Roberto D'AMICO - personale UniMoRe

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Roberto D'AMICO

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

Pubblicazioni

2024 - Effectiveness of patients’ involvement in a medical and nursing pain education programme: a protocol for an open-label randomised controlled trial including qualitative data [Articolo su rivista]
Serafini, Alice; Grazia Rossi, Maria; Alberti, Sara; Borellini, Erika; Contini, Annamaria; Cernesi, Simone; D'Amico, Roberto; Eduardo Díaz Crescitelli, Matías; Ferri, Paola; Fornaciari, Davide; Ghirotto, Luca; Giugni, Linda; Lui, Fausta; Rossi, Francesca; CUOGHI COSTANTINI, Riccardo; Santori, Valentino; Padula, MARIA STELLA
abstract

Introduction Pain is a multidimensional experience that varies among individuals and has a significant impact on their health. A biopsychosocial approach is recommended for effective pain management; however, health professionals’ education is weak on this issue. Patient involvement is a promising didactic methodology in developing a more holistic perspective, however there is a lack of reliable evidence on this topic. The aim of the present study is to evaluate the effectiveness of patient involvement in pain education in undergraduate medicine and nursing students. Methods and analysis An open-label randomised controlled trial including qualitative data will be conducted. After an introductory lesson, each student will be randomly assigned to the intervention group, which includes an educational session conducted by a patient–partner along with an educator, or to the control group in which the session is exclusively conducted by an educator. Both sessions will be carried out according to the Case-Based Learning approach. Primary outcomes will be students’ knowledge, attitudes, opinions and beliefs about pain management, whereas the secondary outcome will be students’ satisfaction. The Pain Knowledge and Attitudes (PAK) and Chronic Pain Myth Scale (CPMS) will be administered preintervention and postintervention to measure primary outcomes. Students’ satisfaction will be measured by a questionnaire at the end of the session. Two focus groups will be conducted to evaluate non-quantifiable aspects of learning. Ethics and dissemination The protocol of this study was approved by the independent Area Vasta Emilia Nord ethics committee.

2024 - Metastatic site patterns by intrinsic subtype and HER2DX in early HER2-positive breast cancer [Articolo su rivista]
Dieci, M. V.; Conte, P.; Bisagni, G.; Bartolini, S.; Frassoldati, A.; Generali, D.; Piacentini, F.; Griguolo, G.; Tagliafico, E.; Braso Maristany, F.; Chic, N.; Pare, L.; Miglietta, F.; Vicini, R.; D'Amico, R.; Balduzzi, S.; Prat, A.; Guarneri, V.
abstract

Background: Even with contemporary treatment strategies, more than 10% of HER2-positive early stage breast cancer patients may experience distant metastasis as first event during follow-up. Tools for predicting unique patterns of metastatic spread are needed to plan personalized surveillance. We evaluated how molecular heterogeneity affects the pattern of distant relapse in HER2-positive breast cancer. Methods: A total of 677 HER2-positive stage I-III breast cancer patients from ShortHER trial, Cher-LOB trial, and 2 institutional cohorts were included. PAM50 molecular subtypes and research-based HER2DX scores were evaluated. The cumulative incidence of distant relapse as the first event (any site and site specific) was evaluated using competing risk analysis. Median follow-up was 8.4 years. Tests of statistical significance are 2-sided. Results: Stage III and high HER2DX risk score identified patients at the highest risk of distant relapse as first event (10-year incidence 24.5% and 19.7%, respectively). Intrinsic molecular subtypes were associated with specific patterns of metastatic spread: compared with other subtypes, HER2-enriched tumors were more prone to develop brain metastases (10-year incidence 3.8% vs 0.6%, P =. 005), basal-like tumors were associated with an increased risk of lung metastases (10-year incidence 11.1% vs 2.6%, P =. 001), and luminal tumors developed more frequently bone-only metastases (10-year incidence 5.1% vs 2.0%, P =. 042). When added to stage or HER2DX risk score in competing risk regression models, intrinsic subtype maintained an independent association with site-specific metastases. Conclusions: The integration of intrinsic molecular subtypes with stage or HER2DX risk score predicts site-specific metastatic risk in HER2-positive breast cancer, with potential implications for personalized surveillance and clinical trials aimed at preventing site-specific recurrence.

2023 - Cosmetic Results and Side Effects of Accelerated Partial-Breast Irradiation Versus Whole-Breast Irradiation for Low-Risk Invasive Carcinoma of the Breast: The Randomized Phase III IRMA Trial [Articolo su rivista]
Meduri, Bruno; Baldissera, Antonella; Iotti, Cinzia; Scheijmans, Luc J E E; Stam, Marcel R; Parisi, Salvatore; Boersma, Liesbeth J; Ammendolia, Ilario; Koiter, Eveline; Valli, Mariacarla; Scandolaro, Luciano; Busz, Dianne; Stenfert Kroese, Marika C; Ciabatti, Selena; Giacobazzi, Patrizia; Ruggieri, Maria P; Engelen, Antoine; Munafò, Tindara; Westenberg, A Helen; Verhoeven, Karolien; Vicini, Roberto; D'Amico, Roberto; Lohr, Frank; Bertoni, Filippo; Poortmans, Philip; Frezza, Giovanni P
abstract

Purpose: The results in terms of side effects vary among the published accelerated partial-breast irradiation (APBI) studies. Here, we report the 5-year results for cosmetic outcomes and toxicity of the IRMA trial. Methods: We ran this randomized phase III trial in 35 centers. Women with stage I-IIA breast cancer treated with breast-conserving surgery, age ≥ 49 years, were randomly assigned 1:1 to receive either whole-breast irradiation (WBI) or external beam radiation therapy APBI (38.5 Gy/10 fraction twice daily). Patients and investigators were not masked to treatment allocation. The primary end point was ipsilateral breast tumor recurrence. We hereby present the analysis of the secondary outcomes, cosmesis, and normal tissue toxicity. All side effects were graded with the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Radiation Morbidity Scoring Schema. Analysis was performed with both intention-to-treat and as-treated approaches. Results: Between March 2007 and March 2019, 3,309 patients were randomly assigned to 1,657 WBI and 1,652 APBI; 3,225 patients comprised the intention-to-treat population (1,623 WBI and 1,602 APBI). At a median follow-up of 5.6 (interquartile range, 4.0-8.4) years, adverse cosmesis in the APBI patients was higher than that in the WBI patients at 3 years (12.7% v 9.2%; P = .009) and at 5 years (14% v 9.8%; P = .012). Late soft tissue toxicity (grade ≥ 3: 2.8% APBI v 1% WBI, P < .0001) and late bone toxicity (grade ≥ 3: 1.1% APBI v 0% WBI, P < .0001) were significantly higher in the APBI arm. There were no significant differences in late skin and lung toxicities. Conclusion: External beam radiation therapy-APBI with a twice-daily IRMA schedule was associated with increased rates of late moderate soft tissue and bone toxicities, with a slight decrease in patient-reported cosmetic outcomes at 5 years when compared with WBI, although overall toxicity was in an acceptable range.

2023 - Early palliative care versus usual haematological care in multiple myeloma: retrospective cohort study [Articolo su rivista]
Giusti, D.; Colaci, E.; Pioli, V.; Banchelli, F.; Maccaferri, M.; Leonardi, G.; Marasca, R.; Morselli, M.; Forghieri, F.; Bettelli, F.; Cuoghi, A.; Bresciani, P.; Messerotti, A.; Gilioli, A.; Candoni, A.; Cassanelli, L.; Sbadili, E.; Bassoli, I.; Longo, G.; Gilioli, F.; Borelli, E.; Bigi, S.; D'Amico, R.; Porro, C. A.; Odejide, O.; Zimmermann, C.; Efficace, F.; Bruera, E.; Luppi, M.; Bandieri, E.; Potenza, L.
abstract

Objectives Although early palliative care (EPC) is beneficial in acute myeloid leukaemia, little is known about EPC value in multiple myeloma (MM). We compared quality indicators for palliative and end of life (EOL) care in patients with MM receiving EPC with those of patients who received usual haematological care (UHC).Methods This observational, retrospective study was based on 290 consecutive patients with MM. The following indicators were abstracted: providing psychological support, assessing/managing pain, discussing goals of care, promoting advance care plan, accessing home care services; no anti MM treatment within 14 and 30 days and hospice length of stay >7 days before death; no cardiopulmonary resuscitation, no intubation, <2 hospitalisations and emergency department visits within 30 days before death. Comparisons were performed using unadjusted and confounder adjusted regression models.Results 55 patients received EPC and 231 UHC. Compared with UHC patients, EPC patients had a significantly higher number of quality indicators of care (mean 2.62 +/- 1.25 vs 1.12 +/- 0.95; p<0.0001)); a significant reduction of pain intensity over time (p<0.01) and a trend towards reduced aggressiveness at EOL, with the same survival (5.3 vs 5.46 years; p=0.74)).Conclusions Our data support the value of integrating EPC into MM routine practice and lay the groundwork for future prospective comparative studies.

2023 - Feasibility, safety, and outcome of second-line nivolumab/bevacizumab in liver transplant patients with recurrent hepatocellular carcinoma [Articolo su rivista]
Di Marco, Lorenza; Pivetti, Alessandra; Foschi, Francesco Giuseppe; D'Amico, Roberto; Schepis, Filippo; Caporali, Cristian; Casari, Federico; Lasagni, Simone; Critelli, Rosina Maria; Milosa, Fabiola; Romanzi, Adriana; Marcelli, Gemma; De Maria, Nicola; Romagnoli, Dante; Catellani, Barbara; Scianò, Filippo; Magistri, Paolo; Colecchia, Antonio; Sighinolfi, Pamela; Di Benedetto, Fabrizio; Martinez-Chantar, Maria-Luz; Villa, Erica
abstract

2023 - Nine-Week Versus One-Year Trastuzumab for Early Human Epidermal Growth Factor Receptor 2â € "Positive Breast Cancer: 10-Year Update of the ShortHER Phase III Randomized Trial [Articolo su rivista]
Conte, P.; Bisagni, G.; Piacentini, F.; Sarti, S.; Minichillo, S.; Anselmi, E.; Aieta, M.; Gebbia, V.; Schirone, A.; Musolino, A.; Garrone, O.; Beano, A.; Rimanti, A.; Giotta, F.; Turletti, A.; Miglietta, F.; Dieci, M. V.; Vicini, R.; Balduzzi, S.; D'Amico, R.; Guarneri, V.
abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final analysis of the phase III noninferiority, randomized ShortHER trial comparing 9 weeks versus 1 year of adjuvant trastuzumab with chemotherapy in patients with human epidermal growth factor receptor 2â € "positive (HER2+) early breast cancer (BC). Women with HER2+ BC were randomly assigned to anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or 9-week trastuzumab (arm B, short). Here, we report the second coprimary end point overall survival (OS), updated disease-free survival (DFS), and outcomes according to hormone receptor status, age, and nodal status. At a median follow-up of 9 years, 10-year DFS is 77% versus 78% in the long versus short arm, respectively. Ten-year OS is 89% versus 88% in the long versus short arm, respectively. 10-year DFS rates in the long versus short arm according to nodal status are N0 81% versus 85%; N1-3 77% versus 79%; and N4+ 63% versus 53%. Ten-year OS rates in long versus short arm according to nodal status are N0 89% versus 95%%; N1-3 92% versus 89%; and N4+ 84% versus 64%. The updated analysis of the ShortHER trial shows that 1-year trastuzumab is the standard treatment for patients with HER2+ early BC as noninferiority cannot be claimed. However, numerically, the differences for the patients at low or intermediate risk (N0/N1-3) is negligible, while patients with N4+ have a clear benefit with 1-year trastuzumab.

2023 - Randomized, double-blind, placebo-controlled trial of rapamycin in amyotrophic lateral sclerosis [Articolo su rivista]
Mandrioli, J.; D'Amico, R.; Zucchi, E.; De Biasi, S.; Banchelli, F.; Martinelli, I.; Simonini, C.; Lo Tartaro, D.; Vicini, R.; Fini, N.; Gianferrari, G.; Pinti, M.; Lunetta, C.; Gerardi, F.; Tarlarini, C.; Mazzini, L.; De Marchi, F.; Scognamiglio, A.; Soraru, G.; Fortuna, A.; Lauria, G.; Bella, E. D.; Caponnetto, C.; Meo, G.; Chio, A.; Calvo, A.; Cossarizza, A.
abstract

In preclinical studies rapamycin was found to target neuroinflammation, by expanding regulatory T cells, and affecting autophagy, two pillars of amyotrophic lateral sclerosis (ALS) pathogenesis. Herein we report a multicenter, randomized, double-blind trial, in 63 ALS patients who were randomly assigned in a 1:1:1 ratio to receive rapamycin 2 mg/m2/day,1 mg/m2/day or placebo (EUDRACT 2016-002399-28; NCT03359538). The primary outcome, the number of patients exhibiting an increase >30% in regulatory T cells from baseline to treatment end, was not attained. Secondary outcomes were changes from baseline of T, B, NK cell subpopulations, inflammasome mRNA expression and activation status, S6-ribosomal protein phosphorylation, neurofilaments; clinical outcome measures of disease progression; survival; safety and quality of life. Of the secondary outcomes, rapamycin decreased mRNA relative expression of the pro-inflammatory cytokine IL-18, reduced plasmatic IL-18 protein, and increased the percentage of classical monocytes and memory switched B cells, although no corrections were applied for multiple tests. In conclusion, we show that rapamycin treatment is well tolerated and provides reassuring safety findings in ALS patients, but further trials are necessary to understand the biological and clinical effects of this drug in ALS.

2022 - "It's All COVID's Fault!": Symptoms of Distress among Workers in an Italian General Hospital during the Pandemic [Articolo su rivista]
Mastroberardino, Michele; Cuoghi Costantini, Riccardo; De Novellis, Antonella Maria Pia; Ferrari, Silvia; Filippini, Costanza; Longo, Fedora; Marchi, Mattia; Rioli, Giulia; Valeo, Laura; Vicini, Roberto; Galeazzi, Gian Maria; D'Amico, Roberto; Vandelli, Paola
abstract

Background: Since the outbreak of the COVID-19 pandemic, healthcare workers (HCWs) have been faced with specific stressors endangering their physical and mental health and their functioning. This study aimed to assess the short-term psychological health of a sample of Italian HCWs and the related influencing factors. In particular, the study focused on the differences related to HCWs' gender and to having been directly in charge of COVID-19 patients or not. Methods: An online survey was administered to the whole staff of the Modena General University Hospital three months after the onset of the pandemic, in 2020. Demographic data and changes in working and living conditions related to COVID-19 were collected; mental health status was assessed by the Depression, Anxiety and Stress Scale (DASS-21) and the Impact of Event Scale-Revised (IES-R). Results: 1172 out of 4788 members returned the survey (response rate = 24.5%), the male/female ratio was 30/70%. Clinically significant symptoms assessed according to the DASS-21 emerged among 21.0% of the respondents for depression, 22.5% for anxiety and 27.0% for stress. Symptoms suggestive of a traumatic reaction were reported by 19.0% of the sample. Symptoms of psychological distress were statistically associated with female gender, job role, ward, changes in lifestyle, whereas first-line work with COVID-19 patients was statistically associated with more stress symptoms. HCWs reported a significant level of psychological distress that could reach severe clinical significance and impact dramatically their quality of life and functioning. Conclusions: Considering the persistence of the international emergency, effective strategies to anticipate, recognize and address distress in HCWs are essential, also because they may impact the organization and effectiveness of healthcare systems.

