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Alessia BARI

Professore Associato
Dipartimento di Scienze Mediche e Chirurgiche Materno-Infantili e dell'Adulto

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Pubblicazioni

2023 - Impact of immunochemotherapy with R-bendamustine or R-CHOP for treatment naïve advanced-stage follicular lymphoma: A subset analysis of the FOLL12 trial by Fondazione Italiana Linfomi [Articolo su rivista]
Nizzoli, M. E.; Manni, M.; Ghiggi, C.; Pulsoni, A.; Musuraca, G.; Merli, M.; Califano, C.; Bari, A.; Massaia, M.; Conconi, A.; Musto, P.; Mannina, D.; Perrone, T.; Re, F.; Galimberti, S.; Gini, G.; Capponi, M.; Vitolo, U.; Usai, S. V.; Stefani, P. M.; Ballerini, F.; Liberati, A. M.; Pennese, E.; Pastore, D.; Skrypets, T.; Catellani, H.; Marcheselli, L.; Federico, M.; Luminari, S.
abstract

We conducted a post hoc analysis of the FOLL12 trial to determine the impact of different initial immunochemotherapy (ICT) regimens on patient outcomes. Patients were selected from the FOLL12 trial, which included adults with stage II–IV follicular lymphoma (FL) grade 1–3a and high tumor burden. Patients were randomized 1:1 to receive either standard ICT followed by rituximab maintenance (RM) or the same ICT followed by a response-adapted approach. ICT consisted of rituximab-bendamustine (RB) or rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), per physician's decision. A total of 786 patients were included in this analysis, 341 of whom received RB and 445 R-CHOP. RB was more frequently prescribed to older subjects, females, patients without bulky disease, and those with grade 1–2 FL. After a median of 56 months of follow-up, R-CHOP and RB had similar progression-free survival (PFS) (Hazard Ratio for RB 1.11, 95% CI 0.87–1.42, p = 0.392). Standard RM was associated with improved PFS compared to response-adapted management both after R-CHOP and RB. Grade 3–4 hematologic adverse events were more frequent with R-CHOP during induction treatment and more frequent with RB during RM. Grade 3–4 infections were more frequent with RB. RB was also associated with a higher incidence of transformed FL. R-CHOP and RB showed similar activity and efficacy, but with different safety profiles and long-term events, suggesting that the treating physician should carefully select the most appropriate chemotherapy regimen for each patient based on patient's individual characteristics, choices, and risk profile.

2022 - Diagnosi di crioproteinemia: preziosa collaborazione tra laboratorio e clinica per la corretta gestione di una patologia rara [Articolo su rivista]
Natali, Patrizia; Debbia, Daria; Sheldon, Joanna; Bari, Alessia; Basile, Umberto; Lavatelli, Francesca; Patel, Dina; Galli, Massimo; Villa, Erica; Salvarani, Carlo; Palladini, Giovanni; Mascia, Maria Teresa; Sandri, Gilda
abstract

Cryoglobulinemia is a rare pathologic condition that can be difficult to diagnose both clinically and in the laboratory, which is why close collaboration between the clinic and laboratory is essential. The laboratory needs the skills and experience to interpret the laboratory tests and the clinician should not hesitate to contact the laboratory when the result is not supported by the clinical signs. To strengthen this collaboration, the Protein Study Group of the Italian Society of Clinical Biochemistry (SIBioC) in collaboration with the Italian Association for the Fight against Cryglobulinemia (ALCRI) under the patronage of the University of Modena and Reggio Emilia, organised a conference in Modena on September 2021 entitled "Cryoglobulinemia: laboratory and clinic, a virtuous collaboration for the correct management of a rare pathology". This collective paper is aimed to summarize the topics discussed during the meeting. The conference consisted of two parts: the first aimed at highlighting the critical components of the pre-, intra- and post-analytical phases of cryoglobulin investigation. Cryoprotein testing remains totally manual and operator dependent so it was important to identify areas where best practice guidance or even harmonisation of the laboratory investigation would be beneficial. The second part of the conference focused on clinical aspects and the effects of therapies, including antiviral drugs with direct action against HCV. These drugs are able to eradicate the virus, but the elimination of HCV-related cryoglobulins is seen in only about half of cases. Finally, the clinical consequences of the diagnosis of cryoglobulinemia and the multidisciplinary implications that this entails were highlighted, underlining how the continuous dialogue between the laboratory and clinic is crucial for the correct management of the patient.

2022 - Second Cancers in Classical Hodgkin Lymphoma and Diffuse Large B-Cell Lymphoma. A Systematic Review by the Fondazione Italiana Linfomi [Articolo su rivista]
Nassi, L.; de Sanctis, V.; Loseto, G.; Gerardi, C.; Allocati, E.; Ciavarella, S.; Minoia, C.; Guarini, A.; Bari, A.
abstract

Background: The increase of lymphoma patient survival led to a modification of the incidence of long-term sequelae, including second malignancies (SM). Several groups have dealt with the incidence of SM, according to the primary treatment; however, a standardized approach for the early detection and screening of SM in the population of lymphoma survivors should be implemented. Methods: A systematic review was conducted by Fondazione Italiana Linfomi (FIL), in order to define the incidence of SM, the impact of modern radiotherapy on SM risk, and the usefulness of tailored follow-up and screening strategies for early diagnosis of SM. Classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) survivors were investigated. The MEDLINE, Embase, and Cochrane Library databases were checked for relevant reports published up to January 2020. The selection process was reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Results: A total of 27 full-text manuscripts resulted as eligible for the analysis. The incidence of SM in cHL patients treated with ABVD was higher compared to the general population and was even higher in patients treated with intensified regimens. The risk increased over time, as well as after 10–15 years from therapy, and was augmented by radiotherapy exposure. In DLBCL, more intensive regimens (i.e., R-CHOEP or R-MegaCHOEP) vs. R-CHOP were associated with a higher SM incidence. Salvage chemotherapy and autologous stem cell transplants increased the risk of SM in both cHL and DLBCL cohorts. A lower incidence of SM, particularly of breast cancer (BC), was shown in cohorts of cHL survivors treated with reduced radiation volumes and doses (involved fields vs. extended fields), but robust trials are still lacking. Considering the advantage of a structured screening for early detection of SM, all the included studies regarded cHL survivors and screening strategy for early BC detection. Moreover, the authors discuss additional papers, to guide the early diagnosis of lung, colorectal, skin, and thyroid cancer in patients at risk due to family history, drug or RT exposure, or unhealthy lifestyles. These screening strategies all passed through patient awareness. Conclusion: A modern approach to chemotherapy and radiotherapy led to a lower risk of SM, which should be confirmed over time. Early detection of secondary cancers could be achieved through a tailored screening program, according to the individual risk profile.

2021 - Correction to: The classic prognostic factors in advanced Hodgkin’s lymphoma patients are losing their meaning at the time of pet-guided treatments (Annals of Hematology, (2020), 99, 2, (277-282), 10.1007/s00277-019-03893-7) [Articolo su rivista]
Bari, A.; Marcheselli, R.; Sacchi, S.; Re, A.; Pagani, C.; Tucci, A.; Botto, B.; Vitolo, U.; Molinari, A. L.; Puccini, B.; Pulsoni, A.; Santoro, A.; Tani, M.; Nassi, L.; Meli, E.; Pavone, V.; Bonfichi, M.; Evangelista, A.; Gioia, D.; Levis, A.; Zinzani, P.
abstract

In the article entitled “The classic prognostic factors in advanced Hodgkin’s lymphoma patients are losing their meaning at the time of Pet-guided treatments”, the affiliation of Armando Santoro should be corrected as follows: Humanitas Clinical and Research Center – IRCCS, Humanitas Cancer Center, via Manzoni 56, 20,089 Rozzano, Milan, Italy and Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini 4, 20,090 Pieve Emanuele – Milan, Italy.

2021 - Management of adverse events and supportive therapy in relapsed/refractory multiple myeloma [Articolo su rivista]
Pozzi, S.; Bari, A.; Pecherstorfer, M.; Vallet, S.
abstract

Relapsed/refractory (RR) multiple myeloma (MM) patients are a fragile population be-cause of prolonged drug exposure and advanced age. Preserving a good quality of life is of high priority for these patients and the treatment of disease-and treatment-related complications plays a key role in their management. By preventing and limiting MM-induced complications, supportive care improves patients’ outcome. Erythropoietin-stimulating agents and bisphosphonates are well-established supportive strategies, yet novel agents are under investigation, such as anabolic bone agents and activin receptor-like kinase (ALK) inhibitors. The recent dramatic changes in the treatment landscape of MM pose an additional challenge for the routine care of RRMM patients. Multi-drug combinations in first and later lines increase the risk for long-lasting toxicities, including adverse cardiovascular and neurological events. Moreover, recently approved first-in-class drugs have unique side-effect profiles, such as ocular toxicity of belantamab mafodotin or gastrointestinal toxicity of selinexor. This review discusses current standards in supportive treatment of RRMM patients, including recommendations in light of the recent SARS-CoV-19 pandemic, and critically looks at the incidence and management of side effects of standard as well as next generation anti-MM agents.

2021 - Management of lymphoma survivor patients in Italy: an evaluation by Fondazione Italiana Linfomi [Articolo su rivista]
Minoia, C.; Bari, A.; Nassi, L.; Banzi, R.; Gerardi, C.; Lenti, V.; Calabrese, M.; Spina, M.; Guarini, A.
abstract

Several outpatient models for the follow-up of cancer survivors have been developed worldwide. A multidisciplinary approach is often necessary to guarantee the best monitoring of long-term toxicities. Guidelines also indicate a close education on healthy lifestyles. In this context, we have analyzed the Italian follow-up modalities of lymphoma survivors, with the aim to have a starting line to hypothesize and plan the best model for Italian hematology centers.

2021 - Pazopanib-related secondary polycythemia in metastatic myxofibrosarcoma: A case report and review of the literature [Articolo su rivista]
Fanelli, M.; Caputo, F.; Cerma, K.; Gelsomino, F.; Bari, A.; Dominici, M.; Pozzi, S.
abstract

Introduction: Pazopanib, a tyrosine kinase inhibitor (TKI), is a standard treatment for various tumours, including metastatic non-adipocytic soft-tissue sarcomas. In literature, erythrocytosis has been described as a TKI-related condition. Case report: A 59-year-old man underwent surgical removal of a sub-scapular mass consistent with myxofibrosarcoma. After distant relapse, he first started chemotherapy, and then Pazopanib. He was found to have increased levels of hemoglobin (Hb) and hematocrit (Hct). He was asymphtomatic, with no history of pulmonary disease nor smoking habit. Erythropoietin (EPO) level was higher than normal. A polycythemia vera was ruled out. Management & outcome: The patient started a prophylactic therapy with lysine acetylsalicylate, and we observed a reduction of Hb, but not Hct. Due to disease progression, we interrupted Pazopanib. After a week from drug discontinuation, Hb levels got back to the normal range, Hct was lowering. We decided not to perform phlebotomy, considering the declining trend in Hb and Hct values and the absence of symptoms. Discussion: We postulated a Pazopanib-related secondary erythrocytosis, since Hb and Hct levels increased from baseline during treatment, then normalized when Pazopanib was discontinued. We used the Naranjo Nomogram to assess the correlation between the adverse effect and Pazopanib, the correlation was “Probable”, a score of 5. To the best of our knowledge, this is the first case report of Pazopanib-related secondary polycythemia in a patient with sarcoma. It is important to pay attention to blood count and to any symptoms potentially related to erythrocytosis in patients treated with TKIs.

2021 - The impact of healthy lifestyles on late sequelae in classical hodgkin lymphoma and diffuse large b-cell lymphoma survivors. A systematic review by the fondazione italiana linfomi [Articolo su rivista]
Minoia, C.; Gerardi, C.; Allocati, E.; Daniele, A.; De Sanctis, V.; Bari, A.; Guarini, A.
abstract

Background: In recent years, the scientific community has been paying ever more attention to the promotion of lifestyles aimed at the prevention of late toxicities related to anti-cancer treatments. Methods: Fondazione Italiana Linfomi (FIL) researchers conducted a systematic review in order to evaluate the evidence in favor of the promotion of lifestyles aimed at the prevention of the main sequelae of long-term classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) in survivors treated at adulthood with first-line or second-line therapy, including autologous stem cell transplants (ASCTs). Pubmed, Embase and Cochrane Library were searched up to December 2020. Results: Seven studies were ultimately included in this systematic review; some of them were eligible for multiple PICOS. The majority of the studies emerged from data extraction regarding cHL; less evidence resulted for DLBCL survivors. Five studies in favor of physical activity provided consistent data for a reduction of the cardiovascular risk in cHL and also in survivors who underwent ASCT. A beneficial effect of physical activity in reducing chronic fatigue was found. Being overweight was associated with a higher risk of coronary heart disease in cHL survivors in one of the two eligible studies. Studies aiming to evaluate the impact of the Mediterranean diet on late toxicities and secondary cancers were lacking. Tailored survivorship care plans (SCP) seemed to represent an optimal tool to guide the follow-up and promote healthier lifestyles in the one eligible study. Thus, promotion of healthy lifestyles and empowering of lymphoma survivors should be implemented through structured models. The study also brought to light numerous areas of future clinical research.

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 - NATURAL HISTORY OF CRYOGLOBULINEMIA FROM 2000 TO 2018 FROM THE LABORATORY POINT OF VIEW: AN ANALYSIS OF CRYOGLOBULIN CHARACTERISTICS IN A SINGLE CENTER. [Abstract in Atti di Convegno]
Sandri, Gilda; Spinella, A; Bari, A; Fontana, F; Trenti, ; Natali, Mascia MT P.; Debbia, D.; Campioli, D.; Amati, G.; Galassi, G.; Mazzoli, M.; Alfano, G.
abstract

2020 - Obinutuzumab and miniCHOP for unfit patients with diffuse large B-cell lymphoma. A phase II study by Fondazione Italiana Linfomi [Articolo su rivista]
Merli, Francesco; Cavallo, Federica; Salvi, Flavia; Tucci, Alessandra; Musuraca, Gerardo; Nassi, Luca; Merli, Michele; Tani, Monica; Gini, Guido; Ferrari, Angela; Molinari Anna, Lia; Liberati Anna, Marina; Conconi, Annarita; Matteucci, Paola; Bari, Alessia; Scalone, Renato; Ferrero, Simone; Zanni, Manuela; Mammi, Caterina; Luminari, Stefano
abstract

Objective: To evaluate activity and safety of obinutuzumab-miniCHOP (Ga101-miniCHOP) combination in older patients with Diffuse Large B-Cell Lymphoma (DLBCL) unfit to receive full dose immunochemotherapy. Materials and Methods: We conducted a Simon's two-stage phase II multicenter trial to investigate response rate (primary endpoint) and safety of six courses of Ga101-miniCHOP in older patients with DLBCL (≥65 years), prospectively defined as unfit according to a simplified Comprehensive Geriatric Assessment (sCGA). Results: Overall, 34 patients were enrolled (median age 82 years; range 68–89), with 27 out of the 33 eligible patients completing all six planned courses. Complete Remission (CR) rate was reported in fourteen patients (42%). After a median follow-up of sixteen months, the two-year Progression Free and Overall Survival (PFS and OS) were 49% (95% Confidence Interval (CI), 28 to 67) and 68% (95% CI, 49 to 81), respectively. The most frequent grade 3–4 adverse event was neutropenia in thirteen patients (26%). Conclusions: Based on the observed CR rate, study accrual was interrupted due to the very low probability of demonstrating the initial study hypothesis that Ga101-miniCHOP could improve results of historical data obtained with R-miniCHOP in this group of patients. Nonetheless, results achieved with the 33 treated patients confirm activity and good tolerability of the Ga101-miniCHOP regimen for older unfit adult patients with DLBCL.

2020 - The classic prognostic factors in advanced Hodgkin’s lymphoma patients are losing their meaning at the time of Pet-guided treatments [Articolo su rivista]
Bari, A.; Marcheselli, R.; Sacchi, S.; Re, A.; Pagani, C.; Tucci, A.; Botto, B.; Vitolo, U.; Molinari, A. L.; Puccini, B.; Pulsoni, A.; Santoro, A.; Tani, M.; Nassi, L.; Meli, E.; Pavone, V.; Bonfichi, M.; Evangelista, A.; Gioia, D.; Levis, A.; Zinzani, P.
abstract

The International Prognostic Score (IPS) is the most commonly used risk stratification tool for patients with advanced Hodgkin lymphoma (HL). It incorporates seven clinical parameters independently associated with a poorer outcome: male sex, age, stage IV, hemoglobin level, white blood cell and lymphocyte counts, and albumin level. Since the development of the IPS, there have been significant advances in therapy and supportive care. Recent studies suggest that the IPS is less discriminating due to improved outcomes with ABVD therapy. The aim of the present study was to asses if classic prognostic factors maintain their prognostic meaning at the time of response-adapted treatment based on interim PET scans. We evaluated the prognostic significance of IPS in the 520 advanced stage HL patients enrolled in the PET-guided, HD0801 trial in which PET2-positive patients underwent a more intense treatment with an early stem-cell transplantation after 2 cycles of ABVD. We observed that in these patients, the IPS completely loses its prognostic value together with all the single parameters that contribute to the IPS. Furthermore, neutrophils, monocytes, lymphocytes, and the ratio among them also no longer had any predictive value. We believe that the substantial improvement in survival outcomes in PET2-positive patients treated with early autologous transplantation could explain the complete disappearance of the residual prognostic significance of the IPS.

2019 - Clusterin enhances AKT2-mediated motility of normal and cancer prostate cells through a PTEN and PHLPP1 circuit [Articolo su rivista]
Bertacchini, Jessika; Mediani, Laura; Beretti, Francesca; Guida, Marianna; Ghalali, Aram; Brugnoli, Federica; Bertagnolo, Valeria; Petricoin, Emanuel; Poti, Francesco; Arioli, Jessica; Anselmi, Laura; Bari, Alessia; Mccubrey, James; Martelli, Alberto M.; Cocco, Lucio; Capitani, Silvano; Marmiroli, Sandra
abstract

Clusterin (CLU) is a chaperone-like protein with multiple functions. sCLU is frequently upregulated in prostate tumor cells after chemo- or radiotherapy and after surgical or pharmacological castration. Moreover, CLU has been documented to modulate the cellular homolog of murine thymoma virus akt8 oncogene (AKT) activity. Here, we investigated how CLU overexpression influences phosphatidylinositol 3′-kinase (PI3K)/AKT signaling in human normal and cancer epithelial prostate cells. Human prostate cells stably transfected with CLU were broadly profiled by reverse phase protein array (RPPA), with particular emphasis on the PI3K/AKT pathway. The effect of CLU overexpression on normal and cancer cell motility was also tested. Our results clearly indicate that CLU overexpression enhances phosphorylation of AKT restricted to isoform 2. Mechanistically, this can be explained by the finding that the phosphatase PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1), known to dephosphorylate AKT2 at S474, is markedly downregulated by CLU, whereas miR-190, a negative regulator of PHLPP1, is upregulated. Moreover, we found that phosphatase and tensin homolog (PTEN) was heavily phosphorylated at the inhibitory site S380, contributing to the hyperactivation of AKT signaling. By keeping AKT2 phosphorylation high, CLU dramatically enhances the migratory behavior of prostate epithelial cell lines with different migratory and invasive phenotypes, namely prostate normal epithelial 1A (PNT1A) and prostatic carcinoma 3 (PC3) cells. Altogether, our results unravel for the first time a circuit by which CLU can switch a low migration phenotype toward a high migration phenotype, through miR-190-dependent downmodulation of PHLPP1 expression and, in turn, stabilization of AKT2 phosphorylation.

2019 - The prognostic role of end of treatment FDG-PET-CT in patients with diffuse large B cell lymphoma can be improved by considering it with absolute monocyte count at diagnosis [Articolo su rivista]
Marcheselli, R.; Franceschetto, A.; Sacchi, S.; Bari, A.; Levy, I.; Pizzichini, P.; Prosperi, D.; D'Apollo, R.; Massi, L.; Casolo, A.; Pozzi, S.; Marcheselli, L.; Tadmor, T.; Prandini, N.; Cox, M. C.
abstract

It is well established that some patients with diffuse large B-cell lymphoma (DLBCL) and the negative end of treatment PET-CT (EOT-PET-CT) will relapse, while a proportion with positive uptake can still obtain long-term EFS. We reviewed data of 200 consecutive, previously untreated patients with DLBCL recorded in Italy and Israel between 2007 and 2015. We found that patients with negative EOT-PET-CT with AMC > 630/mmc have a 3-years EFS of 72%, compared to those with AMC ≤ 630/mmc that have an EFS of 84%. Furthermore, considering patients with positive EOT-PET-CT, those with AMC > 630/mmc have a 3-years EFS of 8%, while those with AMC ≤ 630/mmc have an EFS of 38%. Thus, it appears that combining the gold standard for response evaluation EOT-PET-CT with a simple and inexpensive parameter like AMC at diagnosis, further improves prognostication in DLBCL. Applying this simple method can be useful for all doctors working in lymphoma clinical practice.

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%)

2017 - A Multicenter Phase II Study of Twice-Weekly Bortezomib plus Rituximab in Patients with Relapsed Follicular Lymphoma: Long-Term Follow-Up [Articolo su rivista]
Bari, Alessia; Marcheselli, Raffaella; Marcheselli, Luigi; Alvarez, Isabel; Pozzi, Samantha; Ferri, Paola; Lazzaro, Antonio; Fragasso, Alberto; Neri, Santo; Baldini, Luca; Carella, Angelo Michele; Angrilli, Francesco; Guariglia, Roberto; Buda, Gabriele; Stelitano, Caterina; Sacchi, Stefano
abstract

Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control.

2017 - A concise review of lenalidomide therapy for follicular lymphoma [Articolo su rivista]
Bari, Alessia; Marcheselli, Raffaella; Barbolini, Monica; Ferri, Paola; Sacchi, Stefano; Pozzi, Samantha
abstract

Introduction: Lenalidomide, first introduced for the treatment of multiple myeloma in 2008, has been used in the treatment of various subtypes of non-Hodgkin lymphoma (NHL). Considering its mechanism of action, it has been associated with rituximab, showing strong activity in follicular lymphomas (FL). As the chemo-free treatments are a topic of great relevance we decided to prepare a concise review mainly directed to clinicians involved in the management of NHL patients. Areas covered: This article reviews the clinical trials published since 2008 utilizing lenalidomide alone or in combination for treating relapsed/refractory or treatment naïve patients with FL. Expert opinion: With current rituximab plus chemotherapy treatments, almost all patients will relapse from the disease over time. The introduction of lenalidomide in the management of FL showed good efficacy in particular in combination with rituximab (R2). The high rates of durable responses obtained with the R2 combination were similar to those previously observed with standard chemotherapy plus rituximab. If the results of the ongoing multicenter pivotal phase 3 trial (NCT01476787) are favorable for R2 combination, we may move towards a chemotherapy-free approach in the management of FL, which would finally turn a dream into reality.

2017 - Bendamustine, Low-dose dexamethasone, and lenalidomide (BdL) for the treatment of patients with relapsed/refractory multiple myeloma confirms very promising results in a phase I/II study. [Articolo su rivista]
Pozzi, Samantha; Gentile, M; Sacchi, Stefano; Marcheselli, Raffaella; Corso, A; Cocito, F; Musto, P; Guarini, A; Minoia, C; Vincelli, I; Ria, R; Rivolti, E; Mele, G; Bari, Alessia; Mazzone, C; Badiali, S; Marcheselli, Luigi; Palumbo, A; Morabito, F.
abstract

Lenalidomide and dexamethasone are an effective treatment for naïve and relapsed multiple myeloma (MM) patients. Bendamustine is a good option for B-cell malignancies showing only partial cross resistance with alkylating agents used in MM patients. Based on these considerations, we proposed a phase I/II study testing escalating doses of bendamustine and lenalidomide and fixed low doses of dexamethasone (BdL). Fifteen patients were enrolled in phase I study. Maximum tolerated dose was established at dose "level 0": bendamustine 40 mg/m2 days 1,2; lenalidomide 10 mg days 1-21; d 40 mg days 1,8,15,22 every 28-day cycle, for six cycles. We enrolled 23 patients in the phase II study. BdL combination showed mainly hematological toxicities, fever and infections. Overall response rate was 47%. After median follow up of 22 months, median PFS was 10 months. Two-years OS rate was 65%. BdL combination confirmed to be a promising treatment for patients with relapsed/refractory MM.

2017 - Empathic attitudes among nursing students: a preliminary study [Articolo su rivista]
Ferri, Paola; Rovesti, Sergio; Panzera, Nunzio; Marcheselli, Luigi; Bari, Alessia; Di Lorenzo, Rosaria
abstract

Background and aim: An empathic approach is fundamental for therapeutic relationship between nurse and patient. According to some researchers, female nursing students show higher empathic attitude in comparison with males, but both show a decline in empathy level as their studies progress. This preliminary study evaluated the self-reported emotional empathy level among undergraduate students at first and second year of nursing 3-year course. Method: To assess empathy level, the Balanced Emotional Empathy Scale (BEES) was administered to all students enrolled in the 2015/16 academic year (N=142), at the beginning of first year (T0) and at mid-point of second year (T1) of nursing course. Data were statistically analyzed. Results: 118 nursing students participated in the first and 99 in the second survey. The BEES global mean score for the longitudinal group (n=99) slightly decreased from T0 (mean=37.1±19.5 SD) to T1 (mean=33.5±22.6 SD) (t=1.20, p=0.23; t-test for paired data). Female students reported a statistically significant higher mean BEES score compared to male students in both surveys. Conclusions: Our preliminary data suggest a slight decline in empathy level among nursing students with the progress of study course, in accordance with previous studies. In particular, our study shows higher levels of empathy in female students and lower levels in male students, compared to other studies. Further surveys aimed at investigating the empathy attitude at the end of nursing course could confirm the decline tendency reported by this preliminary study. Other research focusing on the causes of empathy decline are necessary to explain this phenomenon.

2017 - Khorana score and histotype predicts incidence of early venous thromboembolism in Non-Hodgkin lymphomas: A Pooled-Data analysis of 12 clinical trials of fondazione italiana linfomi (FIL) [Articolo su rivista]
Santi, Roberto Mario; Ceccarelli, Manuela; Bernocco, Elisa; Monagheddu, Chiara; Evangelista, Andrea; Valeri, Federica; Monaco, Federico; Vitolo, Umberto; Cortelazzo, Sergio; Cabras, Maria Giuseppina; Spina, Michele; Baldini, Luca; Boccomini, Carola; Chiappella, Annalisa; Bari, Alessia; Luminari, Stefano; Visco, Carlo; Calabrese, Marco; Limberti, Giulia; Levis, Alessandro; Contino, Laura; Ciccone, Giovannino; Ladetto, Marco
abstract

Current data suggests that the risk of venous thromboembolism (VTE) in patients with non-Hodgkin lymphoma (NHL) is comparable to that observed in patients with solid tumours, although more robust confirmatory analyses are required. With that in mind, we investigated the occurrence of VTE in a pooled analysis of 12 “Fondazione Italiana Linfomi” (FIL) prospective clinical studies. Specifically, we wished to assess the cumulative incidence of VTE in NHL patients, evaluate the predictive value of the Khorana Score (KS), and identify other potential risk factors for VTEs. Data for VTE occurrence were retrieved from study databases and pharmacovigilance reports. Our analysis includes 1717 patients from 12 prospective phase II and III trials, including newly diagnosed NHL. We observed 53 VTEs (any grade) in 46 patients, with 20 severe VTEs in 17 patients. The cumulative incidences for „all-grade“ or grade ≥3 VTEs were 2.9 % (95 % CI: 2.1-3.8) and 1.1 % (95 % CI: 0.6-1.6), respectively. KS categories were positively associated with the risk of VTE of any grade, and with severe events (i. e. grade ≥3; Gray’s test p-values = 0.048 and 0.012, respectively). Among NHL patients, those with diffuse large B-cell lymphoma (DLBCL) showed a greater risk of (any grade) VTE (HR: 3.42, 95 % CI: 1.32-8.84, p-value = 0.011). Our study indicates that 1) VTE is a relevant complication for NHL patients, 2) KS is predictive of VTE events and 3) DLBCL histotype is an independent risk factor for VTE incidence, for which preventative interventions could be considered.

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 >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.

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 - Reduced intensity VEPEMB regimen compared with standard ABVD in elderly Hodgkin lymphoma patients: Results from a randomized trial on behalf of the Fondazione Italiana Linfomi (FIL) [Articolo su rivista]
Zallio, Francesco; Tamiazzo, Stefania; Monagheddu, Chiara; Merli, Francesco; Ilariucci, Fiorella; Stelitano, Caterina; Liberati, Anna Marina; Mannina, Donato; Vitolo, Umberto; Angelucci, Emanuele; Rota Scalabrini, Delia; Vallisa, Daniele; Bellei, Monica; Bari, Alessia; Ciccone, Giovannino; Salvi, Flavia; Levis, Alessandro
abstract

Survival rates for elderly Hodgkin Lymphoma (HL) have not improved substantially in recent years, mainly because of a lack of prospective randomized studies, due to difficulties in enrolling patients. Between 2002 and 2006, 54 untreated HL patients, aged between 65 and 80 years and considered 'non-frail' according to a comprehensive geriatric evaluation, were enrolled into a phase III randomized trial to compare a reduced-intensity regimen (vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone, bleomycin; VEPEMB) with standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Primary endpoint was progression-free survival (PFS). Seventeen patients were in early stage (I-IIA), while 37 were advanced stage. Median age was 72 years and median follow-up was 76 months. Five-year PFS rates were 48% vs. 70% [adjusted Hazard ratio (HR) = 2·19, 95% confidence interval (CI) = 0·94-5·10, P = 0·068] and 5-year overall survival (OS) rates were 63% vs. 77% (adjusted HR = 1·67, 95% CI = 0·69-4·03, P = 0·254) for VEPEMB compared to ABVD. Overall treatment-related mortality was 4%. World Health Organization grade 4 cardiac and lung toxicity occurred in four patients treated with ABVD versus no cases in the VEPEMB arm. Standard ABVD regimen resulted in better PFS and OS than the VEPEMB, although the differences were not statistically significant. The low toxicity of both treatments was probably attributable to stringent selection of patients based on a Comprehensive Geriatric Assessment that excluded frail patients.

2016 - Safety and efficacy of lenalidomide in combination with rituximab in recurrent indolent non-follicular lymphoma: Final results of a phase II study conducted by the Fondazione Italiana Linfomi [Articolo su rivista]
Sacchi, Stefano; Marcheselli, Raffaella; Bari, Alessia; Buda, Gabriele; Molinari, Anna Lia; Baldini, Luca; Vallisa, Daniele; Cesaretti, Marina; Musto, Pellegrino; Ronconi, Sonia; Specchia, Giorgina; Silvestris, Franco; Guardigni, Luciano; Ferrari, Angela; Chiapella, Annalisa; Carella, Angelo Michele; Santoro, Armando; Di Raimondo, Francesco; Marcheselli, Luigi; Pozzi, Samantha
abstract

Safety and efficacy of lenalidomide in combination with rituximab in recurrent indolent non-follicular lymphoma: final results of a phase II study conducted by the Fondazione Italiana Linfomi

2016 - The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and enhances tumor cell death in T-cell lymphoma cell lines [Articolo su rivista]
Cosenza, Maria; Civallero, Monica; Fiorcari, Stefania; Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Ferri, Paola; Sacchi, Stefano
abstract

We investigated the cytotoxic interactions of romidepsin, a histone deacetylase inhibitor, and lenalidomide, an immunomodulatory agent, in a T-cell lymphoma preclinical model. Hut-78 and Karpas-299 cells were treated with romidepsin and lenalidomide alone and in combination. The interaction between romidepsin and lenalidomide was evaluated by the Chou–Talalay method, and cell viability and clonogenicity were also evaluated. Apoptosis, reactive oxygen species (ROS) levels, and cell cycle distribution were determined by flow cytometry. ER stress, caspase activation, and the AKT, MAPK/ERK, and STAT-3 pathways were analyzed by Western blot. Combination treatment with romidepsin and lenalidomide had a synergistic effect in Hut-78 cells and an additive effect in Karpas-299 cells at 24 hours and did not decrease the viability of normal peripheral blood mononuclear cells. This drug combination induced apoptosis, increased ROS production, and activated caspase-8, −9, −3 and PARP. Apoptosis was associated with increased hallmarks of ER stress and activation of UPR sensors and was mediated by dephosphorylation of the AKT, MAPK/ERK, and STAT3 pathways.The combination of romidepsin and lenalidomide shows promise as a possible treatment for T-cell lymphoma. This work provides a basis for further studies.

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 - Activity of BKM120 and BEZ235 against lymphoma cells [Articolo su rivista]
Civallero, Monica; Cosenza, Maria; Pozzi, Samantha; Bari, Alessia; Ferri, Paola; Sacchi, Stefano
abstract

Non-Hodgkin lymphomas encompass a heterogeneous group of cancers, with 85-90% arising from B lymphocytes and the remainder deriving from T lymphocytes or NK lymphocytes. These tumors are molecularly and clinically heterogeneous, showing dramatically different responses and outcomes with standard therapies. Deregulated PI3K signaling is linked to oncogenesis and disease progression in hematologic malignancies and in a variety of solid tumors and apparently enhances resistance to antineoplastic therapy, resulting in a poor prognosis. Here, we have evaluated and compared the effects of the pan-PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitor BEZ235 onmantle, follicular, and T-cell lymphomas. Our results suggest that BKM120 and BEZ235 can effectively inhibit lymphoma cell proliferation by causing cell cycle arrest and can lead to cell death by inducing apoptosis and autophagy mediated by ROS accumulation. Despite great advances in lymphoma therapy after the introduction of monoclonal antibodies, many patients still die from disease progression. Therefore, novel treatment approaches are needed. BKM120 and BEZ235 alone and in combination are very effective against lymphoma cells in vitro. If further studies confirm their effectiveness in animal models, they may be promising candidates for development as new drugs.

2015 - Calcium-Carbonate Nanocapsules Improve the Efficacy of BEZ235 in Lymphoma a Cell Line: A Promising New Technology of Drug Delivery [Abstract in Rivista]
Civallero, Monica; Vergaro, Viviana; Citti, Cinzia; Cosenza, Maria; Cannazza, Giuseppe; Parenti, Carlo; Bari, Alessia; Ciccarella, Giuseppe; Sacchi, Stefano; Pozzi, Samantha
abstract

Nanotechnology is a promising branch of the medical field, directed to improve diagnostic and therapeutics strategies, applying nanovectors as drug delivery systems. Efficient encapsulation of anticancer drugs in nanocolloids and microcapsules was recently developed by G. Ciccarella research group (1). Based on our collaboration with the Nantional Nanotechnology Laboratory of the University of Salento and our previous experience with target therapies, we encapsulated BEZ235, a phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin inhibitor (mTOR). BEZ235 efficiently blocks the dysfunctional activation of the PI3K/mTOR pathway in cellular and in vivo settings, thus inhibiting the growth and proliferation of various cancer cells, and phase I/II clinical trials were open in solid cancer. However the scarse solubility limited further development of this promising compound. In order to overcome the solubility issue BEZ235-loaded nanocapsules were generated by the stepwise adsorption of oppositely charged polyelectrolytes into biocompatible CaCO3 cores. First nanocapsules were tested for biocompatibility. The exposition of lymphoma cell lines to empty nanocapsules up to 48 hours, did not induce any cititoxicity, confirming their biocompatibility. Second, encapsulated BEZ235 was compared with free-drug to test the cytotoxicity in a T lymphoma cell line (HUT78) by MTT assay. The results suggested that nanoencapsulated-BEZ235 was extremely efficient compared with free-BEZ235, reaching IC50 just after 5 hours of exposure compared with an IC65% at 48 hours with the free drug. A validated LC-MS/MS method was developed in order to quantify intracellular concentration of BEZ235 over time. Intracellular concentration of BEZ235 in the lymphoma cell line was consistent with biological results since the internalization kinetic and efficiency was increased by the coating. In order to confirm that the encapsuled-BEZ235 was still effective on cell apoptosis, we tested free BEZ and encapsulated BEZ235 at a concentration of 1µM in T cell lymphoma cell lines. Encapsulated-BEZ235 induced apoptosis evidenced by the cleavage of caspase 8, 9 and 3 at an earlier time point compared with free BEZ235 and at significantly lower concentration. We also confirmed that the encapsulated-BEZ235 maintained its effect on the target mTOR/AKT pathway: p-AKT was dephosphorylated at 5h while the free BEZ235 operates at least after 24 hours at concentrations 100 times higher, as previously demonstrated. Keeping in mind a future clinical application of these polymeric particles/capsules, our data can be regarded as a promising new nanotechnology-based strategy to improve the efficacy and bioavailability of old and new drugs. Functional biological studies of BEZ235-encapsulated carrier and its mechanism of internalization are already under way, and animal in vivo studies to evaluated toxicity and distribution of the nanocapsuled compound are ongoing.

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 - The combination of bortezomib with enzastaurin or lenalidomide enhances cytotoxicity in follicular and mantle cell lymphoma cell lines [Articolo su rivista]
Cosenza, Maria; Civallero, Monica; Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Sacchi, Stefano
abstract

We analyzed the combination of a proteasome inhibitor (bortezomib) with enzastaurin (PKC/AKT-inhibitor) or lenalidomide (immunomodulatory agent) for the inhibition of proliferation and induction of apoptosis in B-cell lymphoma cell lines and primary malignant cells. The effects of bortezomib, enzastaurin or lenalidomide, alone or in combinations, on cell viability and apoptosis were evaluated using the Cell Proliferation Kit and flow cytometry analysis. The interaction between drugs was examined by the Chou-Talalay method. Cell cycle analysis was performed by flow cytometry. The PI3K/AKT, PKC and MAPK/ERK signaling pathways were analyzed using western blot. Bortezomib with either enzastaurin or lenalidomide synergistically induced anti-proliferative and pro-apoptotic effects in B-cell lymphoma cells, even in the presence of the bone marrow microenvironment. The direct cytotoxicity is mediated by signaling events involving the PI3K/AKT, PKC and MAPK/ERK pathways leading to cell death. The significant increase of apoptosis was mediated by an increased ratio of pro-apoptotic proteins (Bax, Bad and Bim) to anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1), triggering the cleavage of caspases -3, -9, -8 and PARP. Further evaluation of the combination of bortezomib with enzastaurin or lenalidomide for the treatment of B-cell lymphoma is warranted, with the goal to improve the quality of life and survival of patients. Copyright © 2014 John Wiley &amp; Sons, Ltd.

2014 - Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ) [Capitolo/Saggio]
Pozzi, Samantha; Anesi, Alexandre; Generali, Luigi; Bari, Alessia; Consolo, Ugo; Chiarini, Luigi
abstract

Osteonecrosis of the jaw (ONJ) is a rare condition that has been mainly related to the treatment with i.v. bisphosphonates in patients affected by cancer bone disease. The ethiopathology is still unknown and the frequency is between 0.8 and 12 %. It can appear in edentulous patients, but invasive procedures have been demonstrated to increase the risk of developing this complication. Few cases have been described in the endodontic literature. In the next chapter, we will describe ONJ, will analyze the data from literature, and will report expert opinions and guidelines about the best clinical practice in the endodontic fi eld. Finally, since data in this field are limited, we would like to underline that the best treatment plan for cancer patients receiving bisphosphonates and requiring dental procedures is a multidisciplinary, case-by-case approach.

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 - Dialysis-dependent renal failure at diagnosis continues to be associated with very poor outcome in multiple myeloma - response to Murphy et al [Articolo su rivista]
Pozzi, Samantha; Bari, Alessia; Sacchi, Stefano
abstract

The study by Murphy et al supports the observation made by several groups regarding the benefit of the novel agents in both young and elderly patients affected by multiple myeloma (MM) (Kumar et al, 2008; Ludwig et al, 2008; Turesson et al, 2010; Pozzi et al, 2013). Their single institution data collected over 18 years in 262 patients shows an improvement in overall survival (OS) starting from 1995 with an OS not yet reached in the period 2007–2012, after the introduction of bortezomib in their clinical practice. However the study clearly highlights renal insufficiency as a very poor prognostic factor, with a median OS shorter than 1 year in patients requiring dialysis. In the past few years many attempts have been made to classify and stratify patients based on various refined biological characteristics, however, as clearly stated here, the clinical presentation, particularly organ damage, still represents a negative prognostic factor that not even modern medicine has been able to overcome. The introduction of the International Staging System Criteria (ISS) (Greipp et al, 2005) only indirectly takes renal function into account, while the Durie and Salmon Criteria differentiates stage ‘A’ and ‘B’ MM based on kidney damage (Durie & Salmon, 1975). However Durie-Salmon ‘B’ stage is based on a creatinine cut-off point of 177 lmol/l and it is unable to better differentiate between moderate and severe impairment of renal damage requiring dialysis. It is also unable to predict the response to the treatment and reversibility of the organ damage, between possibly transitory kidney impairment due to dehydration, hyperuricaemia and hypercalacemia, and cast nephropathy. In this subset of MM patients it would be beneficial to introduce further parameters in the staging system (i.e. glomerular filtrate; type of light chain) in order to better stratify the risks and prevent treatment-related toxicity. For this reason, ad hoc clinical trials for this group of patients are strongly needed (Haynes et al, 2012). Finally, the Murphy study highlights the selection of patients enrolled in clinical trials and the necessity to evaluate the survival in the population of every day clinical practice, together with the need to develop high resolution analysis from data collected by cancer registers. Moreover, early diagnosis, compared with late or misdiagnosis, especially for light chains MM, is mandatory to prevent severe organ damage.

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 - The potential of pralatrexate as a treatment of peripheral T-cell lymphoma [Articolo su rivista]
Dondi, Alessandra; Bari, Alessia; Pozzi, Samantha; Ferri, Paola; Sacchi, Stefano
abstract

INTRODUCTION: Peripheral T-cell lymphomas (PTCLs) are a group of rare malignancies originating from clonal proliferation of mature, post-thymic T cells that represent 10 - 15% of all non-Hodgkin's lymphomas with poor prognosis and median survival of 1 - 3 years. The standard treatment for PTCL has not yet been identified. Many patients with PTCL are refractory to first-line therapy. The complete response rate ranges from 36 to 66% according to different PTCL subtypes. Furthermore, those who reached a complete or partial response often have a shorter progression-free survival. AREAS COVERED: This paper discusses the potential of pralatrexate , a methotrexate analogue, as a treatment of PTCL. The authors report on the efficacy and safety data of controlled studies and describe the end points of ongoing trials. Pralatrexate was the first drug to obtain FDA approval for the treatment of patients with relapsed or refractory PTCL. However, the European Medicines Agency has refused marketing authorization. EXPERT OPINION: None of the treatments commonly used today have given satisfactory results. Pralatrexate seems to be one of the most promising agents in the treatment of patients with PTCL. Future efforts should be focused on better understanding the molecular pathogenesis of PTCL and on specific trials for different PTCL subtypes using rational drug combinations that include pralatrexate.

2014 - The undergraduate nursing student evaluation of clinical learning environment: an Italian survey [La valutazione dell'ambiente di apprendimento clinico da parte degli studenti del Corso di Laurea in Infermieristica: una indagine italiana] [Articolo su rivista]
Magnani, Daniela; DI LORENZO, Rosaria; Bari, Alessia; Pozzi, Samantha; DEL GIOVANE, Cinzia; Ferri, Paola
abstract

BACKGROUND: Nursing students have to deal with many different clinical and practical aspects of knowledge to become skilled professionals. Student perception may be considered an indicator of teaching quality, since positive perception of students is strictly related to their effective professional learning. The Clinical Learning Environment and Supervision plus Nurse Teacher (CLES+T) scale is considered the gold standard psychometric instrument to evaluate both the quality and the climate of clinical learning environment. AIMS: To evaluate the quality of nurse teaching by means of CLES+T scale and to highlight significant correlations between CLES+T scale and selected characteristics of both students and clinical environments. METHODS: On 4 March 2013, a cross-sectional survey was conducted at University of Modena: CLES+T scale was administered during a plenary convocation to 242 nursing students who attended the second and third years of Nursing Degree. All 34 items of the scale were statistically analysed using the median test. RESULTS: The median values were uniformly represented by "4" level (on the Likert scale). The final marks of clinical learning experience were the only variable statistically significantly related to the scale scores. The paediatrics and emergency areas obtained the highest scale scores. CONCLUSIONS: The nursing student evaluations were uniformly positive and related to their positive final marks. A positive ward atmosphere was identified as especially important in this study. These data indicate that a non-hostile and hospitable environment can favour the best clinical learning. We conclude that CLES+T scale can be a useful instrument to explore the clinical climate in all hospital areas and to highlight critical clinical situations.

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 - 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 - Rapid loss of response after withdrawal of treatment with azacitidine: A case series in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukemia [Articolo su rivista]
Voso, Maria Teresa; Breccia, Massimo; Lunghi, Monia; Poloni, Antonella; Niscola, Pasquale; Finelli, Carlo; Bari, Alessia; Musto, Pellegrino; Zambello, Renato; Fianchi, Luana; Alimena, Giuliana; Leone, Giuseppe
abstract

In patients with myelodysplastic syndromes (MDS), the likelihood of having a sustained response to azacitidine is increased by maximizing treatment duration. This is important as prognosis postrelapse is poor. There is also the concern that early termination of treatment may result in rapid disease progression. We reviewed outcomes in 13 patients who discontinued azacitidine (decitabine in one patient) while still responding to the treatment. Most patients rapidly relapsed; median time to progression was 5.4 months. Reasons for treatment discontinuation included comorbidities, infections, and patient choice. These findings illustrate the risk of prematurely terminating azacitidine therapy in MDS. © 2013 John Wiley & Sons A/S.

2013 - Rituximab maintenance compared with observation after brief first-line R-FND chemoimmunotherapy with rituximab consolidation in patients age older than 60 years with advanced follicular lymphoma: A phase III randomized study by the fondazione Italiana linfomi [Articolo su rivista]
Vitolo, Umberto; Ladetto, Marco; Boccomini, Carola; Botto, Barbara; Chiappella, Annalisa; Evangelista, Andrea; Lobetti-Bodoni, Chiara; Ciccone, Giovannino; Baldini, Luca; De Angelis, Federico; Tucci, Alessandra; Rossi, Giuseppe; Chiarenza, Annalisa; Pinto, Antonello; De Renzo, Amalia; Zaja, Francesco; Castellino, Claudia; Bari, Alessia; De Celis, Isabel Alvarez; Parvis, Guido; Gamba, Enrica
abstract

Purpose To evaluate the efficacy of rituximab maintenance in 60-to 75-year-old patients with advanced follicular lymphoma responding to brief first-line chemoimmunotherapy followed by rituximab consolidation. Patients and Methods A total of 234 treatment-naive 60-to 75-year-old patients began chemoimmunotherapy with four monthly courses of rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) followed by four weekly cycles of rituximab consolidation. Of these, 210 patients completed the planned treatment, and 202 responders were randomly assigned to rituximab maintenance (arm A) for 8 months, once every 2 months for a total of four doses, or to observation (arm B). Results Median ages in arms A and B were 66 and 65 years, respectively. After induction and consolidation therapy, the overall response rate was 86%, with 69% complete remissions (CR). After a 42-month median follow-up from diagnosis, 3-year progression-free survival (PFS; the primary end point) and overall survival (OS) were 66% (95% CI, 59% to 72%) and 89% (95% CI, 85% to 93%), respectively. After randomization, 2-year PFS was 81% for rituximab maintenance versus 69% for observation, with a hazard ratio of 0.74 (95% CI, 0.45 to 1.21; P.226), although this was not statistically significant. No differences between the two arms were detected for OS. Overall, the regimen was well-tolerated. The most frequent grade 3 to 4 toxicity was neutropenia (25% of treatment courses), with 13 infections. Two toxic deaths (0.8%) occurred during induction treatment. Conclusion A brief R-FND induction plus rituximab consolidation achieved excellent results with high CR and PFS rates, supporting the feasibility of this regimen in patients older than 60 years. A short rituximab maintenance did not achieve a statistically significant PFS improvement over observation.

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.

2012 - Combination of low doses of Enzastaurin and Lenalidomide has synergistic activity in B-non-Hodgkin lymphoma cell lines [Articolo su rivista]
Cosenza, Maria; Civallero, Monica; Grisendi, Giulia; Marcheselli, Luigi; Roat, Erika; Bari, Alessia; Sacchi, Stefano
abstract

Less toxic and more active treatments are needed for indolent lymphomas as there is no curative treatment, and patients eventually die due to complications related to their disease. The purpose of the present study was to assess the antitumour activity of the combination of low doses of Enzastaurin and Lenalidomide (Revlimid) on B-lymphoma cell lines. The combination of Enzastaurin and Lenalidomide, at doses as low as 1 μM, showed strong synergism against indolent lymphomas by reducing cell growth, producing an increase in G0-G1 phase followed by significant decrease in S phase, increasing apoptosis, and inhibiting PI3K/AKT, PKC and MAPK/ERK pathways. These preclinical findings, together with promising results obtained with Lenalidomide for the treatment of non-Hodgkin lymphoma, suggest that further evaluation of the combination of Enzastaurin and Lenalidomide for the treatment of indolent lymphomas is warranted. These compounds, with a favourable toxicity profile, are not classic chemotherapeutic agents, causing severe side effects, and could be considered an example of a new innovative attempt of an anti-cancer 'soft treatment'.

2011 - Genomic profiling of enzastaurin-treated B cell lymphoma RL cells [Articolo su rivista]
Civallero, Monica; Cosenza, Maria; Neri, Antonino; Bari, Alessia
abstract

No abstract is available for this article.

2011 - Radiation therapy improves treatment outcome in patients with diffuse large B-cell lymphoma [Articolo su rivista]
Marcheselli, Luigi; Marcheselli, Raffaella; Bari, Alessia; Liardo, ELIANA VALENTINA; Morabito, F; Baldini, Luca; Brugiatelli, M; Merli, F; Di Renzo, N; Sacchi, Stefano
abstract

The effects of radiotherapy (RT) after chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) remain unclear; several trials have yielded conflicting results. This study examined the effect of RT after cyclophosphamide, doxorubicin, vincristine, and prednisone + rituximab (R-CHOP) treatment on event-free (EFS) and overall (OS) survival. Data from 216 patients with DLBCL who were enrolled in two clinical trials at Italian Lymphoma Study Group sites and were subjected to six R-CHOP cycles and involved-field radiotherapy (IFRT) were retrospectively analyzed. IFRT treatment yielded significant EFS benefit, with a 66% reduction in the risk of death and/or disease progression. Cox analysis, when adjusted for age, gender, stage, performance status (PS), lactate dehydrogenase (LDH), and disease bulk, confirmed the significant EFS benefit of IFRT. The role of RT in DLBCL in the rituximab era is unclear. Future studies must take into account new radiation techniques and the response to chemotherapy based on functional imaging. Prospective randomized trials incorporating response-adapted therapy and modern radiation techniques are needed.

2011 - Rational combinations of enzastaurin with novel targeted agents for patients with B-cell non-Hodgkin's lymphoma [Articolo su rivista]
Civallero, Monica; Cosenza, Maria; Bari, Alessia; Sacchi, Stefano
abstract

Non-Hodgkin’s lymphoma (NHL) is the most common hematologic malignant neoplasm in adults. Combination chemotherapy regimens have been the main-stay of treatment for NHL for several decades. In the 1990s, the introduction of rituximab marked the beginning of the era of immunotherapy with monoclonal antibodies and revolutionized the treatment of B-cell NHL (B-NHL). Chemotherapy combined with anti-CD20 monoclonal antibodies has improved survival in both indolent and aggressive B-NHL; this combination has become the standard of care for these patients. However, a substantial subset of patients does not achieve a cure or long-term disease remission. In recent years, advances in the knowledge of NHL biology have improved our understanding of cell growth, proliferation and cell death in malignant cells. This has promoted the identification of new targeted treatments and new agents that have shown promising efficacy for future B-NHL therapies. Protein kinase C beta (PKC-b), a serine/threonine kinase, is involved in several signal transduction pathways, from differentiation and cell growth to survival and cell migration. It has been shown that PKC-b isoverexpressed in 20-25% of diffuse large B-cell lymphomas (DLBCLs) at diagnosis and 90% of DLBCLs at relapse. Therefore, PKC represents a potential targeted therapy for lymphomas. Enzastaurin (LY317615.HCl), an acyclic bisindolylmaleimide,is one of several new molecules directed against PKC-b. Enzastaurin is an ATP-competitive selective inhibitor of PKC. Enzastaurin suppresses the phosphoinositide 3-kinase (PI3K)/acutely transforming retrovirus (AKT) pathway,which blocks the phosphorylation of glycogen synthase kinase 3 beta (GSK3-b), mammalian target of rapamycin (mTOR) and ribosomal protein S6. It also suppresses cyclin D1 synthesis, induces dephosphorylation of p90 and ribosomal S6 kinase (RSK), regulates the MAPK pathway and seems to be involved inthe interferon-regulated JAK/STAT pathways. Furthermore, it affects BAD, a pro-apoptotic member of the Bcl-2 family proteins, which is particularly important in lymphoma.Based on promising preclinical results and the good tolerability profile, enzastaurin has been introduced in clinical trials as a treatment for patients. Enzastaurin has been used alone or in combination with other agents in more than 40 clinical trials (source: www.clinicaltrials.gov), and 9 of these focused on indolent or aggressive NHL.....

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 - Therapy-related myeloid neoplasm in non-hodgkin lymphoma survivors. [Articolo su rivista]
Bari, Alessia; Marcheselli, Luigi; Marcheselli, Raffaella; Liardo, Ev; Pozzi, Samantha; Ferri, Paola; Sacchi, Stefano
abstract

Relatively little data on secondary cancers is available regarding patients treated for non-Hodgkin lymphoma (NHL), compared with those treated for Hodgkin lymphoma. Evolving treatment regimens have improved survival outcomes for NHL patients. As a result of this improvement, secondary malignancies are becoming an important issue in NHL survivors. This review aims to report data on this topic previously published by our group, adding unpublished results from the Modena Cancer Registry (MCR). We recently performed four studies about secondary neoplasms in NHL survivors: two studies analysing the risk of secondary neoplasms in patients treated for indolent and aggressive NHL; a meta-analysis of 23 studies investigating the risk of secondary malignant neoplasm (SMN) after NHL treatment; and a still-unpublished study evaluating the incidence of therapy-related myeloid neoplasm (t-MN) in patients treated for NHL (from the MCR database). The first two studies analysed 563 patients with indolent NHL and 1280 patients with diffuse large B-cell lymphoma (DLBCL) enrolled in the Gruppo Italiano Studio Linfomi (GISL) trials. Results showed that the cumulative incidence of secondary tumours was 10.5% at 12 years for indolent NHL and 8.2% at 15 years for DLBCL. Results of the meta-analysis indicated that NHL patients experienced a 1.88-fold increased risk for SMN compared with the general population; the standardized incidence risk (SIR) for secondary acute myeloid leukaemia (AML) was 11.07. Based on data from the MCR from 2000 through 2008, we found that the SIR was 1.63 for developing a secondary malignancy after NHL, and 1.99 for developing secondary haematological malignancies. Regarding myelodysplastic syndrome and/or AML incidence, nine NHL patients developed t-MN with a higher risk than expected (SIR 8.8, 95% CI: 4.0-16.6). In conclusion, patients treated for NHL are at increased risk of developing SMN. Regarding t-MN, data from the meta-analysis and the MCR demonstrate an excessive risk of developing AML (SIR 11.07 and 5.7, respectively) compared with solid SMN after treatment for NHL. Thus long-term monitoring should be considered for NHL survivors.

2010 - Phase II Study of Velcade (R) Plus Mabthera (R) In Relapsed Follicular Lymphomas. [Abstract in Rivista]
Sacchi, Stefano; Marcheselli, Raffaella; Bari, Alessia; Liardo, ELIANA VALENTINA; Luminari, Stefano; F., Merli; A., Lazzaro; S., Neri; A. M., Carella; A., Fragasso; S., Falorio; G., Buda; P., Musto; M., Dell'Olio; L., Baldini
abstract

Background: Velcade ® (V) and Mabthera ® (M) have demonstrated an individual considerable efficacy in the treatment of non Hodgkin’s lymphoma. The aim of this study was to evaluate the efficacy and safety of the combination of V and M in patients with relapsed Follicular lymphoma (FL). Methods: Patients (pts) with histologic documentation of CD20+ FL , measurable and active disease, received : 1.3 mg/m2 of V on days 1-4-8-11 every 21 days for 6 cycle and M 375 mg/m2 on day 1 of each cycle from cycle III to VI. Two additional doses of M were administered alone after cycle VI, every 21 days (cycle VII and VIII). Response was assessed after 2 and 8 cycles using the NCI recommendations for Non-Hodgkin’s Lymphomas. Results: At the time of current analysis, initial planned accrual of 41 evaluable pts was not completed. From 2007 to now 37 pts entered into the trial. The pts characteristics at baseline were: median age 66 years (range: 46-84), male 51% , stage IV 43 % elevated values of LDH, 27%, and of Beta2microglobulin 41%. The FLIPI score was calculated in 34 pts (92%) and 11 pts (31%) had a poor prognostic score (> 3). The median number of previous immuno/chemotherapy regimens was 2 (range:1-3), and the median duration of last remission before registration into trial was 23 months (range: 3-67). In four out of the 37 pts who entered into the trial, the treatment is ongoing and thirty-three pts were evaluable for response. The overall response rate in the intent to treat analysis was 58% (19 pts ), of which 16 pts (49%) obtained complete response (CR) and 3 (9%) partial response (PR). Stable disease was seen in 1 pt (3%). Eight pts (24%) had progressive disease and 2 (6%) pts were lost at follow-up. Three pts (9%) had to stop the treatment: one pt (3%) for grade IV peripheral neuropathy, one pt (3%) refused to continue the treatment after 2 cycle and one pt (3%) died during the treatment for toxicity . After a median follow up of 14 month (0-44), the median overall survival and the event free survival were not reached. Overall, 2 pts relapsed (10 %) and 1 pt (5 %) showed a progression of disease. A total of five pts died, four because of lymphoma progression, and one for toxicity during treatment. Complete response are ongoing in 14 pts . Toxicity was evaluable in 33 patients. We observed the following grade 1/2 adverse events: neuropathy (10 pts), neutropenia (2 pts), infection (5 pts), constipation (4 pts), rash (2 pts), fatigue (1 pt). Further we saw the following grade 3/4 adverse events: thrombocytopenia (5 pts), neuropathy (5 pts), neutropenia (1 pt) and infection with fever(1 pt). Three patient interrupted the treatment due to severe neuropathy. Conclusions: The combination of V+M is associated with acceptable toxicity and a promising percentage of response. Further follow-up is required to evaluate the response duration and survival in the whole group of patients

2009 - A RANDOMIZED PHASE II STUDY (GISL - MM03 TRIAL) WITH ORAL MELPHALAN+ PREDNISONE (MP) VERSUS MELPHALAN, + PREDNISONE + THALIDOMIDE (MPT) FOR NEWLY DIAGNOSED ELDERLY PATIENTS WITH MULTIPLE MYELOMA [Abstract in Rivista]
Sacchi, Stefano; Marcheselli, Raffaella; Pozzi, Samantha; Bari, Alessia; O., Ciarcia; L., Masini; A., Lazzaro; F., Morabito; A., Fragasso; N., Di Renzo; G., Quarta; G., Buda; P., Musto; M. L., Vigliotti; A., Pastorini; M., Brugiatelli
abstract

Background. Several papers showed that MPT compared with MP improved response and survival outcomes. However, side effects increase and toxicity, as neutropenia, neuropathy, deep-vein thrombosis, depression and constipation reduce patients compliance. Thus, several patients have to discontinue or reduce the dose of Thalidomide. Aims. Aim of our research is to verify these results in a group of 128 patients not eligible for high dose treatment with stem cells support. Patients and Methods. The MM03 trial was approved by Ethical Committee of Modena and registered at Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali at the end 2004. A total of 128 patients were enrolled between January 2005 to October 2008: 53% entered MPT arm. Median age of patients were 75 years (range: 63-88 yrs), 50% were female, 55% had Durie and Salmon stage II and 45% had stage III. Distribution of M spike were: 67%, 22% and 11% for IgG, IgA and urine light chains. Univariate analysis of variables at baseline did not show any difference between the two arms. In arm A Melphalan was given at a dose of 0.25 mg/kg and Prednisone 60 mg/m2 for 4 days every 28 days; in arm B Thalidomide was added at a dose of 100 mg every day; a maximum of ten cycles was planned. At the end of induction therapy, 26 patients who had obtained Complete Response, Partial Response, Minimal Response or Stable disease were randomized for maintenance with Dexamethasone 20 mg, day 1-4 every 28 days or Dexamethasone at the same dose plus Thalidomide 100 mg/day every day. Only 14 patients follow this indication and assumed maintenance treatment for 6-12 months; no differences were observed between the 2 arm of maintenance. The use of growth factors, was at treating physicians discretion. Starting from May 2005 enoxiparin was recommended during the first 4 cycles of MPT arm. Results. Of 128 patients, 91 patients are evaluable for response while 20 are still on treatment. The response, including MR among all patients who entered protocol were 76%, while 9% had SD and 15% presented PD. Considering separately the two arm, we observed in arm A 12% CR, 43% PR, 9% MR, 3% SD and 23% PD and in arm B 18% CR, 57% PR, 11% MR, 5% SD and 9% PD. A comparison between 55% of CR plus PR in arm A with 75% in arm B shows a p=0.049, showing an advantage for MPT arm. After a median follow up of 14 months, median Overall Survival at 24 months are not still reached. During treatment or progression 24 patients died. Grade III/IV adverse events were: 6 deep-vein thrombosis, all in MPT arm, 1 during enoxaparin prophylaxis, 1 pneumonitis, 6 neutropenia, 3 neurotoxicities, 3 constipation. Conclusions. Our results show that the addition of Thalidomide to MP improve number and quality of response. We are still collecting data for a better definition of OS, FFS and toxicity in arm A in comparison with arm B, and they will be presented during the meeting

2009 - Anthracycline-fludarabine-containing regimens with or without rituximab in the treatment of patients with advanced follicular lymphoma. [Articolo su rivista]
Luminari, Stefano; Marcheselli, Luigi; Sacchi, Stefano; Pozzi, Samantha; Bari, Alessia; F., Ilariucci; C., Stelitano; F., Angrilli; A., Lazzaro; L., Baldini
abstract

BACKGROUND:: Recent experience has suggested that there has been a stepwise improvement in the survival outcomes of patients who have follicular lymphoma with the introduction of new treatment options. In the current study, the authors report the results of 2 subsequent phase 2 trials of 238 previously untreated patients. METHODS:: In a trial of bleomycin, epidoxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP) plus fludarabine, mitoxantrone, and dexamethasone (FND), 144 patients received 2 BACOP treatments followed by 4 FND treatments. In a trial of BACOP plus fludarabine and rituximab (FR), 94 patients received 3 BACOP treatments followed by 4 FR treatments. RESULTS:: The complete remission (CR) rate for BACOP/FND was 62\%. After a median follow-up of 60 months, the failure-free survival (FFS) and overall survival (OS) rates at 4 years were 53\% and 77\%, respectively. The CR rate for BACOP/FR was 79\%. After a median follow-up of 36 months, the FFS and OS rates at 4 years were 56\% and 97\%, respectively, which were significant compared with the CR and OS rates achieved with BACOP/FND. Twenty-five of 42 bcl-2-positive patients attained a molecularly negative CR and had improved FFS. No significant differences were observed between the 2 trials in the percentage of infections or neutropenia. CONCLUSIONS:: The CR and OS rates achieved with BACOP/FR were better, and overall toxicity did not increase. Furthermore, patients who received rituximab had a better FFS compared with patients who received chemotherapy alone. Finally, although conclusions between nonrandomized groups may depend on differences in observed and unobserved prognostic features, the current results suggested that the addition of rituximab to anthracycline-fludarabine-containing regimens have a favorable effect on the prognosis of patients with advanced follicular lymphoma. Cancer 2009. (c) 2009 American Cancer Society.

2009 - Prognostic models for diffuse large B-cell lymphoma in the rituximab era: a never-ending story. [Articolo su rivista]
Bari, Alessia; Marcheselli, Luigi; Sacchi, Stefano; Marcheselli, Raffaella; Pozzi, Samantha; Ferri, Paola; Balleari, E; Musto, P; Neri, S; Aloe Spiriti, Ma; Cox, M. C.
abstract

BACKGROUND: Improved treatment have modified survival outcome in patients with diffuse large B-cell lymphoma (DLBCL) and altered the importance of previously recognized prognostic markers.DESIGN AND METHODS: To evaluate International Prognostic Index (IPI) score before and after rituximab introduction and to validate the absolute lymphocyte count (ALC)/revised International Prognostic Index (R-IPI) model, we carried out a retrospective analysis on a total of 831 patients with DLBCL.RESULTS: Our results show that IPI lost its discriminating power with the introduction of rituximab. The analysis of our second set allowed us to validate the ALC/R-IPI model. The R-IPI and ALC/R-IPI could still be used for designing clinical trials, but both have difficulty recognizing a high percentage of poor prognosis patients, though it remains an important goal of a good prognostic model considering the modest impact of salvage treatments on survival.CONCLUSIONS: A new model on the basis of significant variables in the rituximab era and built on a large database of patients treated with rituximab is urgently needed. As prognostic models are changing with the efficacy and mechanisms of action of treatment utilized, looking for a new prognostic score is a never-ending story in which researchers are trying to hit a continuously moving target.

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 - VALIDATION OF ABSOLUTE LYMPHOCYTE COUNT / REVISED IPI (ALC/R-IPI) SCORE MODEL, AS A PROGNOSTIC INDEX FOR DIFFUSE LARGE-B-CELL LYMPHOMA IN RITUXIMAB ERA [Abstract in Rivista]
F., Mendicino; Marcheselli, Luigi; Bari, Alessia; Marcheselli, Raffaella; S., Falorio; G., Polimeno; M. C., Cox
abstract

Background. The International prognostic index (IPI), since its publication in 1993, became the primary prognostic tool for patients with DIFFUSE LARGE B-CELL LTMPHOMA (DLBCL). However, the introduction of rituximab (R) has improved patients outcomes and has partially changed the predictive capacity of IPI. In 2007, in the R era, a most accurate prognostic index, termed revised IPI (R-IPI) was proposed by Sehn et al. More recently, Cox et al. showed that absolute lymphocyte count (ALC), at diagnosis has a prognostic impact and it is independent from R-IPI. Thus, they have built-up a score, termed ALC/R-IPI, incorporating both parameters (low risk=ALC≥0.84 109/L and R-IPI very good or good, intermediate risk= ALC<0.84 109/L or R-IPI poor; high risk= ALC<0.84 109/L and R-IPI poor). Aim of our research, utilizing Gruppo Italiano Studio Linfomi (GISL) database is to validate the ALC/R-IPI model on a second larger independent patients data set like the GISL database. Methods and Results. From GISL database we collected data of 831 DLBCL patients, of which 560 treated with chemotherapy alone (1988-2003) and 271 treated with R-containing chemotherapy regimens (2003-2007). We have used the Kaplan-Meier curves, c-Harrell concordance index and the Cox proportional hazard regression to evaluate the ability of ALC/R-IPI to discern patients having good or poor survival. The median age of the 271 cases treated with R was 69 years and 51% were male. At diagnosis, 62% were in stage III/IV, 49% had LDH>UNL, 16% a PS>1, 26% had extranodal sites>1 and 26% presented with ALC<0.84 109/L. The distribution of patients in R-IPI was 7%, 48% and 45% in very good (VG), good (G) and poor (P) groups, respectively. The distribution in ALC/R-IPI was 47%, 42% and 11% in low (L), intermediate (I) and high (H) risk groups, respectively. The OS at 3-years was 88%, 64% and 39% in L, I and H risk groups, with significative differences (p<0.001). The HR were: I vs L = 3.7 (p<0.001); H vs I = 2.1 (p=0.012), while the c-Harrell was = 0.71 (CI95% 0.65-0.76). Conclusions. The ALC/R-IPI showed a good ability to discriminate the prognosis of patients in term of OS in our data base. ALC was confirmed as a specific prognostic factor for DLBCL in R era

2008 - : Late toxicity and quality of life (QOL) after treatment for Hodgkin disease (HD): A Gruppo Italiano Studio Linfomi (GISL) cohort study on 223 patients [Abstract in Rivista]
M., Vigliotti; G., Abbadessa; G., Gentile; F., Gentile; C., Stelitano; G., Ianni; P., Gobbi; F., Valentino; F., Merli; E., Barbolini; E., Iannitto; E., Eliardo; A., Lazzaro; C., Mammi; Bari, Alessia; Marcheselli, Raffaella; Sacchi, Stefano
abstract

Background: Because of successful treatment, a large number of HD patients becomelong term survivors and remain at life-long risk for late sequelae that could impairQOL. Aims of this study were to assess late toxicity and to evaluate the QOL.Patients and Method: GISL maintains a central database on characteristics, treatments,outcome and follow up (FU) of patients who entered clinical trial. For thisretrospective study, we extracted data on 223 patients. To evaluate QOL patients weregiven a questionnaire with 21 items, evaluating different psychical spheres, includingrelational, affective, emotional and behaviour areas.Result: 208 patients achieved complete response (CR); relapses occurred in 35 patientsof which16 obtained a 2 CR. After a median FU of 149 months, 168 patients are aliveand 53 died: 22 for progressive disease, 14 for 2 tumours, 6 for cardiac disease, 3 forrespiratory failure, 2 for infection and 6 for unknown causes. Two patients were lost atFU. Overall, late toxicity was observed in 82 patients of which 29 developed a 2tumours and 51 non-malignant toxicity, including cardiac and pulmonary diseases,endocrinal dysfunction, fertility anomalies, gastric disturbances and infections. Theevaluation of QOL is still ongoing and at this time 92 patients have filled out thequestionnaire, principally reporting alteration of adaptation and relational spheres.Conclusion: Late sequelae is an important concern, in particular because of the highnumber of 2 cancer and cardiac and pulmonary diseases. Further, although our dataon QOL are still incomplete, they showed that side effects may heavily impact on QOL,worsening adaptation and relational spheres. An accurate evaluation of late sequelaeand its impact on QOL is important in order to balance treatment efficacy and toxicity.

2008 - Anthracycline-Fludarabine Containing Regimens with or without Rituximab in the Treatment of Advanced Follicular Lymphoma Patients [Abstract in Rivista]
Sacchi, Stefano; Marcheselli, Luigi; Pozzi, Samantha; Bari, Alessia; Luminari, Stefano; F., Ilariucci; C., Stelitano; F., Angrilli; A., Lazzaro; L., Baldini; M., Spriano; G., Caparrotti; M., Musso; G., Quarta; M., Brugiatelli
abstract

Introduction Recent experiences suggest a stepwise improvement in survival outcomes for patients with follicular lymphoma with the introduction of new treatment options. Here we report the results of 2 subsequent phase II trials conducted by Gruppo Italiano Studio Linfomi (GISL) utilizing CHOP-like plus fludarabine regimens with or without rituximab. Our results confirm an improvement in CR rate and show better survival with the addition of rituximab.Materials and MethodsThe BACOP/FND study (bleomycin, epidoxorubicin, cyclophosphamide, vincristine, prednisone/ fludarabine, mitoxantrone, dexamethasone), registered 144 patients between 1997 and 2002. After 2 BACOP, patients received 4 cycles of FND. Then, responsive patients were randomized to observation or to receive alpha-IFN + dexamethasone. The BACOP/FR ( BACOP + fludarabine and rituximab) study registered 94 patients between 2002 and 2006. After 3 BACOP, patients in PR or in CR BCL2+ , received 4 cycles of FR. For both trials, eligible patients had histological documented, previously untreated, advanced follicular lymphoma. ResultsBACOP/FND. Response rates by intent to treat analysis were: ORR 90%, CR 62%. No differences were observed in FFS and OS between the 2 arms of maintenance. At the time of the last follow up, 35 patients had died, 5 lost at follow up, while 85 patients are still alive, 81 with ongoing response and 4 with progressive disease. After a median follow up of 60 months, FFS and OS were 53% and 77% at 4 years, respectively. BACOP/FR . Response rates by intent to treat analysis were: ORR 93%, CR 79%. At the time of the last follow up, 3 patients had died, 3 patients were lost at follow up, 60 are still alive with ongoing response and 14 with progressive disease. After a median follow up of 36 months , FFS and OS at 4 years were 56% and 97%, respectively. PCR assay for BCL2. Forty two of the 80 patients were found to be positive for BCL2 in the bone marrow obtained prior to treatment. Of these 42 patients, 25 obtained CR molecularly negative. We observed an improved FFS rate in patients who became BCL negative after treatment.Toxicity. The most common toxicities were infections and neutropenia. Overall, the haematological toxicities were transient and reversible. Comparison between the results of the two trials. We observed a CR rate of 62% and 79% and an OS at 4 years of 77% and 97%, respectively in BACOP/FND versus BACOP/FR, and the differences were statistically significant. Side effects were more frequent in BACOP/FND, however, no significant differences were observed between the 2 trials.DiscussionThe results obtained with BACOP/FR in comparison with those with BACOP/FND were better in terms of response and overall survival, while overall toxicity did not increase, remaining transient and tolerable. Patients who obtained BCL2 clearance in BACOP/FR showed a better FFS in comparison with patients treated with BACOP/FND. Further, patients treated with rituximab had a better FFS in comparison with all other patients treated only with chemotherapy. Finally, although conclusion between non randomized groups may depend in differences in observed and unobserved prognostic features, we believe that statistical analysis of our results, suggest that the addition of rituximab to anthracycline-fludarabine containing chemotherapy regimen has a favourable effect on prognosis of advanced follicular lymphoma

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 - 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 - Secondary malignancies after treatment for indolent non-Hodgkin's lymphoma: A 16-year follow-up study [Articolo su rivista]
Sacchi, Stefano; Marcheselli, Luigi; Bari, Alessia; Marcheselli, Raffaella; Pozzi, Samantha; Luminari, Stefano; Lombardo, M; Buda, G; Lazzaro, A; Gobbi, Pg; Stelitano, C; Morabito, F; Quarta, G; Brugiatelli, M.
abstract

Relatively little information is available on the incidence of secondary cancer in non-Hodgkin's lymphoma. The aim of this long-term follow-up study was to determine the incidence, the time free of second tumors, and risk factors for developing secondary cancer in a homogeneous group of patients with non-Hodgkin's lymphoma. DESIGN AND METHODS: We evaluated a total of 563 patients with indolent non-Hodgkin's lymphoma enrolled in Gruppo Italiano Studio Linfomi trials from 1988 to 2003. RESULTS: After a median follow-up of 62 months, 39 patients (6.9%) developed secondary cancer: 12 myelodysplastic syndromes/acute myeloid leukemia, and 27 solid tumors. The overall standardized incidence ratio of secondary malignancy in patients with non-Hodgkin's lymphoma was higher than the risk of malignancy in the general population. The standardized incidence ratio was elevated in male patients and in patients under 65 years old at first treatment. Overall, the cumulative incidence of secondary cancer at 12 years was 10.5%, after correction in a competing-risk model. Univariate and multivariate Cox regression analyses showed that older age at the time of diagnosis, male sex, and fludarabine-containing therapy had significant negative impacts on the time free of second tumors. CONCLUSIONS: We have identified subgroups of non-Hodgkin's lymphoma patients with increased standardized incidence ratios of secondary malignancy and variables that have a negative impact on the time free of second tumors. This information could help physicians to select the most appropriate treatments. Finally, taking into account the possible occurrence of secondary neoplasia, long-term monitoring must be considered.

2008 - Treatment of patients with recurrent follicular lymphoma with rituximab in combination with fludarabine and cyclophosphamide [Articolo su rivista]
Sacchi, S.; Marcheselli, L; Marcheselli, R; Bari, A; Ciancia, O.
abstract

[No abstract available

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 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, 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 - Introduction of rituximab in front-line and salvage therapies has improved outcome of advanced-stage follicular lymphoma patients [Articolo su rivista]
Sacchi, Stefano; Pozzi, Samantha; Marcheselli, Luigi; Bari, Alessia; Luminari, Stefano; F., Angrilli; F., Merli; D., Vallisa; L., Baldini; M., Brugiatelli; I. L., Study Group
abstract

BACKGROUND: It is unclear whether new treatment modalities have improved the survival of follicular lymphoma patients. Some data show that there has been no improvement in survival in the last 3 decades of the 20th century, whereas the results of recent retrospective studies suggest that evolving therapy has improved the outcome for follicular lymphoma patients. METHODS: To evaluate the impact of evolving therapies for follicular lymphoma, particularly the introduction of rituximab, the overall survival (OS), failure-free survival (FFS), and survival after recurrence (SAR) was analyzed in 438 advanced-stage follicular lymphoma patients enrolled in consecutive Gruppo Italiano Studio Linfomi (GISL) trials between 1988 and 2004. RESULTS: A stepwise improvement in FFS and a significant reduction in the hazard ratio was observed with succeeding studies. Cox regression analysis showed an improvement over time for OS, with a decline in the hazard ratio particularly evident in the group treated with rituximab. Furthermore, the SAR significantly improved in the group of patients treated with chemotherapy + rituximab. CONCLUSIONS: After adjusting for all parameters with an impact on FFS and OS, the results of multivariate analysis suggest that rituximab therapy has a favorable effect on the prognosis of follicular lymphoma. The data show that FFS and OS have significantly improved in advanced-stage follicular lymphoma patients treated on GISL protocols during the last 18 years. These improvements are related to evolving front-line and salvage therapies, particularly the introduction of rituximab in combination with chemotherapy.

2007 - Is endoscopic ultrasound clinically useful for follow-up of gastric lymphoma? [Articolo su rivista]
Di Raimondo, F; Caruso, L; Bonanno, G; Naso, P; Chiarenza, A; Fiumara, P; Bari, Alessia; Palumbo, Ga; Russo, A; Giustolisi, R.
abstract

BACKGROUND: Endoscopic ultrasound (EUS) is considered the best technique for locoregional staging at diagnosis but its role in the follow-up of patients with gastric lymphoma after organ-conserving strategies has not been established. Design and methods: We retrospectively evaluated 23 patients with primary gastric lymphoma treated with a stomach-conservative approach. Sixteen of them were affected by MALT lymphoma and seven by diffuse large-B-cell lymphoma (DLBCL). Five patients were treated with Helicobacter pylori (HP) eradication therapy alone (omeprazole + amoxicillin + clarithromycin); eight patients received a treatment including HP eradication and chemotherapy and the remaining 10 patients were treated with chemotherapy alone.RESULTS: At the end of treatment, a complete remission was documented in 21 (91%) patients by endoscopy with biopsy (E-Bx) but in only seven (30%) patients by EUS. A total of 99 evaluations with both EUS and E-Bx were evaluated and we found concordance between the two methods in 33 occasions (33%) only. No significant difference on the percentage of concordance was recorded between MALT and DLBCL. After a median follow-up of 36.5 months we have not observed any relapse in 12 patients (six DLBCL and six MALT) with a persistent positive EUS but negative E-Bx.CONCLUSIONS: Although the length of follow-up cannot exclude late relapse, we think that in restaging and follow-up of gastric lymphoma, EUS seems not to be a reliable tool if it is abnormal and E-Bx still remains the gold standard. Therefore, after conventional conservative treatment, persistence of EUS abnormality with a negative histology should not be considered as a clinically relevant persistence of disease and should not be a reason for further treatment.

2007 - Rituximab in combination with chemotherapy has improved survival of patients with follicular lymphoma [Articolo su rivista]
Sacchi, Stefano; Marcheselli, Luigi; Marcheselli, Raffaella; Bari, Alessia; Ferri, Paola
abstract

No abstract available]

2007 - SECOND MALIGNANCIES AFTER TREATMENT FOR INDOLENT LYMPHOMA: A 16 YEARS FOLLOW-UP STUDY [Abstract in Rivista]
Sacchi, Stefano; Marcheselli, Luigi; Bari, Alessia; Marcheselli, Raffaella; Pozzi, Samantha; Luminari, Stefano; M., Lombardo; G., Buda; A., Lazzaro; P., Gobbi; C., Stelitano; M., Brugiatelli
abstract

Background. Second malignancies have been associated with NonHodgkin Lymphoma treatment. Most studies report a high risk of second cancers (2 to 8 fold increase), mainly due to high ncidence of MDS/AML and solid tumors, such as lung, bladder and gastro-intestinal cancers. Nevertheless few analyses have addressed this issue focusing on indolent lymphoma. Aims. Aims of this study are to determine the incidence and the risk factors for the development of second cancers during long term follow up of patients treated for indolent lymphoma. Methods. The Gruppo Italiano Studio Linfomi (GISL) maintains a database on clinical characteristics, treatment and follow up of all patients who entered clinical trials. To address a uniform patients population inthis study, we identified 563 previously untreated patients with histologically confirmed diagnosis of indolent lymphoma, enrolled in GISL trials between 1988 and 2003. The incidence (numbers of second neoplasia by person-years under analysis) of second cancers in the study population was compared to the incidence of solid cancers in the Italian population, utilizing age-, sex- and calendar period-specific incidence rates, derived from ISTAT database. Standardized incidence ratio (SIR, the observed/expected ratio) and absolute excess risk (AER, observedcases in our cohort minus numbers expected, divided by person-years at risk) were calculated after stratifying for age cohorts. Time Free to second Tumor (TF2T) was measured from the end of the first treatment to last follow-up or date of diagnosis of second tumor. TF2T was calculated with a Kaplan-Meier estimate. Effects of potential risk factors on second cancer rates were examined in a Cox proportional-hazard model. Results. After a median follow-up of 62 months , we observed 33 cases (6%) of second cancers, including hematologic malignancies (2%). Ten out of 33 patients developed MDS/AML and 23 solid tumors, including 6 lung cancer, 6 gastro-intestinal cancer and 11 other type of cancers. Overall, incidence rate (1000 person-years) was 11.5. Excess of risk forsecond solid cancer was detected in the cohort age 50-54 (SIR =4,2; 95% CI 1.9-9.40; AER =1.27). Median TF2T was 28 months for MDS/AML, 44 for lung cancer and 47 for gastro-intestinal cancer. By univariate and Cox regression analysis, after stratifying for histology, we observed a significant negative impact (all p<.05) on TF2T for age at first treatment, male sex and fludarabine-containing therapy. Further, we divided thelog(HR), estimated by Cox regression analysis based on age, male sex and fludarabine-containing therapy, at the 33° and the 66° percentiles. Based on this analysis, we observed three groups with significant difference in the risk of developing second cancers (p<0.0001). Conclusions. Patients treated for indolent lymphoma are at elevated risk of developing second primary malignancies. The SIR and AER are increased in patients who were younger at first treatment. Age, male sex and fludarabine-containing chemotherapy have a negative impact on TF2T. Finally,utilizing these parameters in a Cox regression model, we were able to identify groups with an increased risk of second malignancies.

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 - 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.

2005 - Management of multiple myeloma|Terapia del mieloma multiplo [Articolo su rivista]
Di Raimondo, F.; Pennisi, A.; Bari, A.; Fiumara, P.; Palumbo, G. A.
abstract