk characteristics at diagnosis, often relapse despite appropriate therapy with 7-8 drugs combination. Thus it seems to us that such patients are potential candidates for early autografting during first remission. Twelve years ago, we initiated a pilot study to investigate whether patients with very high risk characteristics, would benefit from early autografting. The application of early autografting was compared with our historical group of patients in complete remission after receiving MOPP/ABVD, who had the same negative prognostic characteristics, refused autografting and who did not receive other treatment after achieving complete remission. Among the 22 consecutive patients entered into the pilot study and autografted, 18 are alive and 17 (77%) remain alive in unmaintained remission at a median of 86 months. One patient (4%) died of interstitial pneumonitis in the transplantation group. Only 8/24 (33%) patients, who did not receive an autograft, are currently alive and disease free at a median of 89 months. In conclusion, the early application of autografting appears to improve the outcome in patients with very high risk HD who achieved remission with MOPP/ABVD.

1996 - Vinblastine, bleomycin, and methotrexate chemotherapy plus extended-field radiotherapy in early, favorably presenting, clinically staged Hodgkin's patients: The Gruppo Italiano per lo Studio dei Linfomi Experience [Articolo su rivista]
Pg, Gobbi; C., Pieresca; A., Frassoldati; M., Carotenuto; N., Direnzo; A., Lasala; R., Berte; P., Avanzini; Federico, Massimo; E., Ascari; Silingardi, Vittorio
abstract

Purpose: To ascertain whether vinblastine, bleomycin, and methotrexate (VBM) (CT) combined with extended-field radiotherapy (EF RT) is effective enough to spare laparotomy in early, favorably presenting Hodgkin´s disease (HD) patients. Patients and Methods: Fifty patients with clinical stage IA or IIAHD with favorable or masses entered a prospective multicenter study started in January 1988. The median follow-vp time was 38 months. Results: All patients achieved a complete remission (CR). Five relapsed after 3 to 40 months and underwent successful salvage therapy. The actuarial remission rate wets 0.89% at 3 years and 0.82% at 5 years. Two patients died in CR: one of severe pulmonary toxicity, the other of a second neoplasia (adenocarcinoma of the lung), 2 and 43 months after the end of therapy, respectively. The hematologic toxicity recorded during VBM CT was mild on the whole, Major toxicity was represented by pulmonary side effects and neurologic symptoms. Multiple regression analysis demonstrated that pulmonary toxicity was significantly related only to the amount of RT delivered to the mediastinum and not to the relative dose of bleomycin, to the dose-intensities of the three drugs in the regimen, or to patient age or sex, The same statistical technique showed that the only clinical factor related to grade of neurotoxicity was vinblastine dosage. Conclusion: VBM CT combined with EF RT is an effective treatment early, clinically staged, favorable HD patients, However, the toxicity of this combination suggests that certain modifications should be evaluated.

1995 - A RANDOMIZED, DOUBLE-BLIND, CROSS-OVER STUDY COMPARING A LEVOSULPIRIDE-BASED AND A METOCLOPRAMIDE-BASED COMBINATION IN THE PREVENTION OF PROMECE-CYTABOM-INDUCED EMESIS [Articolo su rivista]
Sabbatini, R; Federico, Massimo; Baldini, L; Barbieri, F; Maiolo, Mt; Silingardi, Vittorio
abstract

Background. To test two different antiemetic regimens for preventing nausea and vomiting in patients with non-Hodgkin's lymphoma (NHL) undergoing systemic chemotherapy (CT) with ProMECE-CytaBOM (P-C). Patients and Methods. Twenty consecutive untreated adult outpatients with histologically confirmed NHL and scheduled to receive P-C chemotherapy were registered in a randomized, double-blind, cross-over study to compare the antiemetic efficacy of a levosulpiride (LS)-based and metoclopramide (MTC)-based regimen. Results. Complete protection from vomiting was recorded in 93% (62/67) of courses with the LS-regimen and in 89% (62/70) with the MTC-regimen (p = 0.428). No nausea was observed in 84% (56/67) of courses with the LS-regimen and in 74% (52/70) with the MTC-regimen (p = 0.183). No differences in prevention of emesis were recorded when patients crossed to the other regimen. Both regimens were well tolerated; however, on day 8 of chemotherapy, when both antiemetic regimens were administered at a higher dose, the LS-based combination showed significantly lower toxicity (p = 0.035). Conclusions. ProMECE-CytaBOM-induced emesis can be prevented in most cases with appropriate, specifically designed antiemetic therapy. Both the LS- and MTC-based combinations resulted in a high percentage of complete protection from emesis, but the higher incidence of side effects observed with MTC makes the LS-based regimen preferable for patients receiving P-C chemotherapy.

1995 - ANAPLASTIC LARGE-CELL LYMPHOMA (CD30+/KI-1+) - ANALYSIS OF 35 CASES FOLLOWED AT GISL CENTERS [Articolo su rivista]
Longo, G; Federico, Massimo; Pieresca, C; Avanzini, P; Iannitto, E; Diprisco, Au; Baldini, L; Brugiatelli, M; Clo, V; Bevini, M; Silingardi, Vittorio
abstract

Between January 1988 and June 1992, 35 patients with primary anaplastic large cell lymphoma (ALCL)CD30+ were referred to one of the institutions participating in GISL (Gruppo Italiano per lo Studio dei Linformi). 16 patients were treated with ProMACE-CytaBOM, two with MACOP-B, one with CHOP and one with LSA(2)-L(2). As of November 1990, all newly diagnosed patients were treated with MOPP/EBV/CAD hybrid. 27 (77%) cases of ALCL CD30+ and 8 (23%) cases of Hodgkin's-related (HR) lymphoma CD30+ were diagnosed. Extranodal disease was present in 22 cases (63%), and 8 patients (23%) had primary bone marrow involvement. Twenty-three complete remissions (CR) (66%), six partial remissions (PR) (17%) and six no remissions (NR) (17%) were achieved with induction therapy. Results achieved with ProMACE-CytaBOM and MOPP/EBV/CAD hybrid were comparable. The overall response rate (CR+PR) was 85% for patients with classic ALCL CD30+ and 87% for those with HR lymphoma CD30+. The 3 year estimated overall survival rate was 66% and the 3 year relapse free survival rate was 65% for the entire group. The only significant favourable prognostic factor was the achievement of CR with initial therapy. Our findings suggest that ALCL (CD30+/Ki-1+) has a clinical outcome similar to aggressive non-Hodgkin's lymphoma (NHL). The use of an anthracycline-containing regimen will provide a change of cure in approximately 65% of cases.

1995 - Cancer incidence and mortality in the province of Modena in 1991 [Monografia/Trattato scientifico]
Federico, Massimo; Mangone, L.; De Girolamo, G.; Fontana, G.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nellaprovincia di Modena

1995 - Daily variation of immunoreactive serum interleukin-6 levels in multiple myeloma [Articolo su rivista]
Bandieri, E.; Luppi, Mario; Luppi, G.; Federico, Massimo; Sabbatini, R.; Torelli, Giuseppe; Piccinini, Lino
abstract

NO ABSTRACT

1995 - Effects of thymostimulin with combination chemotherapy in patients with aggressive non-Hodgkin's lymphoma. [Articolo su rivista]
Federico, Massimo; Gobbi, Pg; Moretti, G; Avanzini, P; Direnzo, N; Cavanna, L; Ascari, E; Silingardi, Vittorio
abstract

The purpose of this study was to test the efficacy and safety of thymostimulin (TS) administered in addition to conventional chemotherapy in patients with intermediate- and high-grade non-Hodgkin's lymphoma (IG, HG-NHL). A total of 150 patients with newly diagnosed IG- or HG-NHL were entered in a multicenter trial to compare the effectiveness of two different third-generation regimens (MACOP-B versus ProMACE-CytaBOM) and were randomized to receive chemotherapy (CT) alone or CT + TS. In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin. TS was administered i.m. at a dose of 1 mg/kg daily on days 22-28 of each drug course to patients treated with ProMACE-CytaBOM, and on days 22-29, 50-57, and 77-85 to patients treated with MACOP-B. There were 134 fully evaluable patients: 68 treated with CT alone and 66 treated with CT + TS. Patients treated with CT + TS had a higher complete remission (CR) rate compared to patients given CT alone (59.1% vs 42.4%; P = .05). CR were significantly higher for patients treated with CT + TS in the groups with IG-NHL (P = .01), in those aged less than 60 years (P = .05), with good performance status (P = .05), and normal hemoglobin levels (P = .05). Four-year survival rates are 64.5% for patients treated with CT + TS and 43.0% for those treated with CT alone (P = .30). No difference between the two treatment arms have been observed as regards drug-related toxicity and the number and severity of infectious episodes. The use of TS during the 7 days before chemotherapy has been associated with a significantly superior CR rate. The advantage of CT + TS was mostly obtained in patients with IG-NHL, and those with good performance status or normal hemoglobin levels. In these patients TS may have potentiated the host reactions against the tumor, leading to an increase in NK activity and the production of cytokines. This postulated increase in the effectiveness of chemotherapy after TS might also explain the absence of the expected myeloprotective action.

1995 - Hairy cell leukemia [Monografia/Trattato scientifico]
Federico, Massimo; Frassoldati, A.; Artusi, Tullio; Castoldi, G. L.; Lauria, F.; Pileri, S.; Pizzolo, G.; Resegotti, L.; Semenzato, G.; Damasio, E. E.
abstract

Monografia contenente una sintesi delle linee guida diagnostico-terapeutiche nella HCL ed una breve rassegna delle principali esperienze condotte dal GCIHCL in 15 anni di attività

1995 - Immunohistochemical labeling index in breast cancer after in vivo administration of bromodeoxiuridine [Articolo su rivista]
Frassoldati, A.; Bandieri, E.; Natalini, G.; Adami, F.; Sabbatini, R.; Criscuolo, M.; Federico, Massimo; Stanzani, C.; Piccinini, Lino; Silingardi, Vittorio
abstract

Cell kinetics have been classically investigated by thymidine Labeling Index (LI). Recently, S-phase fraction of neoplastic cells has been evaluated by in vivo incorporation of bromodeoxyuridine (BRDU), a thymidine analogue, in dividing cells. In several neoplasms, in vivo administration of BRDU can provide prognostic information regarding the tumour growth. In order to establish the feasibility and the usefulness of this analysis in breast cancer, we determined the in vivo BRDU-LI in 28 patients with locally advanced tumours, using an immunohistochemical technique. The intravenous infusions of BRDU- labeled cells were demonstrated satisfactorily by indirect peroxidase method. BRDU-LI resulted by the radio between labeled and neoplastic cells in more then forty 100x microscopic fields randomly analyzed. Six out of 28 patients failed to yield analyzable data. Mean BRDU-LI of 22 evaluable samples was 2.0 ranging between 0.6% and 5%. All analyzable specimens showed a clear uptake of BRDU by neoplastic cells with a diffuse and homogeneous nuclear staining. Labeled cells were uniformly distributed in the tumour tissue, whereas no BRDU incorporation was observed in two normal tissue samples. BRDU-LI resulted significantly higher in aneuploid than in diploid tutours. No relationships between BRDU-LI and cytofluorimetric S-phase fraction, oestrogen and progesterone receptor status, grading, tutour size and number of involved nodes have been observed. immunohistochemical determination of BRDU-LI provides a simple and useful method to achieve information about cell kinetics in breast cancer.

1995 - Preliminary analysis of clinical characteristics of patients enrolled in the HD01 protocol: a randomised trial of high dose therapy and autologous stem cell transplantation versus conventional therapy for patients with advanced Hodgkin's disease responding to first line therapy [Articolo su rivista]
Federico, Massimo; Clo, V; Carella, Am
abstract

this article does not have an abstract

1995 - PROMECE-CYTABOM VS MACOP-B IN ADVANCED AGGRESSIVE NON-HODGKINS-LYMPHOMA - LONG-TERM RESULTS OF A MULTICENTER STUDY OF THE ITALIAN LYMPHOMA STUDY-GROUP (GISL) [Articolo su rivista]
Silingardi, Vittorio; Federico, Massimo; Cavanna, L; Avanzini, P; Gobbi, Pg; Lombardo, M; Carotenuto, M; Frassoldati, A; Pieresca, C; Vallisa, D; Merli, F; Ascari, E; Mauri, C.
abstract

A randomized trial was designed in order to compare the efficacy and feasibility of ProMECE-CytaBOM (P-C) and MACOP-B (M-B) in patients with advanced, aggressive non Hodgkin's lymphoma (NHL). P-C and M-B were chosen due to their association with a very high complete remission rate when compared to other published protocols. The study was conducted on 210 patients with intermediate or high-grade NHL in stage I bulky, or stages II-IV, randomized to receive either 6 courses of P-C delivered every 28 days (106 patients), or 12 weeks of M-B chemotherapy (104 patients). In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin (i.e. 30 mg/m(2) of the analog). At the end of induction therapy patients could receive additional radiotherapy to residual masses or to sites of previous bulky disease. The two groups of patients were compared for response rates, number and severity of therapy related side effects, overall survival, disease-free survival, and time to treatment failure. Sixty-five patients (62%) treated with P-C and 69 patients (67%) treated with M-B achieved a complete remission, with no significant differences between the two treatment arms (P = 0.13). The overall objective response rate (complete + partial remission) was 74% for patients treated with P-C, and 81% for patients treated with M-B, respectively. The 4-year relapse-free survival rate was 59% for P-C and 69% for M-B, respectively (P = 0.11). We observed an eventual total of 120 treatment failures, 64 (61%) in the group treated with P-C and 56 (54%) among those treated with M-B (P = 0.29). Patients alive without disease at four yeats were estimated to be 42% in the P-C arm and 49% in the M-B arm (P = 0.27). The estimated 4-year overall survival was 54% for P-C and 61% for M-B, and the differences were also not significant (P = 0.29). Patients treated with M-B experienced more and more severe side effects, including mucositis, infections, neurologic, pulmonary and cardiac abnormalities. Patients treated with P-C had a 1.3 g mean decrease of hemoglobin over the induction therapy, while patients treated with M-B experienced a 2.2 g mean decrease (P = 0.01). In conclusion, both P-C and M-B resulted in effective treatment for patients with aggressive NHL, and provided similar activity. However P-C was more manageable in an outpatient setting and produced less acute toxic effects.

1994 - Cancer incidence, mortality and survival in the province of Modena, years 1988-1990 [Monografia/Trattato scientifico]
Federico, Massimo; Mangone, L.; Di Gerolamo, G.; Fontana, G.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

1994 - HAIRY-CELL LEUKEMIA - A CLINICAL REVIEW BASED ON 725 CASES OF THE ITALIAN-COOPERATIVE-GROUP (ICGHCL) [Articolo su rivista]
Frassoldati, A; Lamparelli, T; Federico, Massimo; Annino, L; Capnist, G; Pagnucco, G; Dini, E; Resegotti, L; Damasio, Ee; Silingardi, Vittorio
abstract

The Italian Registry for hairy cell leukemia (HCL) has recorded 725 patients with HCL diagnosed over 25 years. We analysed this large series of patients with the aim of providing an evaluation of changes in clinical presentation, impact of initial therapy and modifications in prognostic factors over the period of two decades. Over time, a progressive down-staging of the disease at the onset, along with a reduction of patients with severe anemia and marked splenomegaly, has been observed. A second malignancy was found in 3.7% of patients, mostly detected several years after the onset of HCL. A striking improvement of survival rates has been observed, from 58.9% survival at five years for patients diagnosed before 1985 to 87.5% at five years for patients diagnosed after 1985 (p < 0.0001). Before 1985 hemoglobin alone provided prognostic information, whereas after 1985, clinical stage and the number of leukocytes correlated better with patient outcome. Survivals at 5 and 10 years were 34.4% and 29.6% respectively for untreated patients, 58.8% and 44.1% for patients receiving chemotherapy, steroids or other drugs, 64.1% and 56.1% for splenectomized patients and 88.9% (at 5 years) for alpha interferon (IFN)-treated patients (p < 0.0001). Our findings suggest that IFN has improved the prognosis of HCL, and that it must be considered a good initial treatment for patients with HCL.

1994 - Incidenza e mortalità per tumori in provincia di Modena 1988-1989 [Monografia/Trattato scientifico]
Federico, Massimo; Lauriola, P.; Mangone, L.; Fontana, G.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

1994 - IN-VITRO DRUG-TESTING OF OVARIAN-CANCER USING THE HUMAN TUMOR COLONY-FORMING ASSAY - COMPARISON OF IN-VITRO RESPONSE AND CLINICAL OUTCOME [Articolo su rivista]
Federico, Massimo; Alberts, Ds; Garcia, Dj; Emerson, J; Fanta, P; Liu, R; Salmon, Se
abstract

The purpose of this study was to assess the prognostic value of in vitro drug chemosensitivity testing using the Hamburger-Salmon human tumor colony-forming assay (HTCA) in fresh tumor samples obtained from newly diagnosed patients with stage II-IV ovarian cancer undergoing maximum cytoreductive surgery and prior to platinum-based chemotherapy. The HTCA was performed on fresh ovarian cancers obtained from 93 patients at their initial exploratory laparotomy to evaluate in vitro sensitivity to cisplatin, carboplatin, and cyclophosphamide following a 1-hr drug exposure. Prospective clinical follow-up was performed on all patients with the primary study endpoints being pathologically proven complete response at second-look surgery and disease-free and overall survival durations. In vitro drug sensitivity was strongly dose-dependent. At a concentration of 5 mu g/ml only 23% of tumor samples were sensitive (as defined by a greater than or equal to 50% decrease in tumor colony-forming units compared to controls) to cisplatin; 13% of tumors were sensitive to carboplatin at a concentration of 50 mu g/ml and 11% to 4-OH-cyclolphosphamide at a concentration of 1 mu g/ml. At doses which were 10 times the previously stated concentrations, the sensitivity rates to cisplatin, carboplatin, and 4-OH-cyclophosphamide increased to 72, 63, and 53%, respectively. Subjects were categorized as having drug-sensitive disease if HTCA results showed in vitro drug sensitivity to at least one of the agents used in their primary chemotherapy. Multivariate analysis failed to show any advantage in clinical response rate, progression-free interval, or survival duration for patients with drug-sensitive disease compared to drug-resistant disease; however, there was evidence of a trend toward an enhanced pathologically proven complete response rate in patients who had chemosensitive tumors in vitro. Second-look surgery was performed in 28 of 55 patients with optimal surgical resections and no clinical evidence of disease at the completion of their primary chemotherapy. Fifty percent (5/10) of patients with drug-sensitive disease achieved a pathologic complete response, while only 3/18 (17%) patients with drug-resistant tumors had a documented pathologic complete response (P = 0.13). As reported in other ovarian cancer studies, patient characteristics which were found to be significantly associated with survival were stage of disease (II-III vs IV), optimal primary surgical resection (i.e., <I cm(2) residual tumor) vs suboptimal resection, clinical measurability of disease at initiation of chemotherapy, and response to primary chemotherapy. In conclusion, in vitro drug sensitivity, as measured by the HTCA, does not appear to be an independent prognostic factor for survival in patients with stage II-IV epithelial ovarian cancer who undergo standard treatment with tumor debulking surgery and primary platinum-based chemotherapy. Further studies are indicated to determine whether in vitro drug sensitivity is an independent prognostic factor for pathologically proven complete response at second-look surgery.

1994 - Long term results of alpha interferon as initial therapy and splenectomy as consolidation therapy in patients with hairy cell leukemia. Final report from the Italian cooperative group for HCL [Articolo su rivista]
Federico, Massimo; A., Frassoldati; T., Lamparelli; R., Foa; M., Brugiatelli; L., Annino; L., Baldini; G., Capnist; T., Chisesi; Pf, Dicelle; R., Invernizzi; F., Lauria; M., Truini; L., Resegotti; Silingardi, Vittorio; Ee, Damasio
abstract

Purpose: In 1987 the Italian Cooperative Group for the Study of hairy cell leukemia (HCL) started a prospective trial with the following three major aims: 1) to confirm the effectiveness of alpha-IFN as first-line treatment; 2) to assess the usefulness of splenectomy as consolidation treatment in patients achieving a satisfactory partial remission (PR) with alpha-IFN, and 3) to explore whether splenectomy in patients achieving complete remission (CR) with alpha-IFN can reduce the risk of relapse after discontinuation of the drug. Patients and Methods: One-hundred seventy-seven patients with histologically-confirmed HCL were registered in the HCL88-A trial between December 1987 and January 1992. Inclusion criteria included no previous treatment and age less than 66 years. All patients received total doses of 3 MU of alpha-IFN daily for 12 months except for those who achieved early CR and would stop treatment after 6 or 9 months. Patients could be treated with different alpha-IFNs. At the time of the present analysis, 166 patients (93.8%) were fully evaluable. Results: Treatment of HCL patients with alpha-IFN at the onset of the disease resulted in 28 CR (16.9%), 103 PR (62.0%), and 27 Minor Remissions (MR) (16.3%). Patients treated with different alpha-IFNs achieved similar results: the overall response rate (CR + PR + MR) was 92.7%, 97.2%, and 95.3% for patients treated with r-alpha-2a, r-alpha2b, and alpha-N1, respectively. The presence of a leukemic phase and a poor performance status were associated with a statistically significant lower response rate. Patients who were randomly assigned and underwent splenectomy after achieving a PR had a better but not significant 4-year progression-free survival than cases randomized for observation (53% vs. 22%, p = 0.116). Overall, 5 patients died after study entry, with an actuarial 5-year survival rate of 96% for the entire group of 166 patients. After a mean follow-up time of 38 months, only one second malignancy has been recorded. Conclusions: Initial therapy with alpha-IFN, regardless of the type of alpha-IFN used, induces satisfactory responses in the majority of patients with HCL, but in most instances discontinuation of treatment results in recurrence of disease. In most cases alpha-IFN improves the performance status of patients and favors a satisfactory bone marrow recovery and thus could still play a role in the initial management of the disease. Although splenectomy following alpha-IFN could prolong the progression free survival, its use should be restricted to selected cases.

1994 - Long term results of interferon treatment in hairy cell leukemia [Articolo su rivista]
Capnist, G.; Federico, Massimo; Chisesi, T.; Resegotti, L.; Lamparelli, T.; Fabris, P.; Rossi, G.; Invernizzi, R.; Guarnaccia, C.; Leoni, P.; Lauria, F.; Pagnucco, G.; Frassoldati, A.; Damasio, E.
abstract

Eighty nine of 104 patients with hairy cell leukemia (HCL), enrolled between 1985 and 1987 in a multicenter prospective study on human lymphoblastoid IFN alpha-n1, were evaluable for long-term follow-up. The induction treatment, 3 MU/mq daily for a median of 5.7 months, produced a response of 93%, complete+partial response (CR+PR) = 80%, minor (MR) = 13%. Neither prior splenectomy nor pre-treatment variables were associated with the rate of response to IFN. However maintenance treatment of 3 MU/mq weekly given randomly had a slightly significant effect on failure free survival (FFS). Of the 43 patients who relapsed, 31/36 (86%) obtained a new response with IFN. No differences in FFS were recorded between first and second response. At the third induction 7/11 patients were treated again with IFN, 4/7 obtaining some response, but the FFS was significantly worse. The overall survival is still 85%. We conclude that (1) IFN should be used as chronic uninterrupted treatment for HCL, (2) reduced dosage is sufficient to prolong the disease free status and (3) continuous lymphoblastoid IFN administration seems not to be associated with the development of resistance to retreatment.

1993 - EPIDOXORUBICIN VS IDARUBICIN CONTAINING REGIMENS IN INTERMEDIATE AND HIGH-GRADE NON-HODGKINS-LYMPHOMA - PRELIMINARY-RESULTS OF A MULTICENTRIC RANDOMIZED TRIAL [Articolo su rivista]
Brugiatelli, M; Federico, Massimo; Gobbi, Pg; Avanzini, P; Callea, V; Cavanna, L; Depasquale, A; DI PRISCO, Alfredo Ubaldo; Dirienzo, N; Silingardi, Vittorio; Mauri, C.
abstract

Background. In recent years many therapeutic regimens have been designed in order to improve response rate and response duration in non-Hodgkin's lymphoma (NHL). In 1991 the Italian Lymphoma Study Group (GISL) started a prospective randomized trial on treatment of aggressive and advanced NHL, focused on the efficacy of two Pro-MACE-CytaBom (P-C) derived protocols. Methods. From April 1991 to March 1993, 243 cases of intermediate and high grade NHL (Groups D-H according to the Working Formulation) in stage I bulky, II-IV have been registered from 19 institutions and randomized to receive 6 courses of either epidoxorubicin, 30 Mg/M2 (P-E) or idarubicin, 6 mg/m2 (P-I) containing P-C. The present study deals with the results of an interim analysis of the first 96 cases enrolled up to December 1991 (median follow up of surviving cases 19 months, range 15-23), in terms of overall response rate, toxicity and dose intensity of the two schedules, and overall survival. Results. The overall response rate was: 55 CR (64.0%), 15 PR (17.4%), 5 NR (5.8%) and 11 PG (12.8%). The actuarial survival rate was 61% at 24 months. Hematological and non-hematological toxicity was comparable in the two arms. Dose intensity was high and similar for the two schedules (90% vs 89%). Conclusion. This interim analysis demonstrates that in aggressive NHL both P-C derived schedules with epidoxorubicin or idarubicin are effective, safe and well tolerated, also when used in a large multicentric setting.

1993 - Incidenza e mortalità per tumori inprovincia di Modena nel 1988 [Monografia/Trattato scientifico]
Federico, Massimo; Lauriola, P.; Cassinadri, T.
abstract

Monografia sui dati di incidenza e sopravvivenza delle neoplasie nella provincia di Modena

1993 - MOPP/EBV/CAD hybrid chemotherapy with or without limited radiotherapy in advanced or unfavourably presenting Hodgkin's disease. A report from the Italian Lymphoma Study Group [Articolo su rivista]
Pg, Gobbi; C., Pieresca; Federico, Massimo; N., Direnzo; Narni, Franco; E., Iannitto; G., Grignani; L., Cavanna; P., Avanzini; G., Partesotti; V., Pitini; Silingardi, Vittorio; E., Ascari; C., Mauri
abstract

PURPOSE: We explored the feasibility, toxicity, and preliminary results of a chemotherapy (CT) regimen, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/epidoxirubicin, bleomycin, and vinblastine (EBV)/lomustine (CCNU), doxorubicin, and vindesine (CAD), derived through hybridization, shortening, and intensification of a corresponding 10-drug alternating combination CAD/MOPP/doxorubicin, bleomycin, and vinblastine (ABV), effective in treatment of advanced Hodgkin's disease (HD). PATIENTS AND METHODS: Hybridization involved all drugs except CCNU and mechlorethamine, which were administered in alternating cycles; the length of therapy was reduced from nine to six cycles. The average projected drug doses during the six cycles were increased by 42%, with an overall 1.54 dose-intensification; epidoxorubicin was substituted for doxorubicin at equivalent tumoricidal doses. Radiotherapy (RT) was optional and its indications were limited. RESULTS: Eighty assessable patients with previously untreated, advanced or unfavorably presenting HD were treated in nine cooperating institutions between 1988 and 1991. RT was delivered to 22 patients. Remissions were complete (CR) in 75 patients (93%), partial in three (4%), and null in two (3%). The median relative dose-intensity was 0.71 for the overall regimen. Three of five patients who failed to achieve CR, and two of the four who relapsed, received lower relative dose-intensive cycles. Nonhematologic toxicity was acceptable, but there was considerable hematologic toxicity. Fatal gastrointestinal bleeding was seen in one patient. CONCLUSION: Caution is advised due to the short median follow-up period. Nevertheless, in addition to the excellent response rate, (1) the results were reached through abbreviation, intensification, and hybridization of an existing alternating regimen; (2) RT had limited use in this program, which may have contributed to lowering the risk of second tumors; and (3) the results were obtained in a multicenter study (a condition that often impairs results from clinical trials).

1993 - Profilassi del vomito nei pazienti affetti da linfoma non-Hodgkin trattati con il protocollo ProMECE-CytaBOM. Risultati preliminari di uno studio clinico controllato [Articolo su rivista]
Sabbatini, R.; Federico, Massimo; Baldini, L.; Maiolo, M. T.; Silingardi, Vittorio
abstract

La nausea ed il vomito rappresentano alcuni degli effetti collaterali piu frequenti associati all'uso dei farmaci citostatici (1-3). In alcuni casi I'intensita di questi fenomeni pub essere tale da limitare il prosieguo della terapia antineoplastica. In particolareI'associazione Citarabina, Methotrexate, Vincristina e Bleomicina (VIII giomo dello schema polichemioterapico ProM ECE-CytaBOM)e caratterizzata dalla comparsa, in una significativa percentuale di casi, da nausea e vomito. II farmaco attualmente piu' usato nellaprofilassi del vomito e la Metoclopramide (MTC) (5-8) che, soprattutto se impiegato ad alte dosi, e pero' caratterizzato dallacomparsa di una discreta percentuale di effetti collaterali: reazioni extrapiramidali acute (10-15% dei pazienti), acatisia, sedazione(50% dei pazienti), diarrea. Recentemente e stato proposto I'uso degli antagonisti della 5-idrossitriptamina, che sembrano prowistidi una elevata efficacia, ma il cui impiego in molte strutture e limitato dal loro elevato costo. Altro farmaco dotato di una elevataattivita antiemetica associata ad una scarsa tossicita e la Levosulpiride (LS). Questo isomero della Sulpiride (farmaco che ad una attivita antidopaminergica centrale associa un'azione a livello periferico diretta sull'apparato gastroenterico) si e gia dimostrato efficace nella prevenzione dell'emesi e della nausea indotti da trattamenti citostatici comprendenti il Cisplatino e l'Adriamicina (9).Per cercare di prevenire la comparsa di vomito nei pazienti affetti da linfoma in trattamento con 10 schema ProMECE-CytaBOMabbiamo messo a punto due regimi antiemetici: il CSPP (Clordimetildiazepam, levoSulpiride, Prometazina, Prociorperazina) ed il CMPP (Clordimetildiazepam, Metoclopramide, Prometazina, Proclorperazina). Nel presente lavoro riportiamo i risultati di uno studio randomizzato realizzato per valutare I'efficacia dei due schemi CSPP e CMPP nella prevenzione del vomito e della nausea nei pazienti sottoposti a trattamento citostatico secondo 10 schema ProMECE-CytaBOM.

1993 - SOLUBLE INTERLEUKIN-2 RECEPTOR AND URINARY NEOPTERIN CONCENTRATIONS IN MALIGNANT-LYMPHOMA [Articolo su rivista]
Piccinini, Lino; S., Zironi; Am, Cenci; D., Campioli; Federico, Massimo; F., Barbieri
abstract

The serum concentrations of soluble interleukin-2 receptors and urine neopterin were studied in 82 patients with malignant lymphomas (25 patients with Hodgkin's disease and 57 patients with non-Hodgkin's lymphoma. Increases in soluble interleukin-2 receptors and in urinary neopterin were significantly correlated with the clinical phase of the disease. The average values in both Hodgkin's disease and non-Hodgkin's lymphoma patients suffering from the disease in its active phase were significantly higher than those of patients in complete remission. Neopterin concentrations (but not soluble interleukin-2 receptor concentrations) were also elevated in clinical stages III - IV of each disease. Urinary neopterin correlated directly and significantly with the erythrocyte sedimentation rate and inversely with haemoglobin. Finally, a longitudinal analysis showed a general tendency for the markers to return to normal values, in accordance with the favourable outcome of therapy; this was more evident for urinary neopterin than for soluble interleukin-2 receptors. These findings seem to confirm that soluble interleukin-2 receptors and especially urinary neopterin can be useful markers for monitoring and prognosis of malignant lymphomas.

1993 - The italian experience in the treatment of Hairy cell leukemia [Relazione in Atti di Convegno]
Damasio, E. E.; Federico, Massimo
abstract

No abstract available.

1993 - Utilità diagnostica della risonanza magnetica nucleare in onco-ematologia [Articolo su rivista]
Federico, Massimo; Mauri, C.; Piccinini, Lino; Davolio Marani, S.; Silingardi, Vittorio
abstract

no abstract

1992 - A multicenter randomized trial of two different ProMACE-CytaBOM derived protocols in aggressive non-Hodgkin's Lymphomas (NHL). A preliminary report [Articolo su rivista]
Carotenuto, M.; Federico, Massimo; Avanzini, P.; Baldini, L.; Brugiatelli, M.; Cavanna, L.; Di Renzo, N.; Gobbi, P. G.; Iannitto, E.; Lombardo, M.; Longo, G.; Narni, Franco; Nicoletti, G.; Silingardi, Vittorio; Mauri, C.; For, Gisl
abstract

This article does not have an abstract.

1992 - DETECTION AND QUANTITATION IN RAT-TISSUES OF THE SUPERPARAMAGNETIC MAGNETIC-RESONANCE CONTRAST AGENT DEXTRAN MAGNETITE AS DEMONSTRATED BY ELECTRON-SPIN-RESONANCE SPECTROSCOPY [Articolo su rivista]
Iannone, Anna; Federico, Massimo; Tomasi, Aldo; Magin, Rl; Casasco, A; Calligaro, A; Vannini, V.
abstract

RATIONALE AND OBJECTIVES. The compound studied in this article is a superparamagnetic macromolecular complex of magnetite cores coated with hydrophilic dextran, which is under active investigation as a contrast agent for magnetic resonance imaging (MRI) in liver and spleen. The biodistribution of paramagnetic compounds is problematic and is usually studied by histochemical reactions or by radiolabeling the compound under study. The purpose of this article is to show how electron spin resonance (ESR) spectroscopy detects dextran magnetite (DM) particles in tissues. METHODS. DM injected intravenously in the experimental animal was detected in some reticulo-endothelial organs by ESR. The spectroscopic study was validated using electron microscopy and electron-probe microanalysis. RESULTS. DM exhibits an ESR spectrum; ESR delineated the distribution of DM distribution in liver, spleen, bone marrow, and blood as a function of time. The blood clearance was biphasic, dependent on the size of particles. CONCLUSIONS. ESR spectroscopy is a highly sensitive and reproducible method of studying DM distribution.

1992 - Fattori prognostici nel carcinoma mammario con particolare riferimento al gene c-erbB-2: risultati preliminari [Articolo su rivista]
Criscuolo, M.; Federico, Massimo; Sabbatini, R.; Rossi, E.; Piccinini, Lino; Trentini, G. P.
abstract

no abstract

1992 - HAIRY-CELL LEUKEMIA - SPLENECTOMY AFTER ALPHA-INTERFERON THERAPY [Articolo su rivista]
Damasio, E. E.; Resegotti, L.; Capnist, G.; Federico, Massimo; Foà, R.; Francia, P.; Lamparelli, T.
abstract

no abstract

1992 - HAIRY-CELL LEUKEMIA - THE ITALIAN-COOPERATIVE-GROUP EXPERIENCE [Articolo su rivista]
Federico, Massimo; Frassoldati, A; Lamparelli, T; Dini, E; Resegotti, L; Damasio, Ee
abstract

This article does not have an abstract

1992 - PRIMARY GASTROINTESTINAL LYMPHOMA - A CLINICOPATHOLOGICAL STUDY OF 58 CASES [Articolo su rivista]
M., Cirillo; Federico, Massimo; G., Curci; E., Tamborrino; Piccinini, Lino; V., Silingardi
abstract

Background. Primary non Hodgkin's lymphoma (NHL) of the gastrointestinal tract (GI) is the most frequent extranodal lymphoma accounting for approximately 40% of all extranodal primary NHL. The role of surgery and other treatment modalities in the management of these patients is still controversial. Patients and Methods. We reviewed the records of 68 patients with primary GI-NHL. Ten patients had incomplete records and were excluded from further evaluation. The records of 58 patients were considered, and all were available for analysis and follow-up. Results. The most frequent site of involvement was the stomach (47 patients), followed by ileum (7 patients), large bowel (3 patients) and duodenum (1 patient). Malignant lymphomas of follicular center cell origin represented the most prevalent histologic types, accounting for 58% (34 of 58) of all cases. Stage, evaluated according to the criteria of Musshoff, was I(e) in 15 cases, II(e) in 16, III(e) in 7, and IV in the remaining 20 cases. The median survival for the entire group of 58 patients was 54 months, with 46% of patients surviving at 5 years. The median survival was 71 months for patients in stage I-II, 60 for patients in stage III, and 25 for patients in stage IV (p = 0.016). Moreover, we found significantly improved survival in patients undergoing surgical tumor resection (p = 0.003). Conclusions. Even if at the present time the optimal management of primary GI-NHL is difficult to assess, our data suggest that it is prudent to advise resection followed by adjuvant CT in most patients, whereas CT alone should be considered only when surgery cannot be performed.

1991 - Blood clearance of dextran magnetite particles by a non invasive in vivo ESR method [Articolo su rivista]
Iannone, Anna; Magin, R. L.; Walczac, T.; Federico, Massimo; Swartz, H. M.; Tomasi, Aldo; Vannini, V.
abstract

Dextran magnetite (DM) is a potential MR contrast agent with superparamagnetic properties. Its fast clearance from the blood and selective uptake by tissue macrophages provide advantages for imaging tumors in the liver and spleen. DM consists of a suspension of solid particles with a wide distribution of sizes. In this study we have used ESR spectroscopy to determine the blood clearance of DM injected iv in mice. The spectra are obtained on living animals by inserting the tail of a mice into the waveguide cavity of the ESR spectrometer and recording the ESR spectrum continuously. This procedure allows the direct measurement of the plasma clearance of DM from individual animals, without blood sampling. We applied this method to study the clearance of suspensions of DM particles with different average sizes.

1991 - Carcinoma renale [Monografia/Trattato scientifico]
Federico, Massimo; Barbieri, F.
abstract

Monografia sui dati di incidenza e sopravvivenza del carcinoma renale

1991 - HHV-6 INFECTION AND HUMAN HODGKIN AND NON-HODGKIN LYMPHOMAS [Articolo su rivista]
Torelli, Giuseppe; Marasca, Roberto; Selleri, L; Luppi, Mario; Montorsi, M; Federico, Massimo; Narni, Franco; Ceccherininelli, L; Ferrari, Sergio
abstract

1991 - Human Herpes virus-6 in human lymphomas: identification of specific sequences in Hodgkin's lymphomas by polymerase chain reaction [Articolo su rivista]
Torelli, Giuseppe; Marasca, Roberto; Luppi, Mario; L., Selleri; Ferrari, Sergio; Narni, Franco; Mt, Mariano; Federico, Massimo; L., CECCHERINI NELLI; M., Bendinelli; G., Montagnani; M., Montorsi; Artusi, Tullio
abstract

In search of a possible involvement of the human herpesvirus type 6 (HHV-6) in human Hodgkin's and non-Hodgkin's lymphomas, we studied the levels of anti-HHV-6 antibodies in the sera of 94 cases by an immunofluorescence assay, as well as the presence of HHV-6 sequences in the affected tissues of 66 cases by polymerase chain reaction, using one set of primer oligonucleotides. Our results showed higher anti-HHV-6 antibody titers in human lymphomas than in normal blood donors, but the difference is statistically significant only when normal donors are compared with Hodgkin's lymphoma cases. HHV-6 sequences were detected in 3 of 25 Hodgkin's lymphomas and 0 of the 41 cases of non-Hodgkin's lymphomas studied. The three cases positive for HHV-6 sequences belong to the nodular sclerosis-lymphocyte depletion histologic subtype and share remarkable similarities in their clinical features. Furthermore, Southern blot analysis of total genomic DNA obtained from the neoplastic tissues of two of the three patients showed the same restriction fragment length polymorphism. Our results suggest that: (1) the high level of anti-HHV-6 antibodies in Hodgkin's disease is due to an activation of the immune system not related to the presence of HHV-6 sequences in affected lymph nodes; (2) the presence of HHV-6 sequences in human lymphoid tissues is not a frequent event, rather it is in fact a very rare event in non-Hodgkin's lymphomas, while in Hodgkin's cases it is more frequent than previously reported on the basis of Southern blot analysis; and (3) the presence of HHV-6 sequences in Hodgkin's lymphomas may have a relation with the clinical presentation of the disease.

1991 - METHOTREXATE, VINBLASTINE, EPIDOXORUBICIN AND CISPLATIN (M-VEC) IN PATIENTS WITH LOCALLY ADVANCED TRANSITIONAL BLADDER-CANCER [Articolo su rivista]
Frassoldati, A; Federico, Massimo; Barbieri, F; Brausi, M; Pollastri, C; Berri, G; Castagnetti, G; Palladini, Pp; Silingardi, Vittorio
abstract

M-VEC (methotrexate, vinblastine, epidoxorubicin and cisplatin), a new combined drug regimen in which epidoxorubicin has been substituted to adriamycin to reduce the toxicity of the original M-VAC chemotherapy, has been tested in 23 patients with locally advanced transitional cell bladder cancer (TCBC) (stage T2-T4 N(o) M(o). After two to four courses, an objective response was observed in 19 patients, with 13 clinical complete responses. Seven patients underwent cystectomy after chemotherapy: one patient had no residual tumor on bladder specimens, rive patients had a surgical eradication of the disease, while one patient had only a partial resection. Eight relapses of bladder carcinoma were observed, three among the surgically treated patients and five among patients who did not undergo cystectomy, with a median time-to-relapse of 9.7 months. Progression-free survival at 24 months was 52.3%. M-VEC regimen appears to be effective in locally advanced TCBC, with acceptable toxicity.

1991 - PROMACE-CYTABOM VERSUS MACOP-B IN INTERMEDIATE AND HIGH-GRADE NHL - PRELIMINARY-RESULTS OF A PROSPECTIVE RANDOMIZED TRIAL [Articolo su rivista]
Federico, Massimo; Moretti, G; Gobbi, Pg; Avanzini, P; Cavanna, L; Carotenuto, M; Lombardo, M; Leone, G; Pitini, V; Abbadessa, V; Ascari, E; Silingardi, Vittorio; Mauri, C.
abstract

One hundred seventy-nine patients with intermediate or high-grade non-Hodgkin's lymphoma were randomized to receive either ProMACE-CytaBOM (P-C) or MACOP-B (M-B). At last follow-up 71 patients in the P-C arm and 78 in the M-B arm were assessable for response. Forty-one patients treated with P-C (58%) and 49 patients treated with M-B (63%) achieved a CR. Moreover 18 and 22 patients achieved PR with P-C and M-B, respectively. Twenty-five patients relapsed, 12 in the P-C arm and 13 in the M-B arm. Thirty-nine patients died, 32 from disease progression, 5 from treatment related causes, and 2 from other causes. No differences between the two treatment groups were observed as regard to relapse or death-rate. At 27 months the survival rate was of 71.9% for patients treated with P-C and 70.7% for those treated with M-B. At 2 years the RFD rate was 64% and 60% for patients in P-C and M-B arm, respectively. Patients treated with M-B experienced an high rate of methotrexate-related toxicity. ProMACE-CytaBOM and M-B seem provided with similar activity. However P-C seem less toxic and more manageable in an outpatient setting.

1991 - Should alpha interferon be used as primary treatment for hairy cell leukemia? [Articolo su rivista]
Capnist, G.; Federico, Massimo; Chisesi, T.; Resegotti, L.; Pagnucco, G.; Castoldi, G. L.; Lamparelli, T.; Frassoldati, A.; Guarnaccia, C.; Leoni, P.; Fabris, P.; Rossi, G.; Invernizzi, R.; Ambrosetti, A.; Bernasconi, C.; Damasio, E.
abstract

To answer the question of whether interferon (IFN) should replace splenectomy, we reviewed the Italian HCL Registry: the records of 450 patients with hairy cell leukemia (HCL), seen from 1975 to 1988 were analysed. Of these, 321 were considered for the study: 231 had been splenectomized, 46 of them receiving subsequently IFN and 90 patients had IFN as initial therapy. Patients treated with splenectomy showed different survival according to Jansen and Hermans' staging system, which identified two risk groups: stage 1 and stages 2 and 3, p = 0.0329. On the contrary, patients treated with IFN did not show significantly different survival according to stage. By the comparison of stage 1 patients, either treated with splenectomy or with IFN, no statistical difference in survival was registered. Different survivals emerged for patients stage 2 + 3, which improved when treated with IFN, p = 0.0324. The median failure free survival (FFS) after splenectomy resulted in 89 months versus 33 months after IFN. In conclusion, splenectomy still remains the primary therapy for HCL patients stage 1. For high risk patients, stages 2 and 3, IFN should be adopted as first line therapy, improving substantially the survival. The short duration of response to IFN suggests a sequential combination of the two treatments for this group of patients, IFN reducing tumor mass quite safely and splenectomy assuring long lasting stable disease.

1991 - Urinary neopterin in malignant lymphoma [Articolo su rivista]
Piccinini, Lino; Zironi, S.; Federico, Massimo; Pini, Luigi Alberto; Luppi, G.
abstract

Urinary neopterin levels were studied in 96 patients with malignant lymphomas. Twenty-eight had Hodgkin's disease and 68 non-Hodgkin's lymphoma. Neopterin excretion was significantly related to the clinical stage of the disease. Mean neopterin excretion in patients with active disease (634 +/- 527 mumol neopterin/mol creatinine) was significantly higher (p = 0.000) than in patients in complete remission (198 +/- 105 mumol neopterin/mol creatinine). Mean neopterin levels of patients in stage III-IV were higher than for patients in stage I-II. These findings were the same in patients with Hodgkin's disease and those with non-Hodgkin's lymphoma (659 +/- 593-425 +/- 316 mumol neopterin/mol creatinine), regardless of the histological subtype. A significant correlation was found between neopterin excretion, ESR (r = 0.31; p = 0.003) and hemoglobin (r = -0.40; p = 0.000). Longitudinal analysis showed a trend towards a correlation between response to therapy and neopterin excretion. These findings suggest that neopterin may be a useful prognostic marker in non-Hodgkin's lymphoma.

1990 - Prevention of cisplatin induced vomiting in patients with cancer. A pilot study with a multiagent protocol [Articolo su rivista]
Federico, Massimo; Sabbatini, R.; Piccinini, P.; Zironi, S.; Piccinini, Lino; Silingardi, Vittorio
abstract

Forty patients receiving a total of 102 courses of cisplatin (CDDP)-based treatment were observed in the present study. The patients received an antiemetic prophylaxis with metoclopramide (6 mg/kg), dexamethasone (12 mg/m2), lorazepam (2.5 mg), promethazine (50 mg), and diazepam (10 mg). Complete protection from acute vomiting was obtained in 77.5% of patients during the first course, and partial protection (1 to 3 episodes of vomiting) was observed in 10.1% additional cases. Complete protection was achieved in 84.6% of males vs 57.1% of females. Patients at their first course of chemotherapy had 80% complete protection compared to 66.7% in those who received prior chemotherapy. No differences in the response rate between patients treated with high versus patients receiving low doses of CDDP were noted. The same pattern of response was observed in subsequent courses of therapy. Side effects were minimal (mild sedation in almost all the cases and hiccups in a few cases). No major extrapyramidal reaction was observed. The regimen used in the study showed good efficacy in preventing acute CDDP-induced nausea and vomiting. Moreover, the very low incidence of major side effects makes this protocol safe and recommendable in patients undergoing CDDP chemotherapy.

1990 - SPLENECTOMY AFTER INITIAL THERAPY WITH ALPHA-IFN IN PATIENTS WITH HAIRY-CELL LEUKEMIA (HCL) - A MULTICENTER STUDY BY THE ITALIAN COOPERATIVE GROUP FOR HCL - PRELIMINARY-RESULTS [Articolo su rivista]
Damasio, Ee; Federico, Massimo; Frassoldati, A; Lamparelli, T; Annino, L; Bernasconi, C; Chisesi, T; Foa, R; Lauria, F; Pagnucco, G; Resegotti, L.
abstract

Since December 1987, 115 patients with HCL have been enrolled in a prospective multicenter study to evaluate the role of splenectomy after an induction therapy with alpha interferon. The group of patients was divided into two categories: those younger and those older than 65 years. The schedule of treatment with IFN was, respectively, 1.8 MU/sm/daily and 1.0 MU/daily, 33 patients were treated with r-alpha-2a, 34 with r-alpha-2b, and 25 with alpha-Ly. To date, 92 patients are fully evaluable. The response was assessed every 3 months by bone marrow trephine biopsy. Patients in CR continued IFN therapy for 3 months and, if they were still in CR, could undergo an optional splenectomy. Patients in PR continued therapy for 12 months and subsequently were randomized for splenectomy or observation only. In these preliminary results of an ongoing protocol, CR was obtained in 5 cases (6%), PR in 59 (64%), MR in 25 (27%), NR in 3 (3%). Only 2 of the 5 patients in CR underwent splenectomy and are still in CR. Of the 59 patients in PR, only 15 completed 12 months of therapy. 9 patients in Group A were randomized, 4 were splenectomized and 5 were in the observation arm. All patients were splenectomized safely and no complications occurred. These preliminary results suggest that splenectomy could be effective in consolidating the response obtained with IFN.

1990 - STIFF-MAN SYNDROME IN A PATIENT WITH HODGKINS-DISEASE - AN UNUSUAL PARANEOPLASTIC SYNDROME [Articolo su rivista]
Ferrari, P; Federico, Massimo; Grimaldi, Lme; Silingardi, Vittorio
abstract

A case of stiff-man syndrome (SMS), a rare and dramatic CNS disease characterized by continuous muscle activity and painful spasms resembling a chronic form of tetanus, occurring in a patient with Hodgkin's disease (HD) is reported. The patient developed the clinical features of SMS at the same time as the HD relapse. A satisfactory improvement was obtained with diazepam, but the complete recovery from the stiffness was achieved only after chemotherapy was started. Cerebellar autoantibodies were found in the serum of the patient. With chemotherapy the patient achieved a second complete remission (CR). Eighteen months later the patient developed a second HD relapse, and at that time no signs of SMS were detected.

1989 - Bone marrow infiltration in Hairy cell leukemia after interferon therapy detected by magnetic resonance imagin [Articolo su rivista]
Silingardi, Vittorio; Davolio Marani, S.; Federico, Massimo; Piccinini, Lino; Frassoldati, A.; Sarti, M.; Burani, A.; Canossi, G. C.
abstract

Magnetic resonance imaging (MRI) can detect bone marrow infiltration by neoplastic cells in many hematological malignancies. We studied 10 patients affected by hairy cell leukemia (HCL) and treated with interferon (IFN) with both MRI and bone marrow biopsy. T1-weighted MR scans of femurs and pelvis proved to be effective to score hairy cell infiltration, while less information was obtained from the study of the lumbar vertebral column. A good correlation (less than 10% difference) was noted between biopsy and MRI in over 90% of cases. MR scans showed, in general, a higher grade of infiltration. MR scan, however, can be useful for monitoring the course of HCL and the response to the treatment. Moreover, MRI evaluating a large amount of tissue, can detect a nodular type of infiltration which can be missed in biopsy specimens.

1989 - Bone marrow uptake of liposome-entrapped spin label after liver blockade with empty liposomes [Articolo su rivista]
Federico, Massimo; Iannone, Anna; Chan, H. C.; Magin, R. L.
abstract

Using an ESR spectrometer, we studied the time course of the uptake of the liposome-entrapped spin label 2,2,6,6-tetramethylpiperidine-N-oxyl-4-trimethylammonium in liver, spleen, and bone marrow following reticuloendothelial liver blockade. Our results show that suppression of the phagocytic activity of the liver increases the delivery of liposomes to the spleen and bone marrow without substantially altering uptake by the liver.

1989 - Definizione dell'interessamento vertebrale in corso di mieloma multiplo attraverso la risonanza magnetica nucleare [Articolo su rivista]
Federico, Massimo; Frassoldati, A.; Sabbatini, R.; Davolio Marani, S.
abstract

NO ABSTRACT

1989 - Detection of bone marrow involvement in patients with cancer [Articolo su rivista]
Federico, Massimo; Magin, R. L.; Swartz, H. M.; Wright, R. M.; Silingardi, Vittorio
abstract

Current methods for the study of bone marrow to evaluate possible primary or metastatic cancers are reviewed. Bone marrow biopsy, radionuclide scan, computed tomography and magnetic resonance imaging (MRI) are analyzed with regard to their clinical usefulness at the time of diagnosis and during the course of the disease. Bone marrow biopsy is still the examination of choice not only in hematologic malignancies but also for tumors that metastasize into the marrow. Radionuclide scans are indicated for screening for skeletal metastases, except for those from thyroid carcinoma and multiple myeloma. Computed tomography is useful for cortical bone evaluation. MRI shows a high sensitivity in finding occult sites of disease in the marrow but its use has been restricted by high cost and limited availability. However, the future of MRI in bone marrow evaluation seems assured. MRI is already the method of choice for diagnosis of multiple myeloma, when radiography is negative, and for quantitative evaluation of lymphoma when a crucial therapeutic decision (i.e. bone marrow transplantation) must be made. Finally, methods are being developed that will enhance the sensitivity and specificity of MRI studies of bone marrow.

1989 - Free from failure survival in Hodgkin's disease. Long term analysis of 148 cases treated with a MOPP modified protocol [Articolo su rivista]
Silingardi, Vittorio; Federico, Massimo; Frassoldati, A.; Barbieri, F.; Palomba, G.; Mauri, C.
abstract

The incidence of relapses and second malignant neoplasms was investigated in a group of 148 patients with bad-risk stage II, or stage III and IV Hodgkin's disease treated with a MOPP-modified protocol between 1973 and 1979. Sixty-eight patients received chemotherapy alone, 80 a combined modality treatment including radiotherapy. One hundred and twelve patients achieved complete remission with induction therapy. Thirty-six patients relapsed 3-120 months (median 27 months) after the induction program with a 10-year cumulative risk of relapse of 33.6%. Seven out of 112 complete responders developed a second malignancy 65-145 months from the start of therapy; one more neoplasm has been recorded in a patient with active Hodgkin's disease. Survival after diagnosis of second malignant neoplasm did not exceed 12 months. The cumulative risk of developing a second malignancy was 6.2% at 10 years. The free-from-failure survival was 49.2% at 10 years, being 64.7% for patients achieving complete remission and 92.4% for long-term complete responders. Although an increased number of second malignant neoplasms may occur in patients treated for Hodgkin's disease, the high risk of early relapse, together with the limited effectiveness of salvage therapy, suggests that intensive induction programs should be carried out in patients with advanced or poor-prognosis Hodgkin's disease in order to achieve long-lasting complete remission.

1989 - Hairy Cell Leukemia. A therapeutical update [Articolo su rivista]
Damasio, E. E.; Pagnucco, G.; Federico, Massimo; Annino, L.; Chisesi, T.; Lamparelli, T.; Lauria, F.; Castoldi, G. L.; Resegotti, L.
abstract

This is a review of current treatment for hairy cell leukemia (HCL). Data for this analysis were obtained from the Italian HCL Registry, as well as from other published series. We have given space to the impact of interferon and pentostatin on the management of this disease. Other issues are also discussed, such as the relevance of achieving a complete remission with respect to overall and relapse-free survival. We include a final section on recommendations which may prove useful in designing an appropriate therapeutic strategy.

1989 - Human lymphoblastoid alpha-interferon for hiary cell leukemia. An update of the italian cooperative group [Articolo su rivista]
Federico, Massimo; Frassoldati, A.; Pagnucco, C.; Capnist, G.; Chisesi, T.; Guarnaccia, C.; Lamparelli, T.; Lauria, F.; Bernasconi, C.; Resegotti, L.; Rossi, G.; Damasio, E. E.
abstract

This article does not have an abstract

1989 - Human lymphoblastoid interferon as initial therapy in hairy cell leukemia: a multicenter study in non-splenectomized patients [Articolo su rivista]
Federico, Massimo; Chisesi, T.; Lauria, F.; Bernasconi, C.; Capnist, G.; Castoldi, G.; Damasio, E. E.; Pagnucco, G.; Frassoldati, A.; Resegotti, L.; Silingardi, Vittorio
abstract

The Italian Cooperative Group for Hairy Cell Leukaemia (ICGHCL), between April 1985 and June 1987, conducted a multicentre study using human lymphoblastoid alpha-interferon as primary therapy as an alternative to splenectomy. Forty-eight evaluable patients with HCL entered the study, 38 of them had splenomegaly, in five patients the spleen was not palpable and five were unfit for surgery because of age and general condition. Daily dose of 3 MU s.c. alpha-IFN was given for 12 weeks, or until a satisfactory and stable response was obtained. Among these 48 patients the response rate after 3 months of therapy was 63%, with seven patients (15%) achieving complete remission and 23 (48%) partial remission; 13 (27%) patients had a minor response. In five patients no response was observed and they died within 2 months of treatment. Five other patients, after an initial response, presented a re-expansion of the disease. Actuarial survival at 30 months was 88.8% for the entire group of 48 patients and 92% for the 38 patients who would normally be treated by splenectomy. Thus, alpha-IFN as primary treatment in HCL offered a reasonable therapy for splenomegalic patients. The timing and validity of splenectomy still remains an open question.

1989 - Increasing interdependency of prognosis and therapy-related factors in Hodgkin's disease [Articolo su rivista]
Gobbi, P. G.; Cavalli, C.; Federico, Massimo; Lombardo, M.; Bertoloni, D.; Grignani, G. E.; Pieresca, C.; Ascari, A.; Mauri, C.
abstract

Two subsequent series of patients with Hodgkin's disease (HD) treated according to different therapeutic plans were compared: the study made it possible to analyze the role played by therapy in influencing the individual importance of a group of well-known prognostic factors. Study 1 concerned 667 patients treated in the period 1971-1979 without special measures for mediastinal bulky disease and with four-drug chemotherapy regimens (MOPP, COPP, ABVD) for stage B or IV. Study 2 included 220 patients treated between 1980 and 1984 with combined sandwich chemoradiotherapy when mediastinal bulk was present, and with eight-drug alternating chemotherapy regimens for stages B or IV (MOPP/ABVD, CcVPP/ABVD). Distribution of epidemiologic and clinical characteristics as well as staging accuracy were comparable in the two series. Only sex, serum albumin at onset and success or failure in achieving complete remission showed the same ability to discriminate survival in both studies. Age, stage and histology retained a reduced role in Study 2, where it was found they could be handled as binary variables, i.e. more or less than 50 years of age, stage IV or other stages, lymphocyte depletion histotype or other types. The influence of B symptoms on survival was sharply decreased in patients treated with alternating chemotherapy regimens, whereas combined sandwich therapy showed a truly leveling effect on the role of mediastinal bulk, which has to be considered a very unfavorable factor with other treatments. In HD the evaluation of clinical findings with respect to their impact on prognosis is crucial for validating and graduating the staging process, and for matching the intensity of the therapy to the needs of the patient. The ongoing evolution in the roles of single prognostic factors due to therapy needs periodic reevaluation for proper adjustments of therapeutic strategies.

1989 - Insorgenza di doppia neoplasia metacrona 29 anni dopo la diagnosi di malattia di Hodgkin [Articolo su rivista]
Bisi, D.; Federico, Massimo; Sarti, M.; Barbieri, F.; Curci, Giuseppe
abstract

Viene riferito un caso di malattia di Hodgkin cui ha fatto seguito, dopo una remissione completa durata 26 anni, l'insorgenza di due distinte neoplasie: un linfoma centrocitico diffuso a prevalente localizzaizone cutanea e sottocutanea e un carcinoma basocellulare al dorso della mano destra. Il paziente era stato precedentemente sottoposto ad elevate e ripetute dosi di Roentgen-terapia sulle localizzazioni hodgkiniane sia mediastiniche che linfonodali. Vengono discusse le possibili relazioni tra terapia praticata e insorgenza delle neoplasie metacrone.

1989 - Relationship between prognostic factors and therapy in high grade non Hodgkin's lymphomas over two decades [Articolo su rivista]
Federico, Massimo; Gobbi, P. G.; Barbieri, F.; Silingardi, Vittorio
abstract

We considered the prognostic factors in high-grade non-Hodgkin's lymphomas (HG-NHL) over the past two decades. In an effort to clarify the relationship between prognostic factors and therapy, we pooled the literature reports concerning 3,480 patients into four different periods according to the mean years of the clinical trials. The most important prognostic factors discovered in period A (mean year prior to 1970) were histology, symptoms and stage. In period B (1970 through 1975), in addition to the former indicators, two new factors were pointed out: bone marrow involvement and serum lactic dehydrogenase. In period C (1976 through 1980) the significance of stage was reduced, while bulk and measures of lymph nodal and extranodal involvement (LSI, ESI) were found to be better prognostic factors. In studies related to this period the prognostic role of albumin, hemoglobin and erythrocyte sedimentation rate were also emphasized. Period D (1980 through 1985) was characterized by a decrease in the importance of the Kiel and Working Formulation (WF) classifications by virtue of the better outcome, in different reports, of HG-NHL with respect to low-grade NHL. The conclusion of our analysis is that symptoms, ESI, bulk, LDH, albumin and hemoglobin should be the most important factors used today in planning the therapy and management of patients with HG-NHL. In addition, an update of the WF is necessary.

1989 - Ruolo attuale della chemioterapia nel carcinoma transizionale della vescica muscolo-invasivo [Articolo su rivista]
Frassoldati, A.; Barbieri, F.; Piccinini, Lino; Federico, Massimo; Silingardi, Vittorio
abstract

The present role of chemotherapy in the mana. gement of muscle-invasive transitional cell bladder cancer. The results obtained with chemotherapy (CT) in the management of muscle-infiltrating transitional cell bladder carcinoma (TCBC) are compared with those of radiotherapy (RT) and surgery (S)_ Cisplatin and methotrexate are the most effective agents, with an overall response rate ranging from 20 to 45 % when administered singly. Other chemotherapeutic drugs whichproved of some antitumor activity in TCBC are doxorubicin and vinblastine, with an overall response rate of approximately IS % (range 4-28 %)_ With each drug used singly, however,complete response (CR) is uncommon. Combination CT regimens (cisplatin+methotrexate, cisplatill+methotrexate+vinblastine, methotrexate+vinblastine+doxorubicin+cisplatin) are inducing a higher number of CR with an overall response rate between 40 and 70 %. CT, previously used as adjuvant or salvagetherapy in advanced TCBC, is now given in neo-adjuvant fashion in order to achieve tumor size reduction and control of micrometastases.With these multiagent regimens a significant down-staging can be obtained without major toxicity in over SO % of patients withmuscle-infiltrating TCBC, thus increasing the number of patients which can be cured by surgery. These neo-adjuvant programs suggests potential benefit, yet randomized studies andprolonged observations are required to provide definitive results.

1989 - Utilità della Risonanza Magnetica Nucleare nello studio del midollo osseo di pazienti affetti da hairy Cell Leukemia [Articolo su rivista]
Federico, Massimo; Frassoldati, A.; Piccinini, Lino; Davolio Marani, S.; Bonacorsi, G.; Silingardi, Vittorio
abstract

NO ABSTRACT

1988 - Alimentazione e tumori I. Considerazioni dietetiche generali: gli alimenti [Articolo su rivista]
Piccinini, Lino; Federico, Massimo; Silingardi, Vittorio
abstract

No abstract

1988 - Alimentazione e tumori II. Le vitamine [Articolo su rivista]
Piccinini, Lino; Federico, Massimo; Barbieri, F.; Silingardi, Vittorio
abstract

No abstract

1988 - Alimentazione e tumori III. Gli oligoelementi [Articolo su rivista]
Piccinini, Lino; Federico, Massimo; Frassoldati, A.; Silingardi, Vittorio
abstract

No abstract

1988 - Emesi da Cisplatino [Articolo su rivista]
Piccinini, P.; Zironi, S.; Federico, Massimo
abstract

Il controllo della nausea e del vomito da antiblastici ha acquisito sempre maggiore importanza con il progressivo incremento delle indicazione della terapia medica dei tumori maligni. Gli autori riassumono brevemente le attuali conoscenze sulla fisiopatologia della nausea e del vomito da antiblastici, in particolare da cisplatino. Vengono elencati i principali farmaci attualmente usati nel controlo del vomito da cisplatino ed il loro meccanismo d'azione. Viene infine proposto uno schema di massima di terapia antiemetica nei pazienti in trattamento con dosi medie di cisplatino.

1988 - Hodgkin's disease prognosis: a directly predictive equation [Articolo su rivista]
Gobbi, G. P.; Cavalli, C.; Federico, Massimo; Bertoloni, D.; Di Prisco, A. U.; Rossi, Andrea; Silingardi, Vittorio; Mauri, C.; Ascari, A.
abstract

586 patients with Hodgkin's disease diagnosed between 1970 and 1979 were staged and treated in the same way. Multivariate analysis was used to delineate the prognostic roles of several clinical features at diagnosis. A multiple regression analysis was applied to an exponential model for survival-time distribution, which proved to fit the data accurately. Several clinical characteristics were studied and those that could singly discriminate survival significantly were chosen as predictive variables for the multiple regression. These were: sex, age, stage, histological subtype, presence of constitutional symptoms, mediastinal mass, and erythrocyte sedimentation rate (ESR), and haemoglobin and serum albumin concentrations. ESR, stage, histological subtype, and age proved to be the best prognostic factors, while sex and albumin had minor value. The presence of symptoms, mediastinal bulk, and haemoglobin were not so important. A linear equation for the six variables was derived to calculate the estimated median survival time for any given patient. This equation was validated on an external group of 179 similar patients.

1987 - Efficacia terapeutica della polichemioterapia CcVPP nel morbo di Hodgkin [Relazione in Atti di Convegno]
Lambertenghi Deliliers, G.; Baldini, L.; Radaelli, F.; Federico, Massimo; Polli, E.
abstract

In questo lavoro vengono riportati i risultati ottenuti in 38 pazienti affetti da linfoma di Hodgkin, in diversi stadi, trattati con schemi terapeutici comprendenti la combinazione CcVPP (CCNU, vinblastina, procarbazina e prednisone).Dieci pazienti erano trattati solo con CcVPP, otto ricevevano terapia alternata CcVPP/ABVD e venti terapia combinata CcVPP/radiante. La combinazione CcVPP si dimostrava particolarmente efficace permettendo di ottenere una remissione completa in 26 pazienti (68%) e una remissione parziale in 9 pazienti (24%).A 36 mesi la sopravvivenza globale era pari al 78% e la sopravvivenza libera da malattia dei 26 pazienti responsivi pari all'85%.A parità di efficacia terapeutica, una migliore tolleranza gastroenterica, una minore neurotossicità e la somministrazione orale erano i principali vantaggi del CcVPP rispetto al MOPP.

1987 - Human lymphoblastoid interferon for HCL: results from the Italian Cooperative Group [Articolo su rivista]
Damasio, E. E.; Bernasconi, C.; Castoldi, G. L.; Chisesi, T.; Federico, Massimo; Lamparelli, T.; Lauria, F.; Pagnucco, G.; Resegotti, L.; Rossi, E.
abstract

Since April 1985, 82 patients with HCL entered a multicenter study using lymphoblastoid alpha-interferon; 51 (including 15 who failed splenectomy and 24 with substantial splenomegaly) enrolled before April 1986 are evaluated in this study. The patients were treated with 3 mega units daily subcutaneously until complete or partial response and were thereafter randomly allocated to a maintenance regime of 3 mega units/week or to observation only. Ten cases had a complete response, 18 a partial response, and 15 a minimal response. Two patients had no response, two interrupted therapy due to major toxicity (toxic hepatitis and thrombocytopenia), six died before completing 1 month of therapy of sepsis, and two died of myocardial infarction. In the two groups of splenectomized and nonsplenectomized patients the mean time to hemoglobin recovery was 8.5 and 6.5 weeks, respectively, the neutrophil count recovery was 6.5 and 9.3 weeks, and the time to platelet count recovery was 4.0 and 5.4 weeks, respectively. No significant differences in recovery time and response rate were observed between the two groups. In 31 out of 32 patients with substantial splenomegaly the spleen became either inpalpable (18) or significantly smaller (13). This study confirms the responsiveness of HCL to IFN in nonsplenectomized patients with high tumor burdens and is therefore recommended as a first-line therapy.

1987 - Il morbo di Hodgkin sclero-nodulare. Studio clinico-patologico [Relazione in Atti di Convegno]
Silingardi, Vittorio; Piccinini, Lino; Federico, Massimo; Frassoldati, A.; Artusi, Tullio; DI PRISCO, Alfredo Ubaldo; Gobbi, P. G.; Emilia, Giovanni; Pucci, A.; De Benedettis, A.; Lombardo, M.; Zironi, S.; Artesa, L.; Lamberetenghi Deliliers, G.; Mauri, C.
abstract

Il MOrbo di Hodgkin sclero-nodulare (MH-SN) rappresenta la variante istologica più frequente e, pur presentando una prognosi favorevole, nel suo ambito sono compresi una certa percentuale di pazienti che non rispondono in modo soddisfacente alla terapia.Poichè i quadri istopatologici che si possono osservare nella variante SN del MH sono diversi, gli AA. hanno riesaminato una casistica di 115 casi di MH-SN (in parte retrospettivi ed in parte prospettici) al fine di individuare eventuali sottotipi istologici con diversa prognosi.E' stata valutata l'influenza di 14 parametri istologici ed in base alla composizione cellulare dei noduli la casistica, in analogia a quanto proposto da Bennett e coll. è stata suddivisa prima in 5 sottotipi raggruppati poi in 2: grado 1 e 2.Dei 14 parametri istologici esaminati solo il numero dei linfociti intranodulari ha presentato nella casistica in esame un significato prognostico, mentre gli altri parametri analizzati e la suddivisione dei pazienti in 5 sottotipi non ha permesso di identificare gruppi con sopravvivenze significativamente diverse.Raggruppando i pazienti in due soli sottogruppi (grado 1 e grado 2) si osservano sopravvivenze attuariali diverse, senza tuttavia raggiungere la significatività statistica. L'estensione della malattia sembra inoltre avere un peso prognostico superiore alle caratteristiche istopatologiche.

1987 - La malattia di Hodgkin refrattaria [Relazione in Atti di Convegno]
Federico, Massimo; Barbieri, F.; Bisi, D.; Curci, Giuseppe; Gobbi, P. G.; Attardo Parriello, G.; Palomba, G.; Luppi, G.; Piccinini, P.; Mauri, C.
abstract

Nonostante i successi compiuti negli ultimi anni nella cura della malattia di Hodgkin circa 1/3 dei pazienti non risponde ancora alla terapia. Nella casistica esaminata (242 casi) i pazienti refrattari sono risultati il 36,3%; 62 che non avevano raggiunto la remissione completa (Malattia refrattaria di Tipo I, MR-I) e 26 che erano recidivati entro 3 anni dalla fine della terapia di induzione (Malattia Refrattaria di Tipo II, MR-II).Sono statae valutate numerose variabili cliniche, di laboratorio, istologiche e terapeutiche nel tentativo di individuare utili indici di rischio di refrattarietà. Nella MR-I i parametri più significativi sono risultati l'istotipo, l'età, lo stadio, l'albuminemia, la linfocitopenia e la cupremia. La presenza contemporanea di stadio avanzato, sintomi B ed istotipo DL ha comportato un rischio di insuccesso terapeutico dell'80%. Nella MR-II invece non si sono evidenziate differenze con il gruppo dei pazienti con remissione persistente; le recidive hanno colpito in misura simile i pazienti con malalttia localizzata (14,3%) e quelli con malattia diffusa (14,6%) con o senza istotipo sfavorevole, sintomi B, bulky, etc.La sopravvivenza a 6 anni dei pazienti con MR-I è stata del 47% con una mediana di 36 mesi; quella dei pazienti con MR-II è risultata del 59%.

1987 - La terapia d'induzione nella malattia di Hodgkin.Risultati preliminari di uno studio prospettico multicentrico [Relazione in Atti di Convegno]
Torelli, Umberto; DI PRISCO, Alfredo Ubaldo; Federico, Massimo; Dini, D.; Bagnulo, A.; Croci, E.
abstract

In uno studio prospettico multicentrico condotto in 242 pazienti affetti da malattia di Hodgkin, sono stati valutati i risultati terapeutici ottenuti seguendo le modalità di trattamento concordate con i Centri associati nel gruppo Linfomi della AIL.I dati riferiti, benchè emergenti da una casistica ancora in corso di valutazione, consentono di confermare la maggior efficacia della associazione radiochemioterapica non solo nella malattia avanzata ma anche negli stadi iniziali.Nello stadio I A a localizzazione sopradiaframmatica il trattamento combinato ha consentito di ottenere, sia pure in un numero limitato di pazienti, percentuali di RC e sopravvivenze libere da malattie superiori a quelle ottenute con la sola RT. Il vantaggio della radio-chemioterapia è risultato più evidente nello stadio II A a localizzazione sopradiaframmatica, e particolarmente in quello ad istologia sfavorevole; in questi pazienti la sopravvivenza globale a 6 anni e quella libera da malattia superano il 90%, mentre non raggiungono l'80% nei pazienti trattati con la sola radioterapia e nei quali si dimostra anche una maggior incidenza di recidive.Nella terapia dello stadio III A il trattamento combinato ha consentito di ottenere sopravvivenze libere da malattia superiori a quelle raggiunte dai pazienti trattati con la sola radioterapia.Nei pazienti con la malattia in stadio II B, III B e IV il trattamento associato è risultato più vantaggioso della osla radioterapia sia per quanto riguarda le percentuali di RC (76,6%), sia per quanto riguarda la sopravvivenza globale (86,7%) e quella libera da malattia (81,9%).

1987 - Natura e ontogenesi della componente cellulare neoplastica nella malattia di Hodgkin.Storia recente di un'antica controversia e contributo critico. [Relazione in Atti di Convegno]
Artusi, Tullio; Bonacorsi, G.; Sarti, M.; Federico, Massimo; Piccinini, Lino; Barbieri, F.; Frassoldati, A.; Bisi, D.; Corradini, R.; Silingardi, V.
abstract

Dopo una disamina delle proprietà biologiche della componente cellulare abnorme del m. di Hodgkin, gli AA. ne deducono il carattere neoplastico anche se relativamente autolimitantesi. Quindi, nella ricerca della sua controparte normale, essi optano per un'ontogenesi linfoide sulla base della comune esperienza morfologica e di una serie di dati immunochimici. Considerata non ancora chiusa la questione della CIg sternberghiana, essi rilanciano la candidatura B-immunoblastica accanto a quella T oggi prevalente, anche sulla base di alcuni elementi recentemente emersi dalla letteratura.Gli ultimi dati relativi al riarrangiamento del genoma di queste cellule per le Ig e il TcR sembrano indicare, da un lato l'esistenza di cloni neoplastici B e di cloni neoplastici T all'interno dello stesso istotipo, dall'altro la policlonalità iniziale del processo in ogni singolo individuo, tale da giustificare il sospetto che cloni T e cloni B possono far parte sin dall'inizio e contemporaneamente di un citotipo neoplastico intrinsecamente eterogeneo. Gli AA. tentano infine di armonizzare la tesi istiocito-macrofagica con quella linfoide ipotizzando l'esistenza di linee cellulari linfoidi capaci di modificarsi, nel corso dell'ontogenesi, con acquisizione di proprietà fagocitiche.

1987 - Su di un caso di Morbo di Hodgkin complicato da infestazione da Strongyloides Stercoralis [Articolo su rivista]
Dini, D.; Rivasi, Francesco; Federico, Massimo; Casolari, C.; Barbieri, F.
abstract

Viene riferito un caso di Morbo di Hodgkin complicato da grave infestazione da Strongyloides stercoralis. Lo Strongyloides è un parassita opportunista in grado di determinare quadri clinici particolarmente gravi, per autoinfestazione, in condizioni di immunodepressione. In questi pazienti la comparsa di sintomi gastrointestinali aspecifici deve indurre ad eseguire gli accertamenti necessari per evidenziare, accanto ai più comuni germi patogeni, anche la presenza di parassiti.

1986 - Gli interferoni in terapia antineoplastica [Articolo su rivista]
Barbieri, F.; Frassoldati, A.; Federico, Massimo; Piccinini, Lino; Silingardi, Vittorio
abstract

Gli inteferoni (IF) sono proteine la cui attività antivirale è nota da tempo, tuttavia numerosi studi hanno messo in evidenza la loro efficacia anche come agenti antiproliferativi aprendo la strada ad un loro possibile ruolo in terapia antineoplastica. Vengono riferiti i risultati dei trials più significativi sull'uso degli IF in varie neoplasie umane, valutandone l'importanza rispetto ai presidi terapeutici convenzionali.

1986 - Gruppi-SH sierici in pazienti con emolinfoblastosi fuori terapia [Articolo su rivista]
Piccinini, Lino; Massolo, Fausta; Luppi, G.; Federico, Massimo; Frassoldati, A.
abstract

Da vari contributi è stata sottolineata l'importanza che i gruppi sulfidrilici (gruppi -SH reattivi) delle proteine rivestono in numerosi processi biologici quali la coagulazione del sangue, la mitosi cellulare, le funzioni delle membrane cellulari, il metabolismno proteico (1,2).Studi recenti hanno focalizzato il rilevante ruolo svolto dai gruppi -SH oltre che nei fenomeni immunitari con la modulazione della linfopoiesi e della funzionalità linfocitaria, anche come prima barriera endogena preposta ad antagonizzare i danni biologici dei radicali liberi ossidanti potenzialmente mutageni (3,4).E' già stata da noi segnalata una significativa diminuzione della concentrazione sierica dei gruppi -SH in pazienti con malattie neoplastiche in fase di attività (5,6), mentre il presente studio è stato condotto anche su una casistica di emolinfoblastosi in remissione completa (RC) fuori terapia.

1985 - Hairy cell leukemia: a reversible disease? A report of two cases of spontaneous remission [Articolo su rivista]
Silingardi, Vittorio; Federico, Massimo; Barbieri, F.; Artusi, Tullio; Mauri, C.
abstract

Vengono riportati due casi di remissione spontanea in corso di Hairy cell leukemia (HCL). Entrambi i pazienti hanno presentato all'esordio un quadro clinico simile: grave pancitopenia e marcata splenomegalia. Il decorso della malattia è stato contrassegnato da frequenti episodi infettivi risoltisi con antibiotico-terapia. Nessun altro trattamento, come, ad es., splenectomia o chemioterapia antiblastica, fu instaurato. I pazienti sono tuttora vivi ed in buona salute a distanza rispettivamnete di 17 e 13 anni dalla diagnosi. A quanto ci risulta finora solo un caso di remissione spontanea di HCL è stato segnalato in letteratura.

1985 - I markers tumorali [Articolo su rivista]
Dini, D.; Federico, Massimo; Barbieri, F.; Bisi, D.; Catelli, D.
abstract

Gli autori espongono una rassegna dei principali markers tumorali, precisandone le caratteristiche fondamentali. I markers tumorali vengono suddivisi in cinque categorie (antigeni oncofetali, prodotti di degradazione proteica, ormoni, enzimi, altri); possono essere ricercati con varie metodiche nel siero dei vari liquidi biologici e su preparati istologici. Lo studio combinato di più markers simultaneamente sembra fornire i migliori risultati per la diagnosi e per il monitoraggio delle varie forme tumorali. Viene, infine, prospettato l'uso degli anticorpi monoclonali al fine di ottenere markers specifici per ogni tipo di neoplasia.

1985 - Reevaluation of prognostic significance of symptoms in Hodgkin's disease [Articolo su rivista]
Gobbi, P. G.; Cavalli, C.; Gendarini, A.; Crema, A.; Ricevuti, G.; Federico, Massimo; Di Prisco, A. U.; Ascari, E.
abstract

The prognostic value--at diagnosis--of fever, sweating and weight loss, which enter the Ann Arbor B category, and of pruritus, whose influence on survival is still debated, were systematically reevaluated in 635 patients with Hodgkin's disease, observed between 1972 and 1982. By means of multivariate analysis an intrinsic, more negative prognostic value was demonstrated for each of the following symptoms: fever over 38 degrees C, weight loss more than 10% of body weight in the 6 months before admission, and severe pruritus, which is defined as being generalized, causing multiple excoriations and resisting local and systemic antipruritics. Patients with the mild counterparts of these symptoms, as well as sweats, were found to have a survival rate quite comparable with that of fully asymptomatic patients. A rearrangement of the Ann Arbor B constitutional symptoms which would replace sweats with severe pruritus might be more correct and more suitable for better selecting the patients who require more aggressive therapy.

1985 - Serum albumin in Hodgkin's disease [Articolo su rivista]
Gobbi, P. G.; Gendarini, A.; Crema, A.; Cavalli, C.; Attardo Parrinello, G.; Federico, Massimo; Di Prisco, A. U.; Ascari, E.
abstract

Serum albumin levels were measured by electrophoresis in 552 evaluable patients with Hodgkin's disease. Determinations were made on all patients at onset, on 224 after induction therapy and on 78 in relapse after remissions of variable length. At onset a discrete hypoalbuminemia was evident, inversely related to stage and more marked in symptomatic cases and elder patients. Little or no differences in albumin levels were found with relation to histologic subtypes, sex and presence of weight loss or hepatic damage. Posttherapeutic normalization of serum albumin occurred only after achievement of complete remission and failed after partial remission, while a new clear decrease became evident in relapse. On the basis of 799 albumin measurements during active disease and in remission, the albumin/alpha 2-globulin ratio demonstrated a clear and useful clinical advantage over either albumin or alpha 2-globulin fractions alone as indicator of active disease and relapse. If defective synthesis is the most accepted mechanism for hypoalbuminemia in Hodgkin's disease, these results suggest a casual factor somehow related to the tumoral mass.

1984 - A report of seven long survivors for evidence of prognostic factors in hairy cell leukemia [Articolo su rivista]
Federico, Massimo; Barbieri, F.; Dini, D.; Bonacorsi, G.; Fontana, G.; Rinaldi, G.; Artusi, T.; Silingardi, Vittorio
abstract

The clinical hematologic and pathologic findings of 30 patients with hairy cell leukemia observed between 1966 and 1979 were studied. Twelve patients had long-lasting course of the disease. Seven of them displayed a survival greater than or equal to 120 months, whereas 18 patients died within 36 months of the diagnosis. Their clinical and laboratory characteristics (age of onset, sex, ESR, hemoglobin, WBC, neutrophils, monocytes, platelets, spleen and liver size) were analyzed to ascertain possible prognostic features. Multivariate discriminant analysis, performed both with a direct method and with a stepwise method (Wilks' method), provided a discriminant function able to correctly predict the prognosis of the disease in 83.3% of the examined cases. Spleen size, neutrophil count, age of onset, ESR and liver size turned out to be the most important prognostic factors; in contrast, splenectomy did not significantly affect the prognosis in our cases.

1984 - Hairy cell leukemia. Clinico-pathological study of 30 cases observed 1966 to 1979] [Articolo su rivista]
Silingardi, V; Federico, Massimo; Bonaccorsi, G; Barbieri, F; De Pasquale, A; Piccinini, Lino; Curci, G; Dini, D; Mussini, C; Sacchi, Stefano
abstract

no abstract

1984 - La fibronectina: conoscenze attuali [Articolo su rivista]
Barbieri, F.; Manzini, C. U.; Federico, Massimo
abstract

La fibronectina è una macroglicoproteina presente sulle cellule e nella matrice extracellulare, in grado di legarsi a differenti substrati quali fibrina, collagene, superfici cellulari e glicosaminoglicani. E' presente pure, in forma solubile, nel plasma dove svolge attività opsonizzante. Vengono riferite le conoscenze attuali sulla struttura e sulle attività biologiche della proteina. Gli autori, inoltre, riferiscono sulla distribuzione della fibronectina in varie condizioni patologiche e sulle possibili applicazioni terapeutiche.

1984 - Leucemia e tricoleucociti: studio clinico patologico di 30 casi [Articolo su rivista]
Silingardi, Vittorio; Federico, Massimo; Bonacorsi, G.; Barbieri, F.; De Pasquale, A.; Piccinini, Lino; Curci, Giuseppe; Dini, D.; Mussini, Cirillo; Sacchi, Stefano; Mauri, C.; Venezia, Leonardo; Artusi, Tullio
abstract

Vengono riferiti i risultati di uno studio retrospettivo su 30 casi di leucemia a Hairy cell (HCL) osservati nel periodo 1966-1979. Vengono riportati i reperti clinici, ematochimici e strumentali ed i risultati delle indagini citologiche, istologiche, citochimiche ed ultrastrutturali.16 dei 30 pazienti sono stati splenectomizzati e la loro sopravvivenza mediana attuariale è risultata di 37 mesi, mentre quella di tutta la casistica era di 24 mesi. Al follow-up (31.12.1982) 20 dei 30 pazienti erano deceduti e l'assoluta maggioranza dei decessi si è osservata nei primi 36 mesi dopo la diagnosi per processi infettivi. Con il Log-Rank test è stato valutato il significato prognostico di vari parametri ed è risultato che nella casistica in esame solo la quota monocitaria e la condotta terapeutica (splenectomia si vs splenectomia no) sono stati in grado di modificare in modo statisticamente significativo la sopravvivenza attuariale.Vengono discussi, in rapporto ai dati della letteratura, i vari reperti riscontrati e viene ipotizzata la necessità di indagini randomizzate tra greuppi omogenei di pazienti per una più precisa formulazione della prognosi e per una più corretta impostazione terapeutica.

1984 - Morphological characterization of stationary stromal reticulum cells of the stromal in the mesenteric lymphonode of the Guinea pig [Articolo su rivista]
Severi, B.; Biagini, G.; Govoni, E.; Artusi, Tullio; Federico, Massimo; De Pasquale, A.; Bottanelli, P.; Franchini, M.; Milanesi, S.
abstract

The large mesenteric lymph node taken from guinea pigs in a period of time ranging from the 10th day prepartum till the 26th day postpartum has been examined in order to study: the morphological features of the stromal stationary reticulum cells with particular regard to recognize their stages of development; the possible ontogenetic relationship between these cells during the maturation of the lymphoid tissue. Our data support the hypothesis that from local mesenchymal cells originates a pool of poorly differentiated reticulum cells that can give rise to stromal stationary reticulum cells (myofibroblast-like cells, fibroblast-like cells, pericyte-like cells and dendritic cells). These elements have a characteristic distribution pattern likely related to different local functional requirements.

1984 - Patogenesi complessa di una emopatia sistemica: la tricoleucemia [Articolo su rivista]
Artusi, Tullio; Bonacorsi, G.; Federico, Massimo; Silingardi, Vittorio
abstract

La maggioranza degli studiosi ritiene che il tricoleucocito altro non sia se non una B-cellula, sulla base del suo ben noto immunofenotipo. Nonostante quello B sia l'assetto immunologico prevalente, esso coesiste spesso, nella HC, con altre proprietà che sono invece caratteristiche delle T-cellule, dei macrofagi e persino di certe linee cellulari proprie dei connettivi.A questo si aggiungono il riscontro di saltuarie ma caratteristiche anomalie qualitative dell'emolinfopoiesi residua non neoplastica, nonchè possibili comportamenti clinico-ematologici del tutto inusitati per un'emopatia maligna.Questa complessa fenomenologia suggerisce di non chiudere affrettatamente il problema patogenetico della tricoleucemia, che rimane una delle entità più singolari tra quelle con cui l'ematologo è chiamato periodicamente a cimentarsi.Vengono discusse, in questa rassegna, le seguenti ipotesi: a) che la malattia sia legata ad una profonda perturbazione del commitment staminale; b) che tale perturbazione induca, oltre ad altri fenomeni, l'emergenza di una linea neoplastica a carattere ibrido; c) che la popolazione staminale bersaglio dell'evento oncogeno conservi la capacità di differenziare anche verso certe linee cellulari stromali e, per qualche aberrazione disontogenetica, possa avere sede originaria nella milza anzichè nel midollo osseo.Viene infine sottolineato il carattere parzialmente autolimitantesi del processo.

1983 - Caratterizzazione morfo-funzionale delle cellule reticolari dendritiche. [Relazione in Atti di Convegno]
Biagini, G.; Federico, Massimo; Severi, B.; Govoni, E.; Dini, D.; Laschi, R.
abstract

Le cellule dendritiche sono elementi appartenenti al compartimento stazionario degli organi linfoidi periferici nel quale, sotto il termine generico di cellule reticolari, sono compresi quattro tipi principali di elementi <stromali> non linfoidi fra loro distinguibili in base alle caratteristiche soprattutto ultrastrutturali e citochimiche oltre che, in misura minore, per la differente distribuzione topografica: 1) cellule reticolari istiocitiche; 2) cellule reticolari fibroblastiche; 3) cellule reticolari dendritiche; 4) cellule reticolari interdigitate. A tutt'oggi, per una parte almeno delle cellule reticolari, non si conosce la sicura derivazione citogenetica (si è suppostoche le fibroblastiche e le dendritiche derivino da un comune precursore rappresentato da un acellula mesenchimale "locale"; anche se altri Autori ipotizzano che le cellule dendritiche possano avere un precursore circlante di origine mdollare), nè l'esatto ruolo funzionale.Le cellule reticolari dendritiche sono localizzate esclusivamente nei follicoli linfatici e la loro presenza sembra legata alla situazione immunitaria del soggetto.La prima funzione riconosciuta alle cellule reticolari dendritiche consiste nel raccogliere, captare e trattenere sulla superficie esterna del plasmalemma dei loro lunghi processi citoplasmatici il materiale antigenico, sotto forma di immunocomplessi. Pertanto viene confermato il coinvolgimento diretto delle cellule reticolari dendritiche nel meccanismo della risposta immunitaria; esse, verosimilmente dotate di ricettori di membrana per il framento Fc delle immunoglobuline e per il C3, giocherebbero un ruolo particolare nel creare il "milieu" ecologico adatto alla proliferazione e dalla trasformazione blastica delle cellule B dei centri germinativi.Da un punto di vista istochimico queste cellule sono positive per la 5-nucleotidasi e per le esterasi non specifiche.Al microscopio elettronico le cellule reticolari dendritiche presentano un aspetto stellariforme. Dal corpo cellulare, che è composto da un sottile alone citoplasmatico che circonda un voluminoso nucleo ed in cui è condensato la maggior parte del loro corredo organellare (qualche mitocondrio, sparsi profili di reticolo endoplasmatico rugoso, alcune zone di Golgi, oltre a scarsi microfilamenti intermedi nello ialoplasma) si irradiano i prolungamenti dendritici che circondano gli elementi linfoidi del centro germinativo. Tra i processi citoplasmatici, che possono essere connessi fra loro da desmosomi, è visibile un materiale elettrondenso probabilmente corrispondente ai complessi antigene anticorpo.

1983 - Eritropoiesi extramidollare intratoracica. Considerazioni clinico radiologiche su due casi di talassemia minor [Articolo su rivista]
Romani, F.; Emilia, Giovanni; Pompei, G.; Federico, Massimo; Torricelli, Pietro
abstract

Vengono analizzati due casi di eritropoiesi extramidollare intratoracica, riscontrati in pazienti talassemici, con particolare riguardo ai reperti radiologici: essi, accanto ai dati anamnestici, clinici e di laboratorio, consentono una precisa interpretazione diagnostica.

1983 - I linfomi del centro germinativo: clinica, terapia e prognosi del linfoma maligno centroblastico-centrocitico. [Relazione in Atti di Convegno]
Mauri, C.; Federico, Massimo; Piccinini, Lino; Torelli, Giuseppe; Sacchi, Stefano; Barbieri, F.; Dini, D.; Artusi, Tullio; Silingardi, V.
abstract

Vengono riferiti i risultati di uno studio retrospettivo su 71 casi di linfoma maligno centroblastico-centrocitico osservati nei dipartimenti di Medicina interna e di Ematologia dell'Università di Modena nel periodo 1968-1979. 42 casi presentavano una architettura nodulare e 29 diffusa o nodulare-diffusa.L'età d'esordio è risultata più elevata nelle forme diffuse (52,4 anni) rispetto a quelle nodulari (44,7 anni). Nella quasi totalità dei pazienti erano presenti alla diagnosi linfoadenomegalie superficiali, in circa 1/3 localizzazioni extralinfatiche e in 27 pazienti sintomi B. L'87% dei LMcb/cc diffusi e il 63% dei nodulari già all'esordio erano in stadio III o IV.Sono riferiti i risultati delle principali indagini ematochimiche e strumentali. La terapia di induzione (mono o polichemioterapia e/o terapia radiante) ha determinato RC nel 67% delle forme nodulari e nel 37% delle forme diffuse.La sopravvivenza mediana attuariale di tutta la casistica è risultata di 91 mesi (103 mesi per le forme nodulari e 43 mesi per quelle diffuse). Al follow-up (31-12-81) dei 71 pazienti presi in esame 39 erano viventi (24 in RC e 15 in RP) e 32 deceduti (range 2-128).

1983 - I linfomi del centro germinativo: il linfoma maligno centrocitico [Relazione in Atti di Convegno]
Silingardi, V.; Federico, Massimo; Fontana, G.; Emilia, Giovanni; Curci, Giuseppe; Campioli, D.; Galli, P.; Torelli, Umberto
abstract

Vengono esaminati i dati epidemiologici, clinici, terapeutici e prognostici emersi da uno studio retrospettivo su 35 casi di LM centrocitico osservati nel periodo 1968-1979 nel dipartimento di Medicina interna e di Ematologia dell'Università di Modena.La massima incidenza si è osservata nella VI-VII decade di vita. In 27 pazienti il primo segno della malattia è stata la comparsa di adenomegalie superficiali, in 16 pazienti vi erano sintomi B. Le localizzazioni extranodali erano molto frequenti, specie quelle a carico del midollo osseo (45,7%) e della milza (25,7%). All'esordio 20 pazienti erano allo stadio IV.La terapia di induzione (con mono o polichemioterapia associata o meno a terapia radiante) ha determinato RC nel 41% ed RP nel 44% dei casi.La sopravvivenza mediana attuariale di tutta la casistica è risultata di 41 mesi, quella dei pazienti che hanno presentato RC di 71 mesi. Nella nostra casistica la prognosi è risultata influenzata in modo statisticamente significativo anche dall'età dei pazienti.

1983 - Patologia non neoplastica del follicolo linfatico [Relazione in Atti di Convegno]
Artusi, Tullio; Bonacorsi, G.; Federico, Massimo; Silingardi, V.
abstract

Riallacciandosi alle argomentazioni esposte in tema di citoistofisiologia dell'attività follicolare, gli AA. propongono una distinzione tra quei quadri follicolari che rientrano verosimilmente nella gamma di risposte possibili dell'organismo immunologicamente sano (linfoadenite toxoplasmica, tbc linfonodale a diffusione ematogena), le patologie follicolari da insulto estrinseco, immunologico e tossico (follicoliti epiteliodi acute, follicoli <burnt out> nella linfoadenopatia angio-immunoblastica), e le patologie vere e proprie della risposta follicolare: patologie, cioè, intrinseche al follicolo e a carattere non neoplastico (forse le follicoliti epiteliodi subacute o croniche). Infine, quelle patologie follicolari che fanno parte di processi immunoproliferativi, parimenti non neoplastici, ma a rischio di trasformazione neoplastica. La trattazione è imperniata soprattutto su quest'ultimo raggruppamento, nel cui ambito vengono trattate, nell'ordine: l'alterazione follicolare della linfopatia di Castleman, il <centro germinativo progressivamente trasformato> e i quadri gigantofollicolari nelle ipogammaglobulinemie acquisite.

1982 - Castleman's lymphoadenopathy: twenty years of observation. I. General considerations. Monodenopathic variety [Articolo su rivista]
Artusi, Tullio; Saragoni, A.; Bonacorsi, G.; DI PRISCO, Alfredo Ubaldo; Spedicato, M.; Silingardi, Vittorio; Federico, Massimo
abstract

After a short review of the nosologic definition of Castleman's lymphadenopathy in its monoadenopathic form, the authors describe five cases of this rare condition of lymphatic tissues, personally observed over a period of 17 years. The authors try to evaluate the different pathogenetic hypotheses proposed in the last years. In their opinion the process falls ito the group of autonomous proliferations. A subsequent paper will treat the systemic form of Castleman's lymphadenopathy.

1982 - Castleman's lymphoadenopathy: twenty years of observation. II. Generalized form [Articolo su rivista]
Artusi, Tullio; Bonacorsi, G.; Saragoni, A.; Spedicato, M.; Rinaldi, G.; Federico, Massimo; Silingardi, Vittorio
abstract

The authors continue the discussion on the etiopathogenesis of castelman's lymphadenopathy and review the literature of recent years concerning the generalized form of this condition.They describe five cases of the generalized form. The discussion points out the difficulties of a unique interpretation of heterogeneous clinical patterns linked only by histology.Some pathogenetic hypotheses are proposed.

1982 - New clinical criteria for the assessment of liver involvement in Hodgkin's disease [Articolo su rivista]
Gobbi, P. G.; Attardo Parrinello, G.; DI PRISCO, Alfredo Ubaldo; Federico, Massimo; Bonacorsi, G.; Dini, D.; Marabelli, S.; Rizzo, S. C.; Ascari, E.
abstract

The hepatic involvement in Hodgkin's disease, histologically verified in 133 patients who underwent laparotomy or laparoscopy, proved to be singly related to the following clinical findings: result of the liver isotopic scan, liver and/or spleen enlargement, serum albumin less than or equal to 3.5 g/dl, GOT and/or GPT greater than or equal to 20 mU/ml, serum alkaline phosphatase (SAP) greater than or equal to 210 mU/ml, BSP retention at 45 min greater than or equal to 6.5% and ESR greater than or equal to 51 mm at 1 hr. Such clinical findings were jointly evaluated and further selected by means of a logistic discriminant analysis, and the simplest function with the best discriminant ability between involved and non-involved liver was made by liver scan, spleen enlargement, BSP retention and GOT (89.5% of correct diagnoses). Since the Ann Arbor clinical criteria for liver involvement showed correct diagnoses in 69-80% of the cases, more reliable criteria can be proposed. So, liver involvement is highly probably (a) when three or more of the five variables indicated above are abnormal, or (b) when a markedly abnormal liver scan is associated with alteration of at least one of the other four parameters: otherwise liver will be non-involved.

1981 - Emopoiesi extramidollare endotoracica in Morbo di Cooley dell'adulto [Articolo su rivista]
Federico, Massimo; Gallo, E.; Roversi, P.; Silingardi, Vittorio; Canossi, G. C.
abstract

Viene riferito un caso di <morbo di Cooley in adulto che, oltre ad ascesso splenico da salmonella, presentava focolai di mielopoiesi extramidollare in sede endotoracica.La diagnosi è stata formulata in base ai reperti radiografici e clinici ed ha trovato ulteriore conferma dal riscontro di una riduzione del volume di tali focolai, dopo attenuazione dell'iper-emolisi conseguente alla splenectomia.Sono infine discussi i problemi diagnostici e patogenetici della mielopoiesi extramidollare endotoracica.

1981 - Tonsillectomy: a prognostic factor in Hodgkin's disease [Articolo su rivista]
Gobbi, P. G.; Cavalli, P.; Franzini, B.; DI PRISCO, Alfredo Ubaldo; Federico, Massimo; Bonacorsi, G.
abstract

The clinical features and course of Hodgkin's disease (HD) were investigated in 160 previously tonsillectomized patients and compared with 375 nontonsillectomized ones. In both groups, sex, social class, histologic type, stage and symptoms were almost identically distributed. Tonsillectomized patients showed a higher incidence of initial cervical forms (p less than 0.05) and more frequently developed the disease under 35 years of age (p less than 0.001), thus also reflecting the different policies of the otolaryngologists in the past few decades. Moreover, the tonsillectomized patients enjoyed a significantly better survival (p approximately equal to 0.01) than the nontonsillectomized ones. Adjusted survival curves for age and site of initial involvement proved that the favorable prognostic value of tonsillectomy was not due to the altered distribution of these 2 factors in the 2 groups; in addition, an earlier diagnosis in tonsillectomized patients could be excluded. The favorable effect of tonsillectomy in HD patients might be related specifically to the reduced portion of immunologically reacting oropharyngeal lymphoid tissue remaining after tonsillectomy. A decreased output of the specific immune-complexes, which are responsible for the disease, according to Vianna's theory, might be hypothesized in tonsillectomized patients.

1980 - Appendicectomia e Morbo di Hodgkin [Articolo su rivista]
Gobbi, P. G.; Cavalli, P.; Attardo Parrinello, G.; DI PRISCO, Alfredo Ubaldo; Federico, Massimo
abstract

In una casistica retrospettiva di 535 pazienti affetti da Morbo di Hodgkin i principali paramentri clinici all'esordio e la sopravvivenza sono stati valutati comparativamente nei 136 pazienti precedentemente appendicectomizzati e nei 399 non appendicectomizzati. la distribuzione di sesso, tipo istologico, sedi di prima localizzazione, stadio clinico, sintomi, non è risultata significativamente differente nei due gruppi; la sopravvivenza è stata pressochè identica. I pazienti appendicectomizzatihanno sviluppato l'Hodgkin alquanto più tardi dei non appendicectomzzati ed hanno mostrato una debole ma netta relazione tra età di appendicectomia ed età d'esordio della malattia (r=0,722).Gli AA. ipotizzano che l'intervento, influendo sulla ricircolazione linfocitaria cui l'appendice da normalmente un cospicuo contributo, pssa rallentare quel meccanismo di intrappolamento di linfociti T che, secondo recenti vedute, sarebbe alla base della formazione del tessuto hodgkiniano.

1980 - Hb Hasharon: studio di un nucleo familiare [Articolo su rivista]
Federico, Massimo; Rivasi, P.; Perrotta, C.; Milanti, G.; Bernardi, F.
abstract

Gli Autori riferiscono sulla osservazione casuale di un nucleo familiare di portatori di emoglobina Hasharon (alfa2 47his beta2). Tale emoglobina anomala, presente in percentuale variabile tra il 20 ed il 40 %, è stata finora riscontrata solo in famiglie ebraiche Askhanazy e, in Italia, in soggetti (come anche quelli da noi osservati) originari del Polesine. Viene brevemente discusso il quadro ematologico di tale emoglobinopatia e della associazione Hb Hasharon/beta talassemia.

1979 - Complete remission in a case of aplastic anemia after treatment with antilymphocyte globulin [Articolo su rivista]
Silingardi, Vittorio; Venezia, Leonardo; Federico, Massimo; Torelli, Giuseppe; Salvo, G.
abstract

The Authors report a case of aplastic anemia, resistant to treatment with androgens and prednisone, in which bone marrow regeneration was observed after treatment with antilymphocyte globulin.This observation confirms the possibility of a immune pathogenesis in some cases of aplastic anemia, although no direct evidence was obtained supporting the existence of a humoral or cellular autoimmune process in the patient.The result obtained points to a new approach in the treatment of aplastic anemia.

1979 - Istiocitosi maligna [Articolo su rivista]
Artusi, Tullio; Federico, Massimo; Venezia, Leonardo; Silingardi, Vittorio
abstract

Viene riferito un caso diistiocitosi maligna in apparenza ad esclusiva localizzazione splenica.La malattia, esordita con un quadro di modesta leuco-piatrinopenia, è stata diagnosticata in base ai reperti anatomopatologici dopo splenectomia e presenta decorso cronico.Vengono discusse le peculiarità cliniche ed istologiche del caso, in rapporto anche ai dati della letteratura.

1979 - Sindrome mediastinica da mieloblastoma quale manifestazione d'esordio di leucemia mieloide acuta [Articolo su rivista]
Silingardi, Vittorio; Artusi, Tullio; Torelli, Giuseppe; Federico, Massimo
abstract

The authors report a case of acute myeloblastic leukemia which at the onset was characterized by a granuloblastic mediastinal tumor, without the appearance of a blastic population in the peripheral blood. The diagnosis was allowed by the cytological and cytochemical study of the pleural effusion. The autopsy confirmed the invasion of several organs by the myeloid malignant cells.The authors describe the clinical and histopathological characteristics of the disease. They point out that the histogenesis of this case and other similar ones reported in the literature remains obscure. The possibility is suggested that microenvironmental factors may have a critical role in facilitating the in situ proliferation of circulating blast cells with formation of solid tumor masses.

1979 - Studio clinico immunologico di sei casi di morbo di Behcet [Articolo su rivista]
Silingardi, Vittorio; Montemurno, C.; Venezia, Leonardo; Franceschi, C.; Riva, P. C.; Emilia, Giovanni; Masi, M.; Merelli, E.; Torelli, Giuseppe; Licastro, F.; Fantini, M. P.; Federico, Massimo
abstract

Vengono riferiti 6 casi di morbo di behcet, la cui diagnosi è risultata particolarmente ardua, poichè la triade sintomatologica propria della malattia (afte orali, ulcere genitali, uveite) era mascherata dai disturbi secondari alla localizzazione del processo morboso ad altri organi ed apparati.Le indagini immunologiche eseguite hanno confermato la presenza in questi pazienti di alterazioni di vari tests in vivo ed in vitro ed in particolare sono state evidenziate iper-reattività cutanea aspecifica in 5 casi ed esaltata blastizzazione linfocitaria spontanea e dopo PHA.In base all'esito delle indagini eseguite ed ai dati della letteratura viene prospettata la possibilità che nel morbo di Behcet coesistano alterazioni immunologiche e dei meccanismi che relgolano l'attivazione delle chinine, del complemento e della coagulazione.Da un punto di vista terapeutico è stata confermata l'efficacia, almeno temporanea, della terapia corticosteroidea ed è stata sperimentata per la prima volta in questi pazienti la globulina antilinfocitica, che potrebbe sostituire gli antiblastici immunodepressori già usati con risultati soddisfacenti nei portatori di morbo di Behcet.

1977 - Trapianto di midollo osseo nelle aplasie midollari. [Articolo su rivista]
Silingardi, Vittorio; Torelli, Giuseppe; Dagna Bricarelli, F.; Secchi, E.; Ferrari, S.; Montagnani, G.; Curci, G.; Federico, Massimo; Emilia, Giovanni; DI PRISCO, Alfredo Ubaldo; Venezia, Leonardo; Misley, A.; Torelli, Umberto; Mauri, C.
abstract

Dopo un breve cenno sulla etico-patogenesi delle aplasie midollari, gli AA. riferiscono i dati più salienti della letteratura sul trapianto di midolo osseo allogenico ed isogenico in tali emopatie.Vengono riferiti i risultati a distanza osservati dagli AA. nel primo caso di aplasia midollare globale trattato in Italia con mielotrapianto isogenico.Gli AA. schematizzano infine le indicazioni al mielotrapianto nelle aplasie midollari, senza minimizzare i pericoli che tuttora comporta tale trattamento e gli insuccessi cui si può incorrere.