2022 - 10 years of stagnant clinical research in the Italian academic context [Articolo su rivista]
Moja, L.; Banzi, R.; Cabitza, F.; Capobussi, M.; Castellini, G.; Cereda, D.; Cinquini, M.; Colombo, C.; Costantino, G.; D'Amico, R.; Gianola, S.; Gonzalez-Lorenzo, M.; Lodi, G.; Lucenteforte, E.; Minozzi, S.; Moschetti, I.; Muti, P.; Petri, D.; Podda, G. M.; Squizzato, A.; Tirani, M.; Virgili, G.; Berardinelli, D.
abstract

This article is about current challenges to evidence-based medicine (EMB) in Italy. The authors, who share a 20-year commitment to the field of clinical research, discuss what they define as a phase of "stagnation" in practicing and teaching methods and research tactics, both in clinical and academic settings. Early success of EBM cultural movement was not persistent. The authors reason about how the teaching of EBM has remained a niche, concerning few professionals compared to the needs of the country. The authors identify some reasons that might have led to inconsistent attention to research methodology and address ways to strengthen the contribution of academic medicine to clinical research.

2022 - Anti-GD2 CAR MSCs against metastatic Ewing's sarcoma [Articolo su rivista]
Golinelli, G.; Grisendi, G.; Dall'Ora, M.; Casari, G.; Spano, C.; Talami, R.; Banchelli, F.; Prapa, M.; Chiavelli, C.; Rossignoli, F.; Candini, O.; D'Amico, R.; Nasi, M.; Cossarizza, A.; Casarini, L.; Dominici, M.
abstract

Background: Ewing's sarcoma (ES) is an aggressive cancer affecting children and young adults. We pre-clinically demonstrated that mesenchymal stromal/stem cells (MSCs) can deliver tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) against primary ES after local injection. However, ES is often metastatic calling for approaches able to support MSC targeting to the ES multiple remote sites. Considering that the disialoganglioside GD2 is expressed by ES and to optimise MSC tumour affinity, bi-functional (BF) MSCs expressing both TRAIL and a truncated anti-GD2 chimeric antigen receptor (GD2 tCAR) were generated and challenged against ES. Methods: The anti-GD2 BF MSCs delivering a soluble variant of TRAIL (sTRAIL) were tested in several in vitro ES models. Tumour targeting and killing by BF MSCs was further investigated by a novel immunodeficient ES metastatic model characterized by different metastatic sites, including lungs, liver and bone, mimicking the deadly clinical scenario. Findings: In vitro data revealed both tumour affinity and killing of BF MSCs. In vivo, GD2 tCAR molecule ameliorated the tumour targeting and persistence of BF MSCs counteracting ES in lungs but not in liver. Interpretation: We here generated data on the potential effects of BF MSCs within a complex ES metastatic in vivo model, exploring also the biodistribution of MSCs. Our BF MSC-based strategy promises to pave the way for potential improvements in the therapeutic delivery of TRAIL for the treatment of metastatic ES and other deadly GD2-positive malignancies.

2022 - Cancer Stem Cells and Cell Cycle Genes as Independent Predictors of Relapse in Non-small Cell Lung Cancer: Secondary Analysis of a Prospective Study [Articolo su rivista]
Masciale, V.; Banchelli, F.; Grisendi, G.; D'Amico, R.; Maiorana, A.; Stefani, A.; Morandi, U.; Stella, F.; Dominici, M.; Aramini, B.
abstract

PURPOSE: Cancer stem cells (CSCs) are described as resistant to chemotherapy and radiotherapy. It has been shown that CSCs influence disease-free survival in patients undergoing surgery for lung cancer (NCT04634630). We recently described an overexpression of CSCs recurrence-related genes (RG) in lung cancer. This study aims to investigate CSC frequency and RG expression as predictors of disease-free survival in lung cancer. EXPERIMENTAL DESIGN: This secondary analysis of a prospective cohort study involved 22 surgical tumor specimens from 22 patients harboring early (I-II) and locally advanced (IIIA) stages ACL and SCCL. Cell population frequency analysis of ALDHhigh (CSCs) and ALDHlow (cancer cells) was performed on each tumor specimen. In addition, RG expression was assessed for 31 target genes separately in ALDHhigh and ALDHlow populations. CSCs frequency and RG expression were assessed as predictors of disease-free survival by Cox analysis. RESULTS: CSCs frequency and RG expression were independent predictors of disease-free survival. CSC frequency was not related to disease-free survival in early-stage patients (HR = 0.84, 95%CI = 0.53-1.33, P = .454), whereas it was a risk factor for locally advanced-stage patients (HR = 1.22, 95%CI = 1.09-1.35, P = .000). RG expression-if measured in CSCs-was related to a higher risk of recurrence (HR = 1.19, 95%CI = 1.03-1.39, P = .021). The effect of RG expression measured in cancer cells on disease-free survival was lower and was not statistically significant (HR = 1.12, 95%CI = 0.94-1.33, P = .196). CONCLUSIONS: CSCs frequency and RG expression are independent predictors of relapse in lung cancer. Considering these results, CSCs and RG may be considered for both target therapy and prognosis.

2022 - Early awake proning in critical and severe COVID-19 patients undergoing noninvasive respiratory support: A retrospective multicenter cohort study [Articolo su rivista]
Tonelli, R; Pisani, L; Tabbì, L; Comellini, V; Prediletto, I; Fantini, R; Marchioni, A; Andrisani, D; Gozzi, F; Bruzzi, G; Manicardi, L; Busani, S; Mussini, C; Castaniere, I; Bassi, I; Carpano, M; Tagariello, F; Corsi, G; D' amico, R; Girardis, M; Nava, S; Clini, E.
abstract

Introduction- In non-intubated patients with COVID-19 pneumonia, awake prone position associated with non-invasive respiratory support (NRS) demonstrated only physiological benefits. Nonetheless, it might be arguable that at least a selected subset of these patients is going to obtain significant clinical gains. Methods- This retrospective cohort study was conducted in two teaching hospitals comparing effects of awake prone position in addition to usual care (PP) with standard care alone (SC)in severe and critical COVID-19 patients undergoing NRS. Primary outcome was endotracheal intubation (ETI) rate. In-hospital mortality, time to ETI, tracheostomy, length of RICU and hospital stay served as secondary outcomes. Risk factors associated with ETI were also investigated in PP group. Results- A cohort of 114 patients (38 and 76 in PP and SC group, respectively) was analyzed. Greater ETI risk reduction rate was observed in PP as compared with SC both at unadjusted estimates (HR=0.45 95%CI [0.2-0.9], p=0.02), and even after adjustment for confounders (HR=0.59 95%CI[0.3-0.94], p=0.03). Compared with SC, PP group also showed a favorable difference in terms of days free from respiratory support, length of RICU and hospital stay, but not in mortality or tracheostomy rate. Conclusion- Early awake proning in spontaneously breathing Covid-19 patients is associated with a risk reduction of intubation rate.Findings prompt further randomized controlled trials to answer the pending questions on the real efficacy of PP in this setting.

2022 - Edmonton symptom assessment system Global Distress Score and overall survival in acute leukaemia [Articolo su rivista]
Morselli, M.; Banchelli, F.; Borelli, E.; Cordella, S.; Forghieri, F.; Bettelli, F.; Bigi, S.; Longo, G.; D'Amico, R.; Porro, C. A.; Efficace, F.; Bruera, E.; Luppi, M.; Bandieri, E.; Potenza, L.
abstract

2022 - Edmonton symptom assessment system global distress score and overall survival among patients with advanced cancer receiving early palliative care [Articolo su rivista]
Bandieri, E.; Banchelli, F.; Borelli, E.; D'Amico, R.; Efficace, F.; Bruera, E.; Luppi, M.; Potenza, L.
abstract

2022 - Efficacy of a multiple-component and multifactorial personalized fall prevention program in a mixed population of community-dwelling older adults with stroke, Parkinson's Disease, or frailty compared to usual care: The PRE.C.I.S.A. randomized controlled trial [Articolo su rivista]
LA PORTA, Fabio; Lullini, Giada; Caselli, Serena; Valzania, Franco; Mussi, Chiara; Tedeschi, Claudio; Pioli, Giulio; Bondavalli, Massimo; Bertolotti, Marco; Banchelli, Federico; D'Amico, Roberto; Vicini, Roberto; Puglisi, Silvia; Clerici, Pierina Viviana; Chiari, Lorenzo; and PRECISA Group members, ; LA PORTA, Fabio; Caselli, Serena; Clerici, Pierina Viviana; Cavazza, Stefano; Serraglio, Valeria; Vannini Maria Cristina, ; Bovolenta, Federica; Lullini, Giada; Puglisi, Silvia; Gallo, Angela; Mussi, Chiara; Bertolotti, Marco; Scotto, Roberto; Lancellotti, Giulia; Franco, Valzania; Francesca, Falzone; Monica, Montanari; Maria Luisa De Luca, ; Malagoli, Emanuela; Elisa, Franchini; Luisa, Palmisano; Franca, Serafini; Tedeschi, Claudio; Gioacchino, Anselmi; Valentina, D’Alleva; Mariangela Di Matteo, ; Rosalinda, Ferrari; Costi, Stefania; Filomena, Simeone; Giulia, D’Apote; Alessandra, Rizzica; Galavotti, Maria Beatrice; Marta, Ghirelli; Giulio, Pioli; Bendini, Chiara; Lancellotti, Giulia; Massimo, Bondavalli; Eleni, Georgopoulos; D'Amico, Roberto; Balduzzi, Sara; Vicini, Roberto; Banchelli, Federico; Lorenzo, Chiari; Sabato, Mellone; Alice, Coni
abstract

Fall risk in the elderly is a major public health issue due to the injury-related consequences and the risk of associated long-term disability. However, delivering preventive interventions in usual clinical practice still represents a challenge.

2022 - First-trimester prediction model for placental vascular disorders: an observational prospective study [Articolo su rivista]
Monari, Francesca; Spano' Bascio, Ludovica; Banchelli, Federico; Neri, Isabella; Bertucci, Emma; Ferrari, Francesca; Menichini, Daniela; D'Amico, Roberto; Facchinetti, Fabio
abstract

This study aims to develop a multivariable predictive model for the risk of placental vascular complications (PVC), by using biochemical, biophysical, anamnestic and clinical maternal features available at the first trimester. PVC include gestational hypertension, preeclampsia, placenta abruption, intrauterine growth restriction (IUGR), and stillbirth. Prospective study that included all singleton pregnancies attending the first-trimester aneuploidy screening (11 +0–12 +6 weeks) at Obstetrics Unit of the University Hospital of Modena, in Northern Italy, between June 2018 and December 2019. In a total of 503 women included in the analysis, 40 patients were in the PVC group. The final prediction model for PVC included the following independent variables: pre-pregnancy BMI ≥ 30 (OR = 2.65, 95% CI = 1.04; 6.75, p = 0.0415), increasing values of mean arterial pressure (OR = 1.06, 95% CI = 1.02; 1.10, p = 0.0008), PAPP-A < 2.40465 U/L (OR = 0.43, 95% CI = 0.19; 0.96, p = 0.0388) and decreasing values of PlGf (MoM) (OR = 0.28, 95% CI = 0.10; 0.79, p = 0.0153). The area under the ROC curve was 79.4% indicating a satisfactory predictive accuracy. The best predictive cut-off for this score was equal to − 2.562, which corresponds to a 7.2 % probability of having PVC. By using such a cut-off, the risk of PVC can be predicted in our sample with sensitivity equal to 82,4 % and specificity equal to 69,9 %. This model for early prediction of PVC is a promising tool to early identify women at greater risk for placenta vascular complications.

2022 - Foot-to-Foot Contact Among Initial Goal-Directed Movements Supports the Prognostic Value of Fidgety Movements in HIE-Cooled Infants [Articolo su rivista]
Ferrari, F.; Bedetti, L.; Bertoncelli, N.; Roversi, M. F.; Della Casa, E.; Guidotti, I.; Ori, L.; D'Amico, R.; Valeri, L.; Lugli, L.; Lucaccioni, L.; Berardi, A.
abstract

Background: Few studies conducted to date have observed general movements in infants affected by hypoxic–ischemic encephalopathy (HIE) who underwent therapeutic hypothermia. We investigated whether foot-to-foot contact (FF) could support the predictive value of fidgety movements (FMs) in infants affected by HIE and treated with brain cooling. Methods: Spontaneous motility was video recorded for 3–5 min at 12 weeks post-term age in 58 full-term newborn infants affected by perinatal asphyxia who were cooled due to moderate to severe HIE. FF and FMs were blindly scored by three independent observers. At 24 months, each patient underwent a neurological examination by Amiel-Tison and Grenier. Results: At 24 months, 47 infants had developed typically at neurological examination, eight had developed mild motor impairment, and three developed cerebral palsy (CP). At 12 weeks, 34 (58.6%) infants had shown normal FMs, four of whom developed mild motor impairment. Twenty-four infants (41.4%) exhibited abnormal or no FMs, four of whom developed mild motor impairment and three developed CP. FF was present in 20 infants (34.5%), two of whom developed mild motor impairment. FF was absent in 38 infants (65.5%), six of whom developed mild motor impairment and three developed CP. Both FMs and FF, considered separately, were 100% sensitive for predicting CP at 24 months, but only 61 and 36%, respectively, were specific. Summing the two patterns together, the specificity increases to 73%, considering only CP as an abnormal outcome, and increases to 74% when considering CP plus mild motor impairment. Unexpectedly, fidgety movements were absent in 24 infants with typical motor outcomes, 17 of whom showed a typical motor outcome. Conclusions: FF is already part of motor repertoire at 12 weeks and allows a comparison of spontaneous non-voluntary movements (FMs) to pre-voluntary movements (FF). FF supports FMs for both sensitivity and specificity. A second video recording at 16–18 weeks, when pedipulation is present in healthy infants, is suggested: it may better define the presence or absence of goal-directed motility.

2022 - Identifying unanswered questions and setting the agenda for future systematic research in Multiple Sclerosis. A worldwide, multi-stakeholder Priority Setting project [Articolo su rivista]
Celani, M. G.; Nonino, F.; Mahan, K.; Orso, M.; Ridley, B.; Baldin, E.; Bignamini, A. A.; D'Amico, R.; Cantisani, T. A.; Colombo, C.; Khan, F.; Kopke, S.; Laurson-Doube, J.; Schvarz, C.; Young, C. A.; Peryer, G.; Rosati, P.; Filippini, G.
abstract

Background: Eliciting the research priorities of people affected by a condition, carers and health care professionals can increase research value and reduce research waste. The Cochrane Multiple Sclerosis and Rare Disease of CNS Group, in collaboration with the Cochrane Neurological Sciences Field, launched a priority setting exercise with the aim of prioritizing pressing questions to ensure that future systematic reviews are as useful as possible to the people who need them, in all countries, regardless of their economic status. Method: Sixteen high priority questions on different aspects of MS were developed by members of a multi-stakeholder priority setting Steering Group (SG). In an anonymous online survey translated into 12 languages researchers, clinicians, people with MS (PwMS) and carers were asked to identify and rank, 5 out of 16 questions as high priority and to provide an explanation for their choice. An additional free-text priority research topic suggestion was allowed. Results: The survey was accessible through MS advocacy associations’ social media and Cochrane web pages from October 20, 2020 to February 6, 2021. 1.190 responses (86.73% of all web contacts) were evaluable and included in the analysis. Responses came from 55 countries worldwide, 7 of which provided >75% of respondents and 95% of which were high and upper-middle income countries. 58.8% of respondents live in the EU, 23% in the Americas, 8.9% in the Western Pacific, 2.8% in the Eastern Mediterranean and 0.3% in South Eastern Asia. About 75% of the respondents were PwMS. The five research questions to be answered with the highest priority were: Question (Q)1 “Does MRI help predict disability worsening of PwMS?” (19.9%), Q5 “What are the benefits and harms of treating PwMS with one disease-modifying drug compared to another?” (19.3%), Q3 “Does multidisciplinary care by teams of different social and health professionals improve health outcomes and experiences for PwMS?” (11.9%), Q16 “Does psychological health affect disease progression in PwMS?” (9.2%) and Q10 “What are the benefits and harms of exercise for PwMS?” (7.2%). The multivariable logistic regression analysis indicated a significant influence of geographic area and income level on the ranking of Q1 and a marginal for Q16 as top a priority after accounting for the effect of all other predictors. Approximately 50% of the respondents indicated that they had an important additional suggestion to be considered. Conclusion: This international collaborative initiative in the field of MS offers a worldwide perspective on the research questions perceived as pivotal by a geographically representative sample of multiple stakeholders in the field of MS. The results of the survey could guide the prioritization of research on pharmacological and non-pharmacological interventions which could be meaningful and useful for PwMS and carers, avoiding the duplication of efforts and research waste. High quality systematic reviews elicited by priority setting exercises may offer the best available evidence and inform decisions by healthcare providers and policy-makers which can be adapted to the different realities around the world.

2022 - Impact of sarcopenia in SARS-CoV-2 patients during two different epidemic waves [Articolo su rivista]
Menozzi, R.; Valoriani, F.; Prampolini, F.; Banchelli, F.; Boldrini, E.; Martelli, F.; Galetti, S.; Fari', R.; Gabriele, S.; Palumbo, P.; Forni, D.; Pantaleoni, M.; D'Amico, R.; Pecchi, A.
abstract

Background: Sarcopenia was reported to be associated with poor clinical outcome, higher incidence of community-acquired pneumonia, increased risk of infections and reduced survival in different clinical settings. The aim of our work is to evaluate the prognostic role of sarcopenia in patients with the 2019 novel coronavirus disease (COVID-19). Materials and methods: 272 COVID-19 patients admitted to the University Hospital of Modena (Italy) from February 2020 to January 2021 were retrospectively studied. All included patients underwent a chest computed tomography (CT) scan to assess pneumonia during their hospitalization and showed a positive SARS-CoV-2 molecular test. Sarcopenia was defined by skeletal muscle area (SMA) evaluation at the 12th thoracic vertebra (T12). Clinical, laboratory data and adverse clinical outcome (admission to Intensive Care Unit and death) were collected for all patients. Results: Prevalence of sarcopenia was high (41.5%) but significantly different in each pandemic wave (57.9% vs 21.6% p < 0.0000). At the multivariate analysis, sarcopenia during the first wave (Hazard Ratio 2.29, 95% confidence intervals 1.17 to 4.49 p = 0.0162) was the only independent prognostic factor for adverse clinical outcome. There were no significant differences in comorbidities and COVID19 severity in terms of pulmonary involvement at lung CT comparing during the first and second wave. Mixed pattern with peripheral and central involvement was found to be dominant in both groups. Conclusion: We highlight the prognostic impact of sarcopenia in COVID-19 patients hospitalized during the first wave. T12 SMA could represent a potential tool to identify sarcopenic patients in particular settings. Further studies are needed to better understand the association between sarcopenia and COVID-19.

2022 - Pattern of distant relapse according to intrinsic molecular subtype in patients with HER2-positive breast cancer: a combined analysis of ShortHER, CherLOB, and two institutional cohorts [Poster]
Dieci, Maria Vittoria; Bisagni, Giancarlo; Bartolini, Stefania; Frassoldati, Antonio; Giulio Generali, Daniele; Piacentini, Federico; Griguolo, Gaia; Tagliafico, Enrico; Brasó-Maristany, Fara; Chic, Nuria; Porra, Francesca; Vicini, Roberto; D’Amico, Roberto; Balduzzi, Sara; Prat, Aleix; Conte, Pierfranco; Guarneri, Valentina
abstract

Background: All intrinsic molecular subtypes are represented among HER2-positive breast cancer, with implications on clinical outcome and treatment sensitivity. The impact of molecular subtypes on the pattern and site of relapse is largely unexplored. Methods: 677 patients with HER2-positive early breast cancer from the Shorther trial (n=437), the CherLOB trial (n=84) and two Institutional cohorts (Istituto Oncologico Veneto IRCCS Padova n=39 and Hospital Clinic Barcelona n=117) were included. Only patients with available PAM50 intrinsic molecular subtyping were considered. We analyzed the incidence of distant relapse (at any site and at specific sites) as the first event. Cumulative incidence was estimated according to competing risk analysis (Fine and Gray’s method). Competing risk regression was used to calculate the subdistribution Hazard Ratios (subHR) and their 95% Confidence Interval (CI). Results: The distribution of molecular subtypes was: 130 LumA (19%), 75 LumB (11%), 347 HER2-e (51%), 46 Basal (7%), 79 Normal (12%). Median follow up was 8.4 years (95%CI 8.2-8.6). The 10-yr cumulative incidence rates of distant relapse as first event were: LumA 7.9%, LumB 14.8%, HER2-e 14.7%, Basal 15.5%, Normal 10.4% (HER2-e vs LumA: SubHR 2.21, 95%CI 1.05-4.64, p=0.037). Table 1 shows the 5-yr and 10-yr cumulative incidence rates of distant metastases at specific sites (as first event) according to intrinsic subtype. HER2-e enriched and Basal tumors were more prone as compared to other subtypes to develop brain and lung metastasis as first event, respectively. Isolated brain metastases without extracranial disease occurred only in patients with HER2-e tumors. All brain metastases as first event occurred within 5 years from diagnosis. Bone-only disease as first event was less frequent in HER2-e and Basal subtype (subHR HER2-e vs LumA: 0.32, 95%CI 0.10-10.4. p=0.058). Next, we analyzed the frequency of site-specific first metastasis among patients who experienced a distant metastasis as first event (n=77). Lung metastases were more frequent in Basal tumors (LumA 25.0%, LumB 20.0%, HER2-e 24.4%, Basal 71.4%, Normal 0.0%, p=0.037) and bone metastases were more frequent in Luminal tumors (LumA 100.0%, LumB 60.0%, HER2-e 31.1%, Basal 42.9%, Normal 57.1%, p=0.006). Among 45 HER2-e patients with a first distant relapse, 25.6% were diagnosed with a brain metastasis and 15.6% had brain-only disease. Conclusions: Molecular subtypes influence the metastatic behaviour of clinically HER2-positive breast cancer. These results, if further validated, may have implication in planning personalized monitoring strategies.

2021 - A first trimester prediction model for large for gestational age infants: a preliminary study [Articolo su rivista]
Monari, F.; Menichini, D.; Spano' Bascio, L.; Grandi, G.; Banchelli, F.; Neri, I.; D'Amico, R.; Facchinetti, F.
abstract

Background: Large for gestational age infants (LGA) have increased risk of adverse short-term perinatal outcomes. This study aims to develop a multivariable prediction model for the risk of giving birth to a LGA baby, by using biochemical, biophysical, anamnestic, and clinical maternal characteristics available at first trimester. Methods: Prospective study that included all singleton pregnancies attending the first trimester aneuploidy screening at the Obstetric Unit of the University Hospital of Modena, in Northern Italy, between June 2018 and December 2019. Results: A total of 503 consecutive women were included in the analysis. The final prediction model for LGA, included multiparity (OR = 2.8, 95% CI: 1.6–4.9, p = 0.001), pre-pregnancy BMI (OR = 1.08, 95% CI: 1.03–1.14, p = 0.002) and PAPP-A MoM (OR = 1.43, 95% CI: 1.08–1.90, p = 0.013). The area under the ROC curve was 70.5%, indicating a satisfactory predictive accuracy. The best predictive cut-off for this score was equal to − 1.378, which corresponds to a 20.1% probability of having a LGA infant. By using such a cut-off, the risk of LGA can be predicted in our sample with sensitivity of 55.2% and specificity of 79.0%. Conclusion: At first trimester, a model including multiparity, pre-pregnancy BMI and PAPP-A satisfactorily predicted the risk of giving birth to a LGA infant. This promising tool, once applied early in pregnancy, would identify women deserving targeted interventions. Trial registration: ClinicalTrials.gov NCT04838431, 09/04/2021.

2021 - Adjunctive IgM-enriched immunoglobulin therapy with a personalised dose based on serum igm-titres versus standard dose in the treatment of septic shock: A randomised controlled trial (igm-fat trial) [Articolo su rivista]
Biagioni, E.; Tosi, M.; Berlot, G.; Castiglione, G.; Corona, A.; De Cristofaro, M. G.; Donati, A.; Feltracco, P.; Forfori, F.; Fragranza, F.; Murino, P.; Piazza, O.; Tullo, L.; Grasselli, G.; D'Amico, R.; Girardis, M.
abstract

Introduction In patients with septic shock, low levels of circulating immunoglobulins are common and their kinetics appear to be related to clinical outcome. The pivotal role of immunoglobulins in the host immune response to infection suggests that additional therapy with polyclonal intravenous immunoglobulins may be a promising option in patients with septic shock. Immunoglobulin preparations enriched with the IgM component have largely been used in sepsis, mostly at standard dosages (250 mg/kg per day), regardless of clinical severity and without any dose adjustment based on immunoglobulin serum titres or other biomarkers. We hypothesised that a personalised dose of IgM enriched preparation based on patient IgM titres and aimed to achieve a specific threshold of IgM titre is more effective in decreasing mortality than a standard dose. Methods and analysis The study is designed as a multicentre, interventional, randomised, single-blinded, prospective, investigator sponsored, two-armed study. Patients with septic shock and IgM titres <60 mg/dL will be randomly assigned to an IgM titre-based treatment or a standard treatment group in a ratio of 1:1. The study will involve 12 Italian intensive care units and 356 patients will be enrolled. Patients assigned to the IgM titre-based treatment will receive a personalised daily dose based on an IgM serum titre aimed at achieving serum titres above 100 mg/dL up to discontinuation of vasoactive drugs or day 7 after enrolment. Patients assigned to the IgM standard treatment group will receive IgM enriched preparation daily for three consecutive days at the standard dose of 250 mg/kg. The primary endpoint will be all-cause mortality at 28 days. Ethics and dissemination The study protocol was approved by the ethics committees of the coordinating centre (Comitato Etico dell'Area Vasta Emilia Nord) and collaborating centres. The results of the trial will be published within 12 months from the end of the study and the steering committee has the right to present them at public symposia and conferences. Trial registration details The trial protocol and information documents have received a favourable opinion from the Area Vasta Emilia Nord Ethical Committee on 12 September 2019. The trial protocol has been registered on EudraCT (2018-001613-33) on 18 April 2018 and on ClinicalTrials.gov (NCT04182737) on 2 December 2019.

2021 - Cancer stem cells and macrophages: molecular connections and future perspectives against cancer. [Articolo su rivista]
Aramini, Beatrice; Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Morandi, Uliano; Dominici, Massimo; Husnain Haider, Khawaja
abstract

Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies.

2021 - Children and adolescents with ADHD followed up to adulthood: A systematic review of long-term outcomes [Articolo su rivista]
Di Lorenzo, R.; Balducci, J.; Poppi, C.; Arcolin, E.; Cutino, A.; Ferri, P.; D'Amico, R.; Filippini, T.
abstract

Objective: To highlight the clinical and social outcomes among adults who suffered from ADHD in their childhood/adolescence. Method: PubMed, PsycINFO, Scopus databases were searched for prospective studies published during the last 5 years addressing patients with ADHD in childhood/adolescence followed up to adulthood. We also included studies published before 2015 reported in other reviews with similar outcomes. Results: 1485 studies were identified but only 39 were included for qualitative and 27 for quantitative analysis. Overall, we found that ADHD persisted into adulthood with a mean rate of 43% and was mainly associated with both substance/alcohol use disorders and antisocial behavior and, less frequently, with anxiety and depressive disorders. The prevalence of persistent ADHD in adulthood reported by studies published after 2011 (55%) was higher than that reported by studies published previously from 1985 to 2011 (34%), suggesting a greater focus on ADHD. Conclusion: Our results highlight that ADHD can be considered not only a neurodevelopmental disorder but a persistent and complex condition, with detrimental consequences for quality of life in adulthood.

2021 - Cytomegalovirus reactivation after hematopoietic stem cell transplant with CMV-IG prophylaxis: A monocentric retrospective analysis [Articolo su rivista]
Gilioli, A.; Messerotti, A.; Bresciani, P.; Cuoghi, A.; Pioli, V.; Colasante, C.; Bettelli, F.; Giusti, D.; Forghieri, F.; Potenza, L.; Donatelli, F.; Giubbolini, R.; Galassi, L.; Marasca, R.; Banchelli, F.; D'Amico, R.; Pecorari, M.; Gennari, W.; Trenti, T.; Comoli, P.; Luppi, M.; Narni, F.
abstract

Human cytomegalovirus (CMV) represents the most common viral infection after hematopoietic stem cell transplant (HSCT), mainly occurring as reactivation from latency in seropositive patients, with a different prevalence based on the extent and timing of seroconversion in a specific population. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our Institution between 2013 and 2018, all of whom were prophylactically treated with CMV-IG (Megalotect Biotest®), to define the incidence and clinical outcomes of CMV reactivation and clinically significant infection. CMV infection occurred in 69% of our patient series, mainly resulting from reactivation, and CMV clinically significant infection (CS-CMVi) occurred in 48% of prophylactically treated patients. CMV infection and CS-CMVi impacted neither on relapse incidence nor on overall survival nor on relapse-free survival. Moreover, a very low incidence of CMV end-organ disease was documented. CMV-IG used alone as prophylactic therapy after HSCT does not effectively prevent CMV reactivation.

2021 - Early palliative/supportive care in acute myeloid leukaemia allows low aggression end-of-life interventions: Observational outpatient study [Articolo su rivista]
Potenza, L.; Scaravaglio, M.; Fortuna, D.; Giusti, D.; Colaci, E.; Pioli, V.; Morselli, M.; Forghieri, F.; Bettelli, F.; Messerotti, A.; Catellani, H.; Gilioli, A.; Marasca, R.; Borelli, E.; Bigi, S.; Longo, G.; Banchelli, F.; D'Amico, R.; L Back, A.; Efficace, F.; Bruera, E.; Luppi, M.; Bandieri, E.
abstract

Objectives: Early palliative supportive care has been associated with many advantages in patients with advanced cancer. However, this model is underutilised in patients with haematological malignancies. We investigated the presence and described the frequency of quality indicators for palliative care and end-of-life care in a cohort of patients with acute myeloid leukaemia receiving early palliative supportive care. Methods: This is an observational, retrospective study based on 215 patients consecutively enrolled at a haematology early palliative supportive care clinic in Modena, Italy. Comprehensive hospital chart reviews were performed to abstract the presence of well-established quality indicators for palliative care and for aggressiveness of care near the end of life. Results: 131 patients received a full early palliative supportive care intervention. All patients had at least one and 67 (51%) patients had four or more quality indicators for palliative care. Only 2.7% of them received chemotherapy in the last 14 days of life. None underwent intubation or cardiopulmonary resuscitation and was admitted to intensive care unit during the last month of life. Only 4% had either multiple hospitalisations or two or more emergency department access. Approximately half of them died at home or in a hospice. More than 40% did not receive transfusions within 7 days of death. The remaining 84 patients, considered late referrals to palliative care, demonstrated sensibly lower frequencies of the same indicators. Conclusions: Patients with acute myeloid leukaemia receiving early palliative supportive care demonstrated high frequency of quality indicators for palliative care and low rates of treatment aggressiveness at the end of life.

2021 - Effects of early vocal contact in the neonatal intensive care unit: Study protocol for a multi-centre, randomised clinical trial [Articolo su rivista]
Filippa, M.; Casa, E. D.; D'Amico, R.; Picciolini, O.; Lunardi, C.; Sansavini, A.; Ferrari, F.
abstract

Preterm infants are at risk for developing altered trajectories of cognitive, social, and linguistic competences compared to a term population. This is mainly due to medical and environmental factors, as they are exposed to an atypical auditory environment and simultaneously, long periods of early separation from their parents. The short-term effects of early vocal contact (EVC) on an infant’s early stability have been investigated. However, there is limited evidence of its impact on the infant’s autonomic nervous system maturation, as indexed by heart rate variability, and its long-term impact on infant neurodevelopment. Our multi-centric study aims to investigate the effects of EVC on a preterm infant’s physiology, neurobehaviour, and development. Eighty stable preterm infants, born at 25–32 weeks and 6 days gestational age, without specific abnormalities, will be enrolled and randomised to either an intervention or control group. The intervention group will receive EVC, where mothers will talk and sing to their infants for 10 min three times per week for 2 weeks. Mothers in the control group will be encouraged to spend the same amount of time next to the incubator and observe the infant’s behaviour through a standard cluster of indicators. Infants will be assessed at baseline; the end of the intervention; term equivalent age; and 3, 6, 12, and 24 months corrected age, with a battery of physiological, neurobehavioral, and developmental measures. Early interventions in the neonatal intensive care unit have demonstrated effects on the neurodevelopment of preterm infants, thereby lowering the negative long-term effects of an atypical auditory and interactional environment. Our proposed study will provide new insight into mother–infant early contact as a protective intervention against the sequelae of prematurity during this sensitive period of development. Early intervention, such as EVC, is intuitive and easy to im-plement in the daily care of preterm infants. However, its long-term effects on infant neurodevel-opment and maternal sensitivity and stress are still unclear. Trial Registration: NCT04759573, retrospectively registered, 02/17/2021.

2021 - Efficacy and safety of human papillomavirus vaccination in HIV-infected patients: a systematic review and meta-analysis [Articolo su rivista]
Zizza, A.; Banchelli, F.; Guido, M.; Marotta, C.; Di Gennaro, F.; Mazzucco, W.; Pistotti, V.; D'Amico, R.
abstract

The prophylactic vaccines available to protect against infections by HPV are well tolerated and highly immunogenic. People with HIV have a higher risk of developing HPV infection and HPV-associated cancers due to a lower immune response, and due to viral interactions. We performed a systematic review of RCTs to assess HPV vaccines efficacy and safety on HIV-infected people compared to placebo or no intervention in terms of seroconversion, infections, neoplasms, adverse events, CD4+ T-cell count and HIV viral load. The vaccine-group showed a seroconversion rate close to 100% for each vaccine and a significantly higher level of antibodies against HPV vaccine types, as compared to the placebo group (MD = 4333.3, 95% CI 2701.4; 5965.1 GMT EL.U./ml for HPV type 16 and MD = 1408.8, 95% CI 414.8; 2394.7 GMT EL.U./ml for HPV type 18). There were also no differences in terms of severe adverse events (RR = 0.6, 95% CI 0.2; 1.6) and no severe adverse events (RR = 0.6, 95% CI 0.9; 1.2) between vaccine and placebo groups. Secondary outcomes, such as CD4 + T-cell count and HIV viral load, did not differ between groups (MD = 14.8, 95% CI − 35.1; 64.6 cells/µl and MD = 0.0, 95% CI − 0.3; 0.3 log10 RNA copies/ml, respectively). Information on the remaining outcomes was scarce and that did not allow us to combine the data. The results support the use of the HPV vaccine in HIV-infected patients and highlight the need of further RCTs assessing the effectiveness of the HPV vaccine on infections and neoplasms.

2021 - Green line hospital-territory study: A single-blind randomized clinical trial for evaluation of technological challenges of continuous wireless monitoring in internal medicine, preliminary results [Articolo su rivista]
Pietrantonio, F.; Vinci, A.; Rosiello, F.; Alessi, E.; Pascucci, M.; Rainone, M.; Delli Castelli, M.; Ciamei, A.; Montagnese, F.; D'Amico, R.; Valerio, A.; Manfellotto, D.
abstract

Background: Wireless vital parameter continuous monitoring (WVPCM) after discharge is compared to regular monitoring to provide data on the clinical-economic impact of complex patients (CPs) discharged from Internal Medicine Units of Ospedale dei Castelli, Lazio. Primary outcome: Major complications (MC) reduction. Secondary outcomes: Patients who reached discharge criteria within the 7th day from admission; difference in MC incidence at the conclusion of the standard telemonitoring/clinical monitoring phase, 5 and 30 days after discharge; and conditions predisposing to MC occurrence. Methods: Open label randomized controlled trial with wearable wireless system that creates alerts on portable devices. Continuous glycemic monitoring is performed for patients with diabetes mellitus. Results: There were 110 patients enrolled (mean age: 76.2 years). Comorbidity: Cumulative Illness Rating Scale CIRS-CI (comorbidities index): 3.93, CIRS SI (severity index): 1.93. About 19% scored a BRASS (Blaylock Risk Assessment Screening Score) ≥20 indicating need for discharge planning requiring step-down care. Globally, 48% of patients in the control group had major complications (27 out of 56 patients), in contrast to 22% in the intervention group (12 out of 54 patients). Conclusions: Since WVPCM detects early complications during the post-discharge CPs monitoring, it increases safety and reduces inappropriate access to the Emergency Room, preventing avoidable re-hospitalizations.

2021 - Methylprednisolone as rescue therapy after tocilizumab failure in patients with severe COVID-19 pneumonia [Articolo su rivista]
Guaraldi, Giovanni; Banchelli, Federico; Milic, Jovana; Dolci, Giovanni; Massari, Marco; Corsini, Romina; Meschiari, Marianna; Girardis, Massimo; Busani, Stefano; Cossarizza, Andrea; Salvarani, Carlo; Mussini, Cristina; D'Amico, Roberto
abstract

2021 - New Perspectives in Different Gene Expression Profiles for Early and Locally Advanced Non-Small Cell Lung Cancer Stem Cells. [Articolo su rivista]
Masciale, Valentina; Banchelli, Federico; Grisendi, Giulia; D'Amico, Roberto; Maiorana, Antonino; Stefani, Alessandro; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice
abstract

Introduction: Lung cancer is one of the most common cancers in the world, causing over 1.7 million deaths in 2018. Thus far, no effective treatments against lung cancer for advanced stages have been found. For early stages, although surgery is considered the gold standard treatment, 30–55% of patients develop recurrence within the first 5 years of surgery. Our aim is to assess whether cancer stem cells (CSC) display overexpression of a pool of genes that were previously identified for adenocarcinoma recurrence in patients with early and locally advanced stages of non-small cell lung cancer (NSCLC). Methods: This cross-sectional study was carried out by harvesting surgical tumor specimens obtained from patients harboring early (I-II) and locally advanced (IIIA) stages of NSCLC. For each patient, cell sorting was performed to identify and isolate the ALDHhigh (CSC) and ALDHlow (cancer cells) populations. The mRNA expressions of 31 recurrence-related genes (target genes) in both ALDHhigh and ALDHlow populations were then assessed and compared. Results: Surgical specimens were obtained from 22 patients harboring NSCLC. Sixteen (51.6%) out of 31 recurrence-related genes were significantly overexpressed in ALDHhigh cells in the early stages and 9 (29.0%) were overexpressed in the locally advanced stages of NSCLC. Overall, the relative mRNA expressions for these recurrence-related genes were higher in early-stage patients. The average fold change, considering all 31 recurrence-related genes together, was 4.5 (95% CI = 3.1-6.3) in early-stage patients and 1.6 (95% CI = 1.2-2.2) in locally advanced-stage patients. Conclusions: Our study represents the first attempt toward identifying genes associated with recurrence that are overexpressed in cancer stem cells in patients with early and ocally advanced stages of NSCLC. This finding may contribute to the identification of new target therapies tailored for NSCLC stages.

2021 - Prevalence of uterine rupture among women with one prior low transverse cesarean and women with unscarred uterus undergoing labor induction with pge2: A systematic review and meta-Analysis [Articolo su rivista]
Chiossi, G.; Amico, R. D.; Tramontano, A. L.; Sampogna, V.; Laghi, V.; Facchinetti, F.
abstract

Background As uterine rupture may affect as many as 11/1000 women with 1 prior cesarean birth and 5/10.000 women with unscarred uterus undergoing labor induction, we intended to estimate the prevalence of such rare outcome when PGE2 is used for cervical ripening and labor induction. Methods We searched MEDLINE, ClinicalTrials.gov and the Cochrane library up to September 1st 2020. Retrospective and prospective cohort studies, as well as randomized controlled trials (RCTs) on singleton viable pregnancies receiving PGE2 for cervical ripening and labor induction were reviewed. Prevalence of uterine rupture was meta-Analyzed with Freeman-Tukey double arcsine transformation among women with 1 prior low transverse caesarean section and women with unscarred uterus. Results We reviewed 956 full text articles to include 69 studies. The pooled prevalence rate of uterine rupture is estimated to range between 2 and 9 out of 1000 women with 1 prior low transverse cesarean (5/1000; 95%CI 2-9/1000, 122/9000). The prevalence of uterine rupture among women with unscarred uterus is extremely low, reaching at most 0.7/100.000 (<1/100.000.000; 95%CI <1/100.000.000 0.7/100.000, 8/17.684). Conclusions Uterine rupture is a rare event during cervical ripening and labor induction with PGE2.

2021 - Safety and Success of Lumbar Puncture in Young Infants: A Prospective Observational Study [Articolo su rivista]
Bedetti, L.; Lugli, L.; Marrozzini, L.; Baraldi, A.; Leone, F.; Baroni, L.; Lucaccioni, L.; Rossi, C.; Roversi, M. F.; D'Amico, R.; Iughetti, L.; Berardi, A.
abstract

Objective: This study aims to evaluate safety and success rates of lumbar puncture (LP) and to identify factors associated with adverse events or failure of LP in infants. Methods: This two-center prospective observational study investigated infants younger than 90 days of age who underwent LP. Need for resuscitation oxygen desaturation (SpO2 < 90%), bradycardia and intraventricular hemorrhage were considered adverse events. LP failed if cerebrospinal spinal fluid was not collected or had traces of blood. Logistic regression analysis was used to evaluate whether corrected gestational age (GA), body weight at LP, position, and any respiratory support during LP affected SpO2 desaturation or failure of LP. Results: Among 204 LPs, 134 were performed in full-term and 70 in pre-term born infants. SpO2 desaturations occurred during 45 (22.4%) LPs. At multivariate analysis, lower GA at LP (p < 0.001), non-invasive respiratory support (p 0.007) and mechanical ventilation (p 0.004) were associated with SpO2 desaturations. Transient, self-resolving bradycardia occurred in 7 (3.4%) infants. Two infants had intraventricular hemorrhage detected within 72 h of LP. No further adverse events were registered. Failure of LP occurred in 38.2% of cases and was not associated with any of the factors evaluated. Conclusions: LP was safe in most infants. Body weight or GA at LP did not affect LP failure. These data are useful to clinicians, providing information on the safety of the procedure.

2021 - Serial cervical-length measurements after first episode of threatened preterm labor improve prediction of spontaneous delivery prior to 37 weeks' gestation [Articolo su rivista]
Chiossi, G.; Facchinetti, F.; Vergani, P.; Di Tommaso, M.; Marozio, L.; Acaia, B.; Pignatti, L.; Locatelli, A.; Spitaleri, M.; Benedetto, C.; Zaina, B.; D'Amico, R.
abstract

Objective: To assess whether repeat cervical-length (CL) measurement in women discharged from hospital after their first episode of threatened preterm labor can predict their risk of spontaneous preterm birth. Methods: This was a secondary analysis of a randomized controlled trial of maintenance tocolysis, in which CL was measured on transvaginal ultrasound at the time of hospital discharge and after 2, 4, 8 and 12 weeks, in women who remained undelivered after their first episode of threatened preterm labor. After univariate analysis, multivariate logistic regression analysis was used to assess whether CL < 10 mm at the time of hospital discharge or at any follow-up evaluation could predict spontaneous delivery prior to 37 weeks of gestation. Results: Of 226 women discharged after a diagnosis of threatened preterm labor, 57 (25.2%) delivered spontaneously prior to 37 weeks' gestation. The risk of spontaneous preterm birth was higher among women with CL < 10 mm at hospital discharge compared to those with CL ≥ 10 mm (adjusted odds ratio (aOR), 3.3; 95% CI, 1.2–9.2). Moreover, spontaneous preterm delivery was more common when CL < 10 mm was detected up to 2 weeks (aOR, 2.9; 95% CI, 1.1–7.3) or up to 4 weeks (aOR, 7.3; 95% CI, 2.3–22.8) post discharge, as compared with when CL was persistently ≥ 10 mm. The association was not significant when considering CL measurements at 8 weeks, and there was insufficient information to assess the effect of measurements obtained at 12 weeks. Conclusions: Women who remain undelivered after their first episode of threatened preterm labor continue to be at high risk of spontaneous preterm birth if their CL is below 10 mm at the time of hospital discharge or at any follow-up visit up to 4 weeks later. CL measurement could be included in the antenatal care of these women in order to stratify their risk of preterm birth, rationalize resource utilization and help clinicians improve pregnancy outcome. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

2021 - The impact of tocilizumab on respiratory support states transition and clinical outcomes in COVID-19 patients. A Markov model multi-state study [Articolo su rivista]
Milic, J.; Banchelli, F.; Meschiari, M.; Franceschini, E.; Ciusa, G.; Gozzi, L.; Volpi, S.; Faltoni, M.; Franceschi, G.; Iadisernia, V.; Yaacoub, D.; Dolci, G.; Bacca, E.; Rogati, C.; Tutone, M.; Burastero, G.; Raimondi, A.; Menozzi, M.; Cuomo, G.; Corradi, L.; Orlando, G.; Santoro, A.; Digaetano, M.; Puzzolante, C.; Carli, F.; Bedini, A.; Busani, S.; Girardis, M.; Cossarizza, A.; Miglio, R.; Mussini, C.; Guaraldi, G.; D'Amico, R.
abstract

Background The benefit of tocilizumab on mortality and time to recovery in people with severe COVID pneumonia may depend on appropriate timing. The objective was to estimate the impact of tocilizumab administration on switching respiratory support states, mortality and time to recovery. Methods In an observational study, a continuous-time Markov multi-state model was used to describe the sequence of respiratory support states including: no respiratory support (NRS), oxygen therapy (OT), non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), OT in recovery, NRS in recovery. Results Two hundred seventy-one consecutive adult patients were included in the analyses contributing to 695 transitions across states. The prevalence of patients in each respiratory support state was estimated with stack probability plots, comparing people treated with and without tocilizumab since the beginning of the OT state. A positive effect of tocilizumab on the probability of moving from the invasive and non-invasive mechanical NIV/IMV state to the OT in recovery state (HR = 2.6, 95% CI = 1.2–5.2) was observed. Furthermore, a reduced risk of death was observed in patients in NIV/IMV (HR = 0.3, 95% CI = 0.1–0.7) or in OT (HR = 0.1, 95% CI = 0.0–0.8) treated with tocilizumab. Conclusion To conclude, we were able to show the positive impact of tocilizumab used in different disease stages depicted by respiratory support states. The use of the multi-state Markov model allowed to harmonize the heterogeneous mortality and recovery endpoints and summarize results with stack probability plots. This approach could inform randomized clinical trials regarding tocilizumab, support disease management and hospital decision making.

2021 - Topical antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving mechanical ventilation [Articolo su rivista]
Minozzi, S.; Pifferi, S.; Brazzi, L.; Pecoraro, V.; Montrucchio, G.; D'Amico, R.
abstract

Background: Patients treated with mechanical ventilation in intensive care units (ICUs) have a high risk of developing respiratory tract infections (RTIs). Ventilator-associated pneumonia (VAP) has been estimated to affect 5% to 40% of patients treated with mechanical ventilation for at least 48 hours. The attributable mortality rate of VAP has been estimated at about 9%. Selective digestive decontamination (SDD), which consists of the topical application of non-absorbable antimicrobial agents to the oropharynx and gastroenteric tract during the whole period of mechanical ventilation, is often used to reduce the risk of VAP. A related treatment is selective oropharyngeal decontamination (SOD), in which topical antibiotics are applied to the oropharynx only. This is an update of a review first published in 1997 and updated in 2002, 2004, and 2009. Objectives: To assess the effect of topical antibiotic regimens (SDD and SOD), given alone or in combination with systemic antibiotics, to prevent mortality and respiratory infections in patients receiving mechanical ventilation for at least 48 hours in ICUs. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, PubMed, and Embase on 5 February 2020. We also searched the WHO ICTRP and ClinicalTrials.gov for ongoing and unpublished studies on 5 February 2020. All searches included non-English language literature. We handsearched references of topic-related systematic reviews and the included studies. Selection criteria: Randomised controlled trials (RCTs) and cluster-RCTs assessing the efficacy and safety of topical prophylactic antibiotic regimens in adults receiving intensive care and mechanical ventilation. The included studies compared topical plus systemic antibiotics versus placebo or no treatment; topical antibiotics versus no treatment; and topical plus systemic antibiotics versus systemic antibiotics. Data collection and analysis: We used standard methodological procedures expected by Cochrane. Main results: We included a total of 41 trials involving 11,004 participants (five new studies were added in this update). The minimum duration of mechanical ventilation ranged from 2 (19 studies) to 6 days (one study). Thirteen studies reported the mean length of ICU stay, ranging from 11 to 33 days. The percentage of immunocompromised patients ranged from 0% (10 studies) to 22% (1 study). The reporting quality of the majority of included studies was very poor, so we judged more than 40% of the studies as at unclear risk of selection bias. We judged all studies to be at low risk of performance bias, though 47.6% were open-label, because hospitals usually have standardised infection control programmes, and possible subjective decisions on who should be tested for the presence or absence of RTIs are unlikely in an ICU setting. Regarding detection bias, we judged all included studies as at low risk for the outcome mortality. For the outcome RTIs, we judged all double-blind studies as at low risk of detection bias. We judged five open-label studies as at high risk of detection bias, as the diagnosis of RTI was not based on microbiological exams; we judged the remaining open-label studies as at low risk of detection bias, as a standardised set of diagnostic criteria, including results of microbiological exams, were used. Topical plus systemic antibiotic prophylaxis reduces overall mortality compared with placebo or no treatment (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.73 to 0.96; 18 studies; 5290 participants; high-certainty evidence). Based on an illustrative risk of 303 deaths in 1000 people this equates to 48 (95% CI 15 to 79) fewer deaths with topical plus systemic antibiotic prophylaxis. Topical plus systemic antibiotic prophylaxis probably reduces RTIs (RR 0.43, 95% CI 0.35 to 0.53; 17 studies; 2951 participants; moderate-certainty evidence). Ba

2020 - A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: a retrospective study with an external evaluation [Articolo su rivista]
Prat, A; Guarneri, V; Paré, L; Griguolo, G; Pascual, T; Dieci, Mv; Chic, N; González-Farré, B; Frassoldati, A; Sanfeliu, E; Cejalvo, Jm; Muñoz, M; Bisagni, G; Brasó-Maristany, F; Urso, L; Vidal, M; Brandes, Aa; Adamo, B; Musolino, A; Miglietta, F; Conte, B; Oliveira, M; Saura, C; Pernas, S; Alarcón, J; Llombart-Cussac, A; Cortés, J; Manso, L; López, R; Ciruelos, E; Schettini, F; Villagrasa, P; Carey, La; Perou, Cm; Piacentini, F; D'Amico, R; Tagliafico, E; Parker, Js; Conte, P
abstract

Background: In early-stage HER2-positive breast cancer, escalation or de-escalation of systemic therapy is a controversial topic. As an aid to treatment decisions, we aimed to develop a prognostic assay that integrates multiple data types for predicting survival outcome in patients with newly diagnosed HER2-positive breast cancer. Methods: We derived a combined prognostic model using retrospective clinical-pathological data on stromal tumour-infiltrating lymphocytes, PAM50 subtypes, and expression of 55 genes obtained from patients who participated in the Short-HER phase 3 trial. The trial enrolled patients with newly diagnosed, node-positive, HER2-positive breast cancer or, if node negative, with at least one risk factor (ie, tumour size >2 cm, histological grade 3, lymphovascular invasion, Ki67 >20%, age ≤35 years, or hormone receptor negativity), and randomly assigned them to adjuvant anthracycline plus taxane-based combinations with either 9 weeks or 1 year of trastuzumab. Trastuzumab was administered intravenously every 3 weeks (8 mg/kg loading dose at first cycle, and 6 mg/kg thereafter) for 18 doses or weekly (4 mg/kg loading dose in the first week, and 2 mg/kg thereafter) for 9 weeks, starting concomitantly with the first taxane dose. Median follow-up was 91·4 months (IQR 75·1-105·6). The primary objective of our study was to derive and evaluate a combined prognostic score associated with distant metastasis-free survival (the time between randomisation and distant recurrence or death before recurrence), an exploratory endpoint in Short-HER. Patient samples in the training dataset were split into a training set (n=290) and a testing set (n=145), balancing for event and treatment group. The training set was further stratified into 100 iterations of Monte-Carlo cross validation (MCCV). Cox proportional hazard models were fit to MCCV training samples using Elastic-Net. A maximum of 92 features were assessed. The final prognostic model was evaluated in an independent combined dataset of 267 patients with early-stage HER2-positive breast cancer treated with different neoadjuvant and adjuvant anti-HER2-based combinations and from four other studies (PAMELA, CHER-LOB, Hospital Clinic, and Padova) with disease-free survival outcome data. Findings: From Short-HER, data from 435 (35%) of 1254 patients for tumour size (T1 vs rest), nodal status (N0 vs rest), number of tumour-infiltrating lymphocytes (continuous variable), subtype (HER2-enriched and basal-like vs rest), and 13 genes composed the final model (named HER2DX). HER2DX was significantly associated with distant metastasis-free survival as a continuous variable (p<0·0001). HER2DX median score for quartiles 1-2 was identified as the cutoff to identify low-risk patients; and the score that distinguished quartile 3 from quartile 4 was the cutoff to distinguish medium-risk and high-risk populations. The 5-year distant metastasis-free survival of the low-risk, medium-risk, and high-risk populations were 98·1% (95% CI 96·3-99·9), 88·9% (83·2-95·0), and 73·9% (66·0-82·7), respectively (low-risk vs high-risk hazard ratio [HR] 0·04, 95% CI 0·0-0·1, p<0·0001). In the evaluation cohort, HER2DX was significantly associated with disease-free survival as a continuous variable (HR 2·77, 95% CI 1·4-5·6, p=0·0040) and as group categories (low-risk vs high-risk HR 0·27, 0·1-0·7, p=0·005). 5-year disease-free survival in the HER2DX low-risk group was 93·5% (89·0-98·3%) and in the high-risk group was 81·1% (71·5-92·1). Interpretation: The HER2DX combined prognostic score identifies patients with early-stage, HER2-positive breast cancer who might be candidates for escalated or de-escalated systemic treatment. Future clinical validation of HER2DX seems warranted to establish its use in different scenarios, especially in the neoadjuvant setting.

2020 - ALDH Expression in Angiosarcoma of the Lung: A Potential Marker of Aggressiveness? [Articolo su rivista]
Aramini, Beatrice; Masciale, Valentina; Bianchi, Daniel; Manfredini, Beatrice; Banchelli, Federico; D'Amico, Roberto; Bertolini, Federica; Dominici, Massimo; Morandi, Uliano; Maiorana, Antonino
abstract

Background: Primary angiosarcoma of the lung is a very aggressive rare malignant disease resulting in a severe prognosis (1). This type of cancer represents about 2% of all soft tissue sarcomas and has a high rate of metastasis through the hematogenous route. For the rarity of this malignant vascular tumor it is still challenging to set a diagnosis (1). The diagnostic features that have thus far been considered include primarily clinical and radiological findings. In some cases, immunohistochemical characteristics based on the most common markers used in pathology have been described. The aim of this report is to present two cases of angiosarcoma of the lung in which the aldehyde dehydrogenase (ALDH) marker was analyzed by immunohistochemistry. Methods: We report two cases of angiosarcoma of the lung in patients underwent lung surgery at our Unit. In addition to the standard histopathological analysis for this disease, immunohistochemistry using an ALDH1A1 antibody was performed in both of the cases. For ALDH quantification, a semi-quantitative method based on the positivity of the tumor cells was used: 0 (<5%), 1 (5–25%), 2 (>25–50%), 3 (>50–75%), 4 (>75%). Results: One patient with recurrent lung disease survived, achieving complete remission after chemo- and radiotherapy. The second patient died of recurrent disease within 5 years of diagnosis. ALDH1A1 was evaluated in both of these cases using an immunohistochemistry scoring system based on the positivity for this marker. The scores were consistent with the patients’ clinical outcomes, as the lower (score 1) was observed in the patient with the better clinical outcome, while the higher (score 3) was seen in the patient with the worse outcome. Conclusion: Our data suggest that ALDH may be an important clinical marker in angiosarcoma of the lung. Although further studies need to be performed in a larger cohort of patients, we believe that, if the results will be confirmed, ALDH1A1 may be used to stratify patients in terms of prognosis and for targeted therapy.

2020 - CD44+/EPCAM+ cells detect a subpopulation of ALDHhigh cells in human non-small cell lung cancer: A chance for targeting cancer stem cells? [Articolo su rivista]
Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Sighinolfi, Pamela; Stefani, Alessandro; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice
abstract

Objectives: Several studies demonstrated that aldehyde dehydrogenase (ALDH) and CD44 are the most considered cancer stem cells (CSC) markers. However, a comparison between ALDH high cells and CD44+ cells have been previously described with no significant correlation. Indeed, the aim of the present research is to identify a superficial marker able to match with ALDH high cells population in freshly isolated human lung cancer cells. Materials and Methods: This cross-sectional study analyzed the expression of ALDHhigh/low cells and the positivity for CD44 and epithelium cell adhesion molecule (EPCAM) antigens in surgical lung cancer tissues. The main approach was a cytofluorimetric analysis of ALDH expression and positivity for CD44/EPCAM on primary cell population obtained from 23 patients harboring NSCLC. Results: There was a highly positive correlation between the expressions of ALDHhigh and CD44+/EPCAM+ cells, with a Pearson’s correlation coefficient equal to 0.69 (95% CI 0.39–0.86; P = 0.0002), and Spearman’s correlation coefficient equal to 0.52 (P = 0.0124). The average paired difference between the expression of ALDHhigh and CD44+/EPCAM+ cells was very close to 0, being 0.1% (SD 2.5%); there was no difference between these subpopulations in terms of means (95% CI = –1.0; 1.2%, P = 0.8464). These results highlight a strong similarity between ALDHhigh and CD44+/EPCAM+ cells. Conclusions: Our study is the first attempt which identifies a high correlation between the ALDHhigh and the CD44+/EPCAM+ cells, thus suggesting the possibility to use this superficial marker for future target treatments against lung cancer stem cells.

2020 - Cancer Stem-Like Cells in a Case of an Inflammatory Myofibroblastic Tumor of the Lung. [Articolo su rivista]
Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Sighinolfi, Pamela; Brugioni, Lucio; Stefani, Alessandro; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice
abstract

Background: Inflammatory myofibroblast tumor (IMT) is a rare tumor with obscure etiopathogenesis in which different inflammatory cells and myofibroblastic spindle cells are seen histologically. Although the majority of these neoplasms have a benign clinical course, the malignant form has also been reported. The gold standard is surgical treatment for complete removal. Our report describes a 50-year-old woman who underwent surgery for IMT of the lung. The aim is to determine whether cancer stem cells may be present in IMT of the lung. Methods: In April 2018, the patient underwent surgery for tumor mass asportation through lateral thoracotomy. The histology of the tumor was consistent with IMT of the lung. The ALDEFLUOR assay, after tissue digestion, was used to identify and sort human lung cancer cells expressing high and low aldehyde dehydrogenase (ALDH) activity. SOX2, NANOG, OCT-4, and c-MYC positivity were additionally determined by immunohistochemistry. Results: The specimen contained 1.10% ALDHhigh cells among all viable lung cancer cells, which indicates the population of cancer stem cells is not negligible. Immunohistochemically assessed cell positivity for ALDH1A1, SOX2, NANOG, OCT-4, and c-MYC, which are considered as lung cancer stem-like cells markers. Conclusion: For the first time, we demonstrated the presence of cancer stem cells in a case of IMT of the lung. This finding may provide a base for considering new pathological and molecular aspects of this tumor. This perspective suggests further studies to understand the possibility of developing recurrence depending on the presence of cancer stem cells.

2020 - Correlation Between Immune-related Adverse Event (IRAE) Occurrence and Clinical Outcome in Patients With Metastatic Renal Cell Carcinoma (mRCC) Treated With Nivolumab: IRAENE Trial, an Italian Multi-institutional Retrospective Study [Articolo su rivista]
Vitale, M. G.; Pipitone, S.; Venturelli, M.; Baldessari, C.; Porta, C.; Iannuzzi, F.; Basso, U.; Scagliarini, S.; Zucali, P. A.; Galli, L.; Rossetti, S.; Caserta, C.; Bracarda, S.; Iacovelli, R.; Masini, C.; Cortellini, A.; Di Girolamo, S.; Buti, S.; Fornarini, G.; Carrozza, F.; Santoni, M.; Caputo, F.; Giaquinta, S.; Balduzzi, S.; D'Amico, R.; Vitale, G.; Mighali, P.; Sabbatini, R.
abstract

Background: Immunotherapy has brought clinical benefits to patients with metastatic renal cell cancer (mRCC). Most patients tolerate immunotherapy but serious immune-related adverse events (irAEs) have been reported. Some studies indicate a correlation between irAEs and clinical response in other cancer types (eg, lung cancer and melanoma). For patients with mRCC, the impact of irAE on clinical outcome is unknown. Patients and Methods: A retrospective review of 167 patients with mRCC treated with nivolumab as standard of care between March 2017 and January 2018 in 16 Italian centers was performed. irAEs were assessed using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results: Any grade and grade 3/4 irAEs occurred in 46% and 8.9% of patients, respectively. The median time to appearance of irAEs was 10 weeks; 38.8% of patients required steroid treatment. The most common irAEs were cutaneous (33.7%) and gastrointestinal (23.3%). The median overall survival and progression-free survival were 20.13 and 7.86 months, respectively. Patients with irAEs showed a greater overall survival (hazard ratio, 0.38; 95% confidence interval [CI], 0.23-0.63) and progression-free survival (hazard ratio, 0.44; 95% CI, 0.29-0.66) benefit as well as better overall response rate (27.3% vs. 13.7%; odds ratio, 2.36; 95% CI, 1.03-5.44) and disease control rate (68.8% vs. 48%; odds ratio, 2.4; 95% CI, 1.23-4.67) if compared with those without irAEs. No correlation was found between steroid use and clinical outcomes. Conclusions: Our analysis revealed that the appearance of irAEs was associated with better outcomes in patients treated with nivolumab. This data may be limited by sample size and the retrospective nature of the study. In the past years, immunotherapy has demonstrated an important role in the treatment of several types of cancer. Some studies indicate a correlation between immune-related adverse events (irAEs) and clinical response in other cancer types. For patients with metastatic renal cell carcinoma, the impact of irAEs on clinical outcome is unknown. We conducted a retrospective observational review of 167 patients with metastatic renal cell carcinoma, previously treated with standard treatment, who received nivolumab in monotherapy as clinical practice. Any grade and grade 3/4 irAEs occurred in 46% and 8.9% of patients, respectively. Patients with irAEs showed a more significant overall survival and progression-free survival benefit, and better objective response rate and disease control rate if compared with patients without irAEs. No correlation was found between steroid use and clinical outcomes. Our analysis reveals that the appearance of irAE correlates with better outcomes in patients treated with nivolumab. This data may be limited by sample size and the retrospective nature of the study.

2020 - Early inspiratory effort assessment by esophageal manometry early predicts noninvasive ventilation outcome in de novo respiratory failure: a pilot study. [Articolo su rivista]
Tonelli, Roberto; Fantini, Riccardo; Tabbì, Luca; Castaniere, Ivana; Pisani, Lara; Pellegrino, Maria Rosaria; DELLA CASA, Giovanni; D'Amico, Roberto; Girardis, Massimo; Nava, Stefano; Clini, Enrico M.; Marchioni, Alessandro
abstract

Rationale: The role of inspiratory effort has still to be determined as a potential predictors of non-invasive mechanical ventilation (NIV) failure in acute hypoxic de novo respiratory failure (AHRF). Objectives: We explore the hypothesis that inspiratory effort might be a major determinant of NIV failure in these patients. Methods: Thirty consecutive patients with AHRF admitted to a single center and candidates for a 24-hour NIV trial were enrolled. Clinical features, tidal changes in esophageal (ΔPes) and dynamic transpulmonary pressure (ΔPL), expiratory tidal volume, and respiratory rate were recorded on admission and 2-4-12-24 hours after NIV start, and were tested for correlation with outcomes. Measurements and Main Results: ΔPes and ΔPes/ΔPL were significantly lower 2 hours after NIV start in patients who successfully completed the NIV trial (n=18) compared to those who needed endotracheal intubation (n=12) [median=11 (IQR=8–15) cmH2O vs 31.5 (30–36) cmH2O, p<0.0001] while other variables differed later. ΔPes was not related to other predictors of NIV failure at baseline. NIV-induced reduction in ΔPes of 10 cmH2O or more after 2 hours of treatment was strongly associated to avoidance of intubation, and represented the most accurate predictor of treatment success (OR=15, 95%CI 2.8-110, p=0.001, AUC=0.97, 95%CI 0.91–1, p<0.0001). Conclusions: The magnitude of inspiratory effort relief as assessed by ΔPes variation within the first 2 hours of NIV was an early and accurate predictor of NIV outcome at 24 hours.

2020 - Early versus delayed palliative/supportive care in advanced cancer: An observational study [Articolo su rivista]
Bandieri, E.; Banchelli, F.; Artioli, F.; Mucciarini, C.; Razzini, G.; Cruciani, M.; Potenza, L.; D'Amico, R.; Efficace, F.; Bruera, E.; Luppi, M.
abstract

Objective: The positive impact of early palliative care interventions in advanced cancer patients has so far been largely evaluated in randomised controlled trials. This study aimed at providing information on the value of early palliative/supportive care, integrated with standard oncologic care, in a real-life setting. Methods: This was a retrospective observational study of 292 advanced cancer patients consecutively admitted at Carpi Hospital in Modena, Italy, between 2014 and 2017. For the purpose of this analysis, patients were classified into two groups (early and delayed palliative/supportive care patients), and analysed for different clinical indicators. Early and delayed palliative/supportive care were classified according to the time elapsed from advanced cancer diagnosis until palliative/supportive care start. Results: A total of 200 patients (68%), with at least three visits, were included in the analyses. The frequency of chemotherapy use in the last 60 days of life was 3.4% and 24.6% in the early and delayed groups, respectively (adjusted OR=0.1; 95% CI 0.0 to 0.4; p=0.002). The estimated survival probability at 1 year was 74.5% (95% CI 65.0% to 85.4%) and 45.5% (95% CI 37.6% to 55.0%), in the early and delayed groups, respectively. Performance status, pain and all the Edmonton Symptom Assessment Scale items, assessed at baseline and at 1 to 12 weeks after the intervention, showed significant improvement over time. However, no between-group differences were found with regard to symptom outcomes. Conclusions: An earlier palliative/supportive care intervention was associated with reduced aggressiveness of therapy, in patients receiving community oncology care. Symptom burden was improved by early palliative/supportive care, independently of the timing of patient referral.

2020 - Effectiveness of Progestogens as Maintenance Tocolysis and Urogenital Cultures: Secondary Analysis of the PROTECT Trial [Articolo su rivista]
Pignatti, L.; D'Amico, R.; Vergani, P.; Di Tommaso, M.; Acaia, B.; Benedetto, C.; Facchinetti, F.
abstract

Background In a recently published multicenter randomized controlled trial, we demonstrated that progestogens are not effective as maintenance tocolysis. Objective This study was aimed to evaluate if previous finding may be affected by positive urine culture and/or vaginal swab. Study Design We performed a secondary analysis of the PROTECT trial (NCT01178788). Women with singleton pregnancy between 22 and 31 6/7weeks' gestation, admitted for threatened preterm labor were considered. At admission, we collected urine culture and vaginal swabs. At discharge, women with a cervical length ≤25 mm were randomized to vaginal progesterone or 17α-hydroxyprogesterone caproate or observation group. We used Chi-square statistics, considering 97.5% CI (confidence interval) and p -value less than 0.025 for significance. Results Urine culture and vaginal swabs were collected in 232 out of 235 patients included in the primary analysis. Overall, 31 out of 232 women (13.4%) had positive urine culture and 60 out of 232 (25.9%) had positive vaginal swab. In women with negative urine culture, a higher rate of preterm birth was found in vaginal progesterone group (27/69, 39.7%) respect with controls (14/68, 20.6%; relative risk [RR] = 1.90; 97.5% CI: 1.01-3.57; p = 0.018). Conclusion Among women with negative urine culture, the rate of preterm birth <37 weeks' gestation was significantly increased in those receiving vaginal progesterone, reinforcing our previous findings in symptomatic women.

2020 - Engaging clinicians to identify and prioritize disinvestment opportunities in the treatment of neurodegenerative diseases: a qualitative study [Articolo su rivista]
Ciannameo, A.; Chiarenza, A.; Filippini, G.; D'Amico, R.; Grilli, R.
abstract

Introduction. The overuse of health care interventions is a problem which has clinical and economic implications. On a clinical level this means that ineffective interventions or effective interventions in inappropriate clinical indications are used. On an economic level it refers to allocative inefficiency which implies that these resources could possibly be used for interventions of major clinical utility. The contribution of health professionals in the context of reallocation disinvestment policies is still little investigated. This study involved 25 neurologists in the process of identifying low value interventions in the management of stroke, dementia, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Methods. The Nominal Group Technique was applied in the context of 5 Focus Groups (FG) in order to reach a consensus to identify and prioritize disinvestment opportunities in the treatment of the 5 neurodegenerative diseases. Qualitative data were coded, categorised, and analysed, applying the six-phase approach to thematic analysis, with the support of Atlas Ti7. Results. Within 5 categories of “low value intervention”, 25 clinical interventions were identified: 6 pharmacological, 16 diagnostic, 3 clinical-therapeutic. FG findings describe: how clinicians view the issue of disinvestment, both in absolute and relative terms; the factors which contribute to the use of low-value interventions; the explicit link between the disinvestment process and the reallocation of resources. Discussion. This study revealed that factors that hinder the disinvestment of inappropriate practices involve elements that are not only technical or clinical, but also relational and care-related contexts.

2020 - Epidemiology and clinical outcomes of latent tuberculosis infection in adults affected with acute leukemia or aplastic anemia: a retrospective single-center study [Articolo su rivista]
Bettelli, F.; Giusti, D.; Morselli, M.; Colaci, E.; Nasillo, V.; Pioli, V.; Gilioli, A.; Iotti, S.; Galassi, L.; Giubbolini, R.; Colasante, C.; Catellani, H.; Barozzi, P.; Lagreca, I.; Vallerini, D.; Maffei, R.; Franceschini, E.; Mussini, C.; Banchelli, F.; D'Amico, R.; Marasca, R.; Narni, F.; Potenza, L.; Comoli, P.; Luppi, M.; Forghieri, F.
abstract

2020 - Expression of ALDH and SOX-2 in Pulmonary Sclerosing Pnemocytoma (PSP) of the Lung: Is There a Meaning Behind? [Articolo su rivista]
Aramini, Beatrice; Masciale, Valentina; Manfredini, Beatrice; Bianchi, Daniel; Banchelli, Federico; D'Amico, Roberto; Bertolini, Federica; Dominici, Massimo; Morandi, Uliano; Maiorana, Antonino
abstract

Background: Pulmonary sclerosing pneumocytoma (PSP) is a rare benign pulmonary tumor that derives from primitive respiratory epithelium of the pulmonary alveolus. The etiology and pathogenesis are still unclear. Histopathological diagnosis focuses on cells that are positive for TTF1, EMA, cytokeratin-7, and CAM 5.2. The aim of our study is to highlight the elevated expression of ALDH and the presence of SOX-2 in pulmonary sclerosing pneumocytoma. Methods: We report five cases of pulmonary sclerosing pneumocytoma undergone surgery at our Division of Thoracic Surgery, during a period between 1994 and 2011. ALDH and SOX-2 markers were also tested for positivity in all the patients. Results: Patients showed elevated expression of ALDH during immunohistochemistry and mild expression of SOX-2, although in two cases in which SOX-2 was highly expressed. Among these two patients, one presented with lymph node recurrence while the other had no recurrence with a PET-positive nodule. In particular, the patient who had developed recurrence had an ALDH score of 4 and a SOX-2 score of 3, whereas the patient with the PET-positive nodule showed an ALDH score of 4 with a mild SOX-2expression of score 1. Conclusions: This is the first attempt demonstrating the elevated expression of ALDH in this disease. SOX-2 expression was noted in both the patient who developed recurrence and the patient with a PET-positive nodule. We believe that further investigation may be highly useful to better characterize these two markers as well as understandtheir function.

2020 - GREASE II. A phase II randomized, 12-month, parallel-group, superiority study to evaluate the efficacy of a Modified Atkins Diet in Autosomal Dominant Polycystic Kidney Disease patients [Articolo su rivista]
Testa, Francesca; Marchiò, Maddalena; D’Amico, Roberto; Giovanella, Silvia; Ligabue, Giulia; Fontana, Francesco; Alfano, Gaetano; Cappelli, Gianni; Biagini, Giuseppe; Magistroni, Riccardo
abstract

Introduction Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a condition that causes progressive renal function decline. Preclinical data suggest the presence of a profound metabolic derangement in ADPKD. Cystic cells shift their energy metabolism from oxidative phosphorylation to aerobic glycolysis, show inhibition of fatty acid oxidation and become glutamine and arginine dependent. Recent preclinical experiences have suggested beneficial effect in terms of reduction of cystic size, interstitial fibrosis and disease progression, targeting these deregulated metabolic pathways by ketosis induction. The dietetic approach to ADPKD, because of low cost and absence of toxicity, represents an interesting therapeutic strategy. Methods and analysis The protocol describes a phase II clinical trial that will evaluate the effect on Total Kidney Volume, safety and tolerability of a ketogenic diet in a selected ADPKD population. The trial will have, as secondary objective, the evaluation of the ability of the ketogenic diet to slow down the renal function decline. This will be a 12-month randomized, parallel group, two arm, superiority trial with 1:1 allocation to evaluate the efficacy of a Modified Atkins Diet protocol compared to a balanced normocaloric diet on 90 ADPKD patients. Dissemination The study results will be released to the patients and the medical community.

2020 - Introduction and methods of the evidence-based guidelines for the diagnosis and management of autism spectrum disorder by the Italian National Institute of Health [Articolo su rivista]
Morgano, G. P.; Fulceri, F.; Nardocci, F.; Barbui, C.; Ostuzzi, G.; Papola, D.; Fatta, L. M.; Fauci, A. J.; Coclite, D.; Napoletano, A.; De Crescenzo, F.; D'Alo, G. L.; Amato, L.; Cinquini, M.; Iannone, P.; Schunemann, H. J.; Scattoni, M. L.; Arduino, M.; Bellosio, C.; Biasci, S.; Buono, S.; Cappa, C.; Cordo, C.; Di Tommaso, E.; Duff, C. M.; Felici, C.; Massagli, A.; Molteni, M.; Reali, L.; Tancredi, R.; Valeri, G.; Venturini, L.; Zuddas, A.; Andreoli, M.; Bergamin, C.; Bertelli, M.; Catania, D.; Cavagnola, R.; Cirrincione, P.; Corti, S.; Crognale, M.; Faggioli, R.; Giogoli, A. M.; Grittani, S.; Keller, R.; Pace, P.; Politi, P.; Starace, F.; Valenti, M.; Balduzzi, S.; Basile, M.; Cruciani, F.; D'Amico, R.; Davoli, M.; Lorenzo, M. G.; Minozzi, S.; Mitrova, Z.; Moschetti, I.; Pistotti, V.; Saulle, R.; Vecchi, S.
abstract

Background: Autism Spectrum Disorder (ASD) is a neuro-developmental disorder that affects communication and behavior with a prevalence of approximately 1% worldwide. Health outcomes of interventions for ASD are largely Participant Reported Outcomes (PROs). Specific guidelines can help support the best care for people with ASD to optimize these health outcomes but they have to adhere to standards for their development to be trustworthy. Objective: The goal of this article is to describe the new methodological standards of the Italian National Institute of Health and novel aspects of this guideline development process. This article will serve as a reference standard for future guideline development in the Italian setting. Methods: We applied the new standards of the Italian National Institute of Health to the two guidelines on diagnosis and management of children/adolescents and adults with ASD, with a focus on the scoping, panel composition, management of conflict of interest, generation and prioritization of research questions, early stakeholders' involvement, and PROs. Recommendations are based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence-to-Decision frameworks. Results: Following a public application process, the ISS established two multidisciplinary panels including people with ASD and/or their caregivers. Seventy-nine research questions were identified as potentially relevant for the guideline on children and adolescents with ASD and 31 for the one on adults with ASD. Questions deemed to have the highest priority were selected for inclusion in the guidelines. Other stakeholders valued their early involvement in the process which will largely focus on PROs. The panels then successfully piloted the development of recommendations using the methodological standards and process set by the ISS with a focus on PROs. Conclusions: In this article, we describe the development of practice guidelines that focus on PROs for the diagnosis and management of ASD based on novel methods for question prioritization and stakeholder involvement. The recommendations allow for the adoption or adaptation to international settings.

2020 - Investigating the association between physicians self-efficacy regarding communication skills and risk of “burnout” [Articolo su rivista]
Messerotti, Andrea; Banchelli, Federico; Ferrari, Silvia; Barbieri, Emiliano; Bettelli, Francesca; Bandieri, Elena; Giusti, Davide; Catellani, Hillary; Borelli, Eleonora; Colaci, Elisabetta; Pioli, Valeria; Morselli, Monica; Forghieri, Fabio; Galeazzi, Gian Maria; Marasca, Roberto; Bigi, Sarah; D’Amico, Roberto; Martin, Peter; Efficace, Fabio; Luppi, Mario; Potenza, Leonardo
abstract

2020 - Kidney dysfunction and short term all-cause mortality after transcatheter aortic valve implantation [Articolo su rivista]
Sgura, F. A.; Arrotti, S.; Magnavacchi, P.; Monopoli, D.; Gabbieri, D.; Banchelli, F.; Tondi, S.; Denegri, A.; D'Amico, R.; Guiducci, V.; Vignali, L.; Boriani, G.
abstract

Background: Acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) has been associated with worse outcomes. However, the impact on outcome of AKI in TAVI-patients is not well established. Methods: Inoperable patients with severe aortic stenosis (AS) undergoing TAVI in 2010-2018 were enrolled in this study. AKI and chronic kidney disease (CKD) were defined according to KDIGO guidelines. Patients were divided in two groups according to post-procedural AKI development. The primary endpoint was 30-day all-cause mortality across the two groups. Results: A total of 373 patients (mean age 82.3 ± 6) were analyzed. Compared to non-AKI patients, those who developed AKI, were treated more frequently with trans-apical TAVI (66% vs 35%, p<0.01), with greater amount of contrast medium (200.6 vs 170.4 ml, p=0.02) and in presence of clinically significant peripheral artery disease (PAD, 33% vs 21%, p=0.04). Trans-apical access (OR 3.24, 95% CI 1.76-5.60, p<0.01) was associated with a 3-fold risk of AKI. After adjustment for age, Society of Thoracic Surgery risk score (STS), PAD, access type, EF and contrast medium amount, patients with AKI presented an increased risk of 30-day all-cause mortality (HR=1.25, 95%CI 1.09-1.69, p=0.008). Patients with CKD IV and V, who developed AKI, presented a 9-fold 30-day mortality risk (HR=9.71, 95% CI 2.40-39.2, p=0.001). Conclusion: In our analysis, AKI was a strong predictor of 30-day all-cause mortality. Particularly, patients with severe CKD with AKI showed the highest 30-day mortality risk. Thus, this group of patients might benefit from closer monitoring and specific kidney protection therapies.

2020 - Multi-centre, three arm, randomized controlled trial on the use of methylprednisolone and unfractionated heparin in critically ill ventilated patients with pneumonia from SARS-CoV-2 infection: A structured summary of a study protocol for a randomised controlled trial [Articolo su rivista]
Busani, S.; Tosi, M.; Mighali, P.; Vandelli, P.; D'Amico, R.; Marietta, M.; Forfori, F.; Donati, A.; Cinnella, G.; De Monte, A.; Pasero, D.; Bellani, G.; Tascini, C.; Foti, G.; Ranieri, M.; Girardis, M.
abstract

OBJECTIVES: To assess the hypothesis that an adjunctive therapy with methylprednisolone and unfractionated heparin (UFH) or with methylprednisolone and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill ventilated patients with pneumonia from SARS-CoV-2 infection compared to LMWH alone. TRIAL DESIGN: The study is designed as a multi-centre, interventional, parallel group, superiority, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. PARTICIPANTS: Inpatients will be recruited from 8 Italian Academic and non-Academic Intensive Care Units INCLUSION CRITERIA (ALL REQUIRED): 1. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 2. Positive pressure ventilation (either non-invasive or invasive) from > 24 hours 3. Invasive mechanical ventilation from < 96 hours 4. PaO2/FiO2 ratio lower than 150 mmHg 5. D-dimer level > 6 times the upper limit of normal reference range 6. C-reactive Protein > 6-fold upper the limit of normal reference range EXCLUSION CRITERIA: 1. Age < 18 years 2. On-going treatment with anticoagulant drugs 3. Platelet count < 100.000/mm3 4. History of heparin-induced thrombocytopenia 5. Allergy to sodium enoxaparin or other LMWH, UFH or methylprednisolone 6. Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment 7. Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery 8. Chronic assumption or oral corticosteroids 9. Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available 10. Clinical decision to withhold life-sustaining treatment or "too sick to benefit" 11. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 12. Lack or withdrawal of informed consent INTERVENTION AND COMPARATOR: • LMWH group: patients in this group will be administered enoxaparin at standard prophylactic dosage. • LMWH + steroid group: patients in this group will receive enoxaparin at standard prophylactic dosage and methylprednisolone. • UFH + steroid group: patients in this group will receive UFH at therapeutic dosages and methylprednisolone. UFH will be administered intravenously in UFH + steroid group at therapeutic doses. The infusion will be started at an infusion rate of 18 UI/kg/hour and then modified to obtain aPTT Ratio in between the range of 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with UFH will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Enoxaparin will be administered in both LMWH group and LMWH + steroid group at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously once a day up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered in both LMWH + steroid group and UHF + steroid group intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14. MAIN OUTCOMES: Primary Efficacy Endpoint: All-cause mortality at day 28 Secondary Efficacy Endpoints: - Ventilation free days (VFDs) at day 28, defined

2020 - Overall survival in patients with lung adenocarcinoma harboring "niche" mutations: an observational study [Articolo su rivista]
Aramini, Beatrice; Banchelli, Federico; Bettelli, Stefania Raffaella; Manfredini, Samantha; D'Amico, Roberto; Masciale, Valentina; Pinelli, Massimo; MORETTI FANTERA, Margherita; Stefani, Alessandro; Bertolini, Federica; Dominici, Massimo; Morandi, Uliano; Maiorana, Antonino
abstract

Objective: In addition to the most common somatic lung cancer mutations (i. e., KRAS and EGFR mutations), other genes may harbor mutations that could be relevant for lung cancer. We defined BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET mutations as “niche” mutations and analyzed. The aim of this retrospective cohort study was to assess the differences in the overall survival (OS) of patients with lung adenocarcinoma harboring niche somatic mutations. Results: Data were gathered for 252 patients. Mutations were observed in all genes studied, except c-MET, DDR2, MAP2K1, and RET. The multivariable analysis showed that 1) niche mutations had a higher mortality than EGFR mutations (HR = 2.3; 95% CI = 1.2–4.4; p = 0.009); 2) KRAS mutations had a higher mortality than EGFR mutations (HR = 2.5; 95% CI = 1.4–4.5; p = 0.003); 3) niche mutations presented a similar mortality to KRAS mutations (HR = 0.9; 95% CI = 0.6–1.5; p = 0.797). Methods: Three cohorts of mutations were selected from patients with lung adenocarcinoma and their OS was compared. Mutations that were searched for, were 1) BRAF, c-MET, DDR2, HER2, MAP2K1, NRAS, PIK3CA, and RET; 2) K-RAS; and 3) EGFR. Differences in OS between these three cohorts were assessed by means of a multivariable Cox model that adjusted for age, sex, smoking habits, clinical stages, and treatments. Conclusions: Niche mutations exhibited an increased risk of death when compared with EGFR mutations and a similar risk of death when compared with KRAS mutations.

2020 - PIK3CA MUTATIONS IN HER2-POSITIVE BREAST CANCER PATIENTS ENROLLED IN THE ADJUVANT RANDOMIZED SHORT-HER STUDY. [Poster]
Guarneri, Valentina; Dieci, Maria Vittoria; Bisagni, Giancarlo; Brandes, Alba A.; Frassoldati, Antonio; Cavanna, Luigi; Musolino, Antonino; Giotta, Francesco; Rimanti, Anita; Garrone, Ornella; Elenabertone, ; Cagossi, Katia; Nanni, Oriana; Piacentini, Federico; Orvieto, Enrico; Curtarello, Matteo; Chic, Nuria; D'Amico, Roberto; Prat, Aleix; Conte, Pierfranco
abstract

2020 - PIK3CA Mutation in the ShortHER Randomized Adjuvant Trial for Patients with Early HER2þ Breast Cancer: Association with Prognosis and Integration with PAM50 Subtype. [Articolo su rivista]
Guarneri, Valentina; Dieci, Maria Vittoria; Bisagni, Giancarlo; Brandes, Alba A.; Frassoldati, Antonio; Cavanna, Luigi; Musolino7, Antonino; 8, ; Giotta9, Francesco; Rimanti10, Anita; Garrone11, Ornella; Bertone, Elena; Cagossi, Katia; Nanni, Oriana; Piacentini, Federico; Orvieto, Enrico; Griguolo, Gaia; Curtarello, Matteo; Urso, Loredana; Pare, Laia; Chic, Nuria; D'Amico, Roberto; Prat and Pierfranco Conte, Aleix
abstract

Purpose: We explored the prognostic effect of PIK3CA mutation in HER2þ patients enrolled in the ShortHER trial. Patients and Methods: The ShortHER trial randomized 1,253 patients with HER2þ breast cancer to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. PIK3CA hotspot mutations in exon 9 and 20 were analyzed by pyrosequencing. Expression of 60 genes, including PAM50 genes was measured using the nCounter platform. Results: A mutation of the PIK3CA gene was detected in 21.7% of the 803 genotyped tumors. At a median follow-up of 7.7 years, 5-year disease-free survival (DFS) rates were 90.6% for PIK3CA mutated and 86.2% for PIK3CA wild-type tumors [HR, 0.84; 95% confidence interval (CI), 0.56–1.27; P ¼ 0.417]. PIK3CA mutation showed a favorable prognostic impact in the PAM50 HER2-enriched subtype (n ¼ 232): 5-year DFS 91.8% versus 76.1% (log-rank P ¼ 0.049; HR, 0.46; 95% CI, 0.21–1.02). HER2-enriched/PIK3CA mutated versus wild-type tumors showed numerically higher tumor-infiltrating lymphocytes (TIL) and significant upregulation of immune-related genes (including CD8A, CD274, PDCD1, and MYBL2, a proliferation gene involved in immune processes). High TILs as well as the upregulation of PDCD1 and MYBL2 were associated with a significant DFS improvement within the HER2-enriched subtype (HR, 0.82; 95% CI, 0.68–0.99; P ¼ 0.039 for 10% TILs increment; HR, 0.81; 95% CI, 0.65–0.99; P ¼ 0.049 for PDCD1 expression; HR, 0.72; 95% CI, 0.53–0.99; P ¼ 0.042 for MYBL2 expression). Conclusions: PIK3CA mutation showed no prognostic impact in the ShortHER trial. Within the HER2-enriched molecular subtype, patients with PIK3CA mutated tumors showed better DFS versus PIK3CA wild-type, which may be partly explained by upregulation of immune-related genes.

2020 - Precision Medicine in Lung Cancer: Challenges and Opportunities in Diagnostic and Therapeutic Purposes. [Capitolo/Saggio]
Aramini, Beatrice; Masciale, Valentina; Banchelli, Federico; D'Amico, Roberto; Dominici, Massimo; Husnain Haider, Khawaja
abstract

Lung cancer is one of the leading causes of cancer death among both men and women, making up almost 25% of all cancer deaths. Precision medicine shows promise for improving many aspects of health and healthcare, including tests, drugs, and other technologies that support innovation, with the possibility of new partnerships with scientists in a wide range of specialties. Non–small-cell lung cancer (NSCLC) has become a prominent example of the success of precision medicine in treating solid tumor malignancies. The first step in this process involves new bloodbased diagnostics, which can now noninvasively provide clinically useful information. However, the identification of novel biomarkers that could be used in early diagnosis is urgently needed, especially for guiding initial therapy and predicting relapse or drug resistance following the administration of novel targeted therapies.

2020 - Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): A structured summary of a study protocol [Articolo su rivista]
Marietta, M; Vandelli, P; Mighali, P; Vicini, R; Coluccio, V; D'Amico, R; Aschieri, D; Brugioni, L; Clini, E; Codeluppi, M; Imberti, D; Magnacavallo, A; Meschiari, M; Mussini, C; Orlando, S; Pinelli, G; Pietrangelo, A; Sarti, L; Silva, M.
abstract

To assess whether high doses of Low Molecular Weight Heparin (LMWH) (i.e. Enoxaparin 70 IU/kg twice daily) compared to standard prophylactic dose (i.e., Enoxaparin 4000 IU once day), in hospitalized patients with COVID19 not requiring Invasive Mechanical Ventilation [IMV], are: a)more effective in preventing clinical worsening, defined as the occurrence of at least one of the following events, whichever comes first: 1.Death2.Acute Myocardial Infarction [AMI]3.Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]4.Need of either: a.Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) orb.IMV in patients who at randomisation were receiving standard oxygen therapy5.IMV in patients who at randomisation were receiving non-invasive mechanical ventilationb)Similar in terms of major bleeding risk TRIAL DESIGN: Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study.

2020 - The predicted probability of live birth in In Vitro Fertilization varies during important stages throughout the treatment: analysis of 114,882 first cycles [Articolo su rivista]
La Marca, A.; Capuzzo, M.; Donno, V.; Mignini Renzini, M.; Giovane, C. D.; D'Amico, R.; Sunkara, S. K.
abstract

Research Question: How much the variability in patients’ response during in vitro fertilization (IVF) may add to the initial predicted prognosis based only on patients’ basal characteristics? Design: Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). Data involving 114,882 stimulated fresh IVF cycles were retrospectively analyzed. Logistic regression was used to develop the models. Results: Prediction of live birth was feasible with moderate accuracy in all of the three models; discrimination of the model based only on basal patients’ characteristics (AUROC 0.61) was markedly improved adding information of number of embryos (AUROC 0.65) and, mostly, number of oocytes (AUROC 0.66). Conclusions: The addition to prediction models of parameters such as the number of embryos obtained and especially the number of oocytes retrieved can statistically significantly improve the overall prediction of live birth probabilities when based on only basal patients’ characteristics. This seems to be particularly true for women after the first IVF cycle. Since ovarian response affects the probability of live birth in IVF, it is highly recommended to add markers of ovarian response to models based on basal characteristics to increase their predictive ability.

2019 - Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer. [Articolo su rivista]
Dieci, Mv; Conte, P; Bisagni, G; Brandes, Aa; Frassoldati, A; Cavanna, L; Musolino, A; Giotta, F; Rimanti, A; Garrone, O; Bertone, E; Cagossi, K; Sarti, S; Ferro, A; Piacentini, F; Maiorana, A; Orvieto, E; Sanders, M; Miglietta, F; Balduzzi, S; D'Amico, R; Guarneri, V.
abstract

BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.

2019 - Cancer stem-neuroendocrine cells in an atypical carcinoid case report. [Articolo su rivista]
Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice
abstract

Lung neuroendocrine cells tumor (NET) classification and diagnosis, particularly for typical and atypical carcinoids, are complicated by a variable natural history and nonspecific symptoms. Mechanisms for the development and progression of well-differentiated lung NETs are still unclear. An accurate and timely diagnosis can ensure the implementation of appropriate treatment and impact on prognosis. One of the main unclear point is the definition of these cells’ composition. In fact, it is known that carcinoids are mainly constituted by neuroendocrine cells. Aim of our report is to show for the first time the presence of a high percentage of cancer stem cells (CSCs) in an atypical carcinoid. The ALDEFLUOR assay was used to identify and sort ALDHhigh and ALDHlow human lung cancer cells following tissue digestion. SOX2 was additionally determined by immunohistochemistry. All specimens contained the 53.10% of ALDHhigh cells among all viable lung cancer cells, which indicates that more than half of the entire tumor cell population was composed by CSCs. As expected also in immunohistochemistry, about a half of the nuclei of the cells were positive for SOX2. We strongly support the hypothesis of the presence of cancer stem-neuroendocrine cells (CSCs-NETs) as subpopulation in these types of tumors.

2019 - Clinical differences in sarcoidosis patients with and without lymphoma: a single-center retrospective cohort analysis. [Articolo su rivista]
Cerri, Stefania; Fontana, Matteo; Balduzzi, Sara; Potenza, Leonardo; Faverio, Paola; Luppi, Mario; Damico, Roberto; Spagnolo, Paolo; Clini, Enrico; Luppi, Fabrizio
abstract

We retrospectively reviewed the database of the “Center for Rare Lung Diseases” at the University Hospital of Modena to identify all subjects with a diagnosis of sarcoidosis between 1990 and 2013, with the aim to evaluate clinical, functional and serological differences related to the presence of lymphoma in sarcoidosis patients, as well as difference in survival. This study suggests the existence of clinical, radiological and serological differences in sarcoidosis with or without lymphoma syndrome. The knowledge of these differences seems important for a timely diagnosis and treatment. However, further prospective studies are required to confirm present observations.

2019 - Correlating tumor-infiltrating lymphocytes and lung cancer stem cells: a cross-sectional study. [Articolo su rivista]
Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Sighinolfi, Pamela; Pinelli, Massimo; Lovati, Eleonora; Stefani, Alessandro; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice
abstract

Background: Lung cancer stem cells (LCSCs) are endowed with high aldehyde dehydrogenase (ALDH) expression and play roles in tumor proliferation, metastasis, and drug resistance. Their elusive nature may allow them to escape the immune response by tumor-infiltrating lymphocytes (TILs), which can positively affect the outcome in non-small cell lung cancer (NSCLC) patients. Despite independent investigations on both LCSCs and TILs, the relationship between the two has been very marginally considered. We analyzed whether these two cell types may be related as a prerequisite for novel diagnostic and therapeutic approaches. Methods: In this cross-sectional study, NSCLC human surgical specimens from 12 patients were tested by ALDEFLUOR assay to identify ALDHhigh cells. Fluorescence-activated cell sorting (FACS) analyses for CD3+, CD4+, and CD8+ TILs were performed in combination with immunohistochemistry evaluation. Results: Statistically positive correlations were found between ALDH+ and CD8+, and between ALDH+ and CD3+ cells populations; no correlation was found between ALDH+ and CD4+ cells. The expression of CD3+ and CD8+ by cells accounted for 40.1% and 58.7%, respectively, of the variability of ALDH+ cell expression by an R-squared index, which highlights the strong correlation between TILs and LCSCs. Immunohistochemistry revealed 6–25% positive cells. Conclusions: We report a correlation between cytotoxic TILs and LCSCs, which may contribute to the future development of targeted therapies focusing on the different roles of lymphocytes against lung cancer.

2019 - Diagnostic accuracy of a velcro sound detector (VECTOR) for interstitial lung disease in rheumatoid arthritis patients: The InSPIRAtE validation study (INterStitial pneumonia in rheumatoid ArThritis with an electronic device) [Articolo su rivista]
Manfredi, A.; Cassone, G.; Cerri, S.; Venerito, V.; Fedele, A. L.; Trevisani, M.; Furini, F.; Addimanda, O.; Pancaldi, F.; Della Casa, G.; D'Amico, R.; Vicini, R.; Sandri, G.; Torricelli, P.; Celentano, I.; Bortoluzzi, A.; Malavolta, N.; Meliconi, R.; Iannone, F.; Gremese, E.; Luppi, F.; Salvarani, C.; Sebastiani, M.
abstract

Background: Interstitial lung disease (ILD) is a severe systemic manifestation of rheumatoid arthritis (RA). High-resolution computed tomography (HRCT) represents the gold standard for the diagnosis of ILD, but its routine use for screening programs is not advisable because of both high cost and X-ray exposure. Velcro crackles at lung auscultation occur very early in the course of interstitial pneumonia, and their detection is an indication for HRCT. Recently, we developed an algorithm (VECTOR) to detect the presence of Velcro crackles in pulmonary sounds and showed good results in a small sample of RA patients. The aim of the present investigation was to validate the diagnostic accuracy of VECTOR in a larger population of RA patients, compared with that of the reference standard of HRCT, from a multicentre study. Methods: To avoid X-ray exposure, we enrolled 137 consecutive RA patients who had recently undergone HRCT. Lung sounds of all patients were recorded in 4 pulmonary fields bilaterally with a commercial electronic stethoscope (ES); subsequently, all HRCT images were blindly evaluated by a radiologist, and audio data were analysed by means of VECTOR. Results: Fifty-nine of 137 patients showed ILD (43.1%). VECTOR correctly classified 115/137 patients, showing a diagnostic accuracy of 83.9% and a sensitivity and specificity of 93.2 and 76.9%, respectively. Conclusions: VECTOR may represent the first validated tool for the screening of RA patients who are suspected for ILD and who should be directed to HRCT for the diagnosis. Moreover, early identification of RA-ILD could contribute to the design of prospective studies aimed at elucidating unclear aspects of the disease.

2019 - Direct oral anticoagulants vs non-vitamin K antagonist in atrial fibrillation: A prospective, propensity score adjusted cohort study [Articolo su rivista]
Marietta, M.; Banchelli, F.; Pavesi, P.; Manotti, C.; Quintavalla, R.; Sinigaglia, T.; Guazzaloca, G.; Pattacini, C.; Urbinati, S.; Malavasi, V. L.; Boriani, G.; Voci, C.; D'Amico, R.; Magrini, N.
abstract

2019 - Effect of expert-patient teaching on empathy in nursing students: a randomized controlled trial [Articolo su rivista]
Ferri, P; Rovesti, S; Padula, Ms; D’Amico, R; Di Lorenzo, R
abstract

Background: Empathy is a relevant clinical competence for nursing students. Involvement of expert patients in nursing education could help students develop their innate capacity to empathize. Objective: To evaluate the effect of expert-patient teaching on empathy development in nursing students. Methods: This randomized controlled trial was conducted among 144 first-year undergraduate nursing students divided into two equal groups. In the experimental group, the educational intervention consisted of a seminar focused on empathy, followed by a presentation on expert-patient function. Subsequently, each student participated in two interactive meetings with nursing teacher and expert patient. At the end, the nursing teacher encouraged students to reflect on this experience. In the control group, students only attended a similar seminar focused on empathy and afterward participated in two interactive meetings with a nursing teacher to reflect on this topic without expert-patient involvement. Before (T0) and after (T1) the training intervention, the Balanced Emotional Empathy Scale, Jefferson Scale of Empathy — Health Professions Student (JSE-HPS), and a short demographic questionnaire were administered to the two student groups to measure their empathy levels. The study was approved by the Local Ethics Committee of Area Vasta Emilia Nord (protocol 1763, May 11, 2017). Data were statistically analyzed. Results: We found a statistically significant difference between mean scores at T0 and T1 in both scales in the experimental group. Male students, who presented significantly lower levels of empathy at baseline in comparison with females, showed increased in empathy after training on the the Balanced Emotional Empathy Scale in both the experimental and control groups. Conclusion: The present study highlights that involvement of expert patients in teaching is effective in improving empathy levels in both male and female nursing students. Expert-patient teaching can be a promising nursing-education modality for developing empathy.

2019 - FETR-ALS Study Protocol: A Randomized Clinical Trial of Fecal Microbiota Transplantation in Amyotrophic Lateral Sclerosis [Articolo su rivista]
Mandrioli, J.; Amedei, A.; Cammarota, G.; Niccolai, E.; Zucchi, E.; D'Amico, R.; Ricci, F.; Quaranta, G.; Spanu, T.; Masucci, L.
abstract

Background and Rationale: Among the key players in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), microglia and T regulatory lymphocytes (Treg) are candidate cells for modifying the course of the disease. The gut microbiota (GM) acts by shaping immune tolerance and regulating the Treg number and suppressive function, besides circulating neuropeptides, and other immune cells that play in concert through the gut-brain axis. Previous mouse models have shown an altered enteric flora in early stage ALS, pointing to a possible GM role in ALS pathogenesis. Fecal Microbial Transplantation (FMT) is a well-known therapeutic intervention used to re-establish the proper microenvironment and to modulate enteric and systemic immunity. Methods: We are going to perform a multicenter randomized double-blind clinical trial employing FMT as a therapeutic intervention for ALS patients (NCT0376632). Forty-two ALS patients, at an early stage, will be enrolled with a 2:1 allocation ratio (28 FMT-treated patients vs. 14 controls). Study duration will be 12 months per patient. Three endoscopic procedures for intestinal biopsies in FMT and control groups are predicted at baseline, month 6 and month 12; at baseline and at month 6 fresh feces from healthy donors will be infused at patients in the intervention arm. The primary outcome is a significant change in Treg number between FMT-treated patients and control arm from baseline to month 6. Secondary outcomes include specific biological aims, involving in-depth analysis of immune cells and inflammatory status changes, central and peripheral biomarkers of ALS, besides comprehensive analysis of the gut, saliva and fecal microbiota. Other secondary aims include validated clinical outcomes of ALS (survival, forced vital capacity, and modifications in ALSFRS-R), besides safety and quality of life. Expected Results: We await FMT to increase Treg number and suppressive functionality, switching the immune system surrounding motorneurons to an anti-inflammatory, neuroprotective status. Extensive analysis on immune cell populations, cytokines levels, and microbiota (gut, fecal and saliva) will shed light on early processes possibly leading the degenerative ALS course. Conclusions: This is the first trial with FMT as a potential intervention to modify immunological response to ALS and disease progression at an early stage.

2019 - Heated tobacco and politics in Italy [Articolo su rivista]
Formoso, G.; Celani, M. G.; Minozzi, S.; Cinquini, M.; Mosconi, P.; Pistotti, V.; Cantisani, T.; D'Amico, R.
abstract

2019 - Home care for heart failure: can caregiver education prevent hospital admissions? A randomized trial in primary care [Articolo su rivista]
Padula, Maria S; D'Ambrosio, Gaetano Giorgio; Tocci, Marina; D'Amico, Roberto; Banchelli, Federico; Angeli, Letizia; Scarpa, Marina; Capelli, Oreste; Cricelli, Claudio; Boriani, Giuseppe
abstract

To assess the feasibility and effectiveness of a low-complexity, low-cost model of caregiver education in primary care, targeted to reduce hospitalizations of heart failure patients.

2019 - Isolation and Identification of Cancer Stem-Like Cells in Adenocarcinoma and Squamous Cell Carcinoma of the Lung: A Pilot Study [Articolo su rivista]
Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Maiorana, Antonino; Sighinolfi, Pamela; Stefani, Alessandro; Morandi, Uliano; Dominici, Massimo; Aramini, Beatrice
abstract

Background: Lung cancer stem cells (CSCs) share many characteristics with normal stem cells, such as self-renewal and multipotentiality. High expression of aldehyde dehydrogenase (ALDH) has been detected in many tumors, particularly in the CSC compartment, and it plays an important role in tumor proliferation, metastasis, and drug resistance. CD44 is commonly used as a cell surface marker of cancer stem-like cells in epithelial tumors. The aim of this study was to isolate and analyze cancer stem-like cells from surgically removed specimens to compare lung adenocarcinoma (ADENO) and squamous (SQUAMO) cell carcinoma. Methods: The ALDEFLUOR assay was used to identify and sort ALDHhigh and ALDHlow human lung cancer cells following tissue digestion. Fluorescence-activated cell sorting analysis for CD44 was performed with tumor cells. Quantitative real-time PCR was performed to assess the expression of SOX2 and NANOG as stemness markers. ALDH1A1 expression was additionally determined by immunohistochemistry. Anchorage-independent ALDHhigh cell growth was also evaluated. ALDHhigh ADENO and SQUAMO cells were cultured to analyze spheroid formation. Results: All specimens contained 0.5–12.5% ALDHhigh cells with 3.8–18.9% CD44-positive cells. SOX2 and NANOG relative expression in ALDHhigh compared to ALDHlow cells in ADENO and SQUAMO was analyzed and compared between the histotypes. Immunohistochemistry confirmed the presence of ALDH1A1 in the sections. SOX2 and NANOG were expressed at higher levels in the ALDHhigh subpopulation than in the ALDHlow subpopulation only in ADENO cells, and the opposite result was seen in SQUAMO cells. In vitro functional assays demonstrated that ALDHhigh cells exhibited migration capacity with distinct behaviors between ALDHhigh spheres in ADENO vs. SQUAMO samples. Conclusions: Our results highlight the importance of a better characterization of cancer stem-like cells in ADENO and SQUAMO histotypes. This may suggest new differential approaches for prognostic and therapeutic purposes in patients with non-small-cell lung cancer.

2019 - Motor and Postural Patterns Concomitant with General Movements Are Associated with Cerebral Palsy at Term and Fidgety Age in Preterm Infants [Articolo su rivista]
Ferrari, Fabrizio; Plessi, Carlotta; Lucaccioni, Laura; Bertoncelli, Natascia; Bedetti, Luca; Ori, Luca; Berardi, Alberto; Della Casa, Elisa; Iughetti, Lorenzo; D'Amico, Roberto
abstract

General movements (GMs) in combination with neurological examination and magnetic resonance imaging at term age can accurately determine the risk of cerebral palsy. The present study aimed to assess whether 11 motor and postural patterns concomitant with GMs were associated with cerebral palsy. Video recordings performed after birth in 79 preterm infants were reviewed retrospectively. Thirty-seven infants developed cerebral palsy at 2 years corrected age and the remaining 42 showed typical development. GMs were assessed from preterm to fidgety age and GM trajectories were defined. The 11 motor and postural patterns were evaluated at each age and longitudinally, alone and in combination with GM trajectories. A logistic regression model was used to assess the association between GMs, concomitant motor and postural patterns, and cerebral palsy. We confirmed that high-risk GM trajectories were associated with cerebral palsy (odds ratio = 44.40, 95% confidence interval = 11.74-167.85). An association between concomitant motor and postural patterns and cerebral palsy was found for some of the patterns at term age and for all of them at fidgety age. Therefore, at term age, concomitant motor and postural patterns can support GMs for the early diagnosis of cerebral palsy.

2019 - New Direct-Acting Antivirals for the Treatment of Patients With Hepatitis C Virus Infection: A Systematic Review of Randomized Controlled Trials [Articolo su rivista]
Pecoraro, V.; Banzi, R.; Cariani, E.; Chester, J.; Villa, E.; D'Amico, R.; Bertele', V.; Trenti, T.
abstract

Background: New direct-acting antiviral agents (DAAs) approved for the treatment of patients infected by Hepatitis C virus (HCV) are well tolerated and increase sustained virological response (SVR) rate. We summarize current evidence on the efficacy and safety from comparative randomized controlled trials (RCTs) of DAAs. Methods: We systematically searched MEDLINE, Embase, Scopus, CENTRAL, and Lilacs as well as a list of reference literature. We included RCTs comparing DAAs with placebo or active control and reporting response rates and adverse events according to antiviral regimens. Risk ratios (RRs) were pooled as appropriate. We assessed the risk of bias of included studies and graded the quality of evidence according to the GRADE method. Results: We included 28 RCTs, enrolling more than 7000 patients. The quality of evidence was generally low. Twelve-week treatment with DAAs in naïve patients significantly increased SVR12 and SVR24 compared with placebo (RR 1.4, 95% CI 1.3–1.6; RR 1.5, 95% CI 1.4–1.6, respectively). This means that for every 1000 patients, 240 or 260 more patients experienced SVR12 or SVR24 if treated with any DAAs. We could not find RCTs assessing progression of liver disease or development of hepatocellular carcinoma. DAAs were not associated with higher incidence of serious adverse events or discontinuation due to adverse events. Conclusions: This systematic review confirms that new DAAs are more effective in inducing SVR than placebo. Outside clinical trials, in real word, HCV cure with DAA regimens occurs in less than 90% of patients, so further comparative evaluations are needed to establish their long-term effects.

2019 - Pectoralis Muscle Transposition in Association with the Ravitch Procedure in the Management of Severe Pectus Excavatum. [Articolo su rivista]
BACCARANI, ALESSIO; Aramini, Beatrice; DELLA CASA, GIOVANNI; BANCHELLI, FEDERICO; D'AMICO, Roberto; RUGGIERO, Ciro; Starnoni, Marta; Pedone, Antonio; STEFANI, Alessandro; MORANDI, Uliano; DE SANTIS, Giorgio
abstract

Background: Pectus excavatum (PE) is the most common congenital chest wall deformity. PE is sometimes associated with cardiorespiratory impairment, but is often associated with psychological distress, especially for patients in their teenage years. Surgical repair of pectus deformities has been shown to improve both physical limitations and psychosocial well-being in children. The most common surgical approaches for PE treatment are the modified Ravitch technique and the minimally invasive Nuss technique. A technical modification of the Ravitch procedure, which includes bilateral mobilization and midline transposition of the pectoralis muscle flap, is presented here. Methods: From 2010 to 2016, 12 patients were treated by a modified Ravitch procedure with bilateral mobilization and midline transposition of the pectoralis muscle flap for severe PE. Outcomes, morphological results, and complications were analyzed with respect to this new combined surgical approach. Results: There was a statistically significant difference between pre- and postoperative values (P = 0.0025) of the Haller index at the 18-month follow-up, showing a significant morphological improvement for all treated patients. After surgery, no morbidity and mortality were noted. The mean hospital stay was 7 days, and all patients were discharged without major complications. Conclusion: This technique significantly improved patients’ postoperative morphological outcomes and significantly reduced long-term complications, such as wound dehiscence, skin thinning, and hardware exposure.

2019 - Proteostasis and ALS: Protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS) [Articolo su rivista]
Mandrioli, J.; Crippa, V.; Cereda, C.; Bonetto, V.; Zucchi, E.; Gessani, A.; Ceroni, M.; Chio, A.; D'Amico, R.; Monsurro, M. R.; Riva, Nicoletta; Sabatelli, M.; Silani, V.; Simone, I. L.; Soraru, G.; Provenzani, A.; D'Agostino, V. G.; Carra, S.; Poletti, Arcadio
abstract

Introduction: Disruptions of proteasome and autophagy systems are central events in amyotrophic lateral sclerosis (ALS) and support the urgent need to find therapeutic compounds targeting these processes. The heat shock protein B8 (HSPB8) recognises and promotes the autophagy-mediated removal of misfolded mutant SOD1 and TDP-43 fragments from ALS motor neurons (MNs), as well as aggregating species of dipeptides produced in C9ORF72-related diseases. In ALS-SOD1 mice and in human ALS autopsy specimens, HSPB8 is highly expressed in spinal cord MNs that survive at the end stage of disease. Moreover, the HSPB8-BAG3-HSP70 complex maintains granulostasis, which avoids conversion of dynamic stress granules (SGs) into aggregation-prone assemblies. We will perform a randomised clinical trial (RCT) with colchicine, which enhances the expression of HSPB8 and of several autophagy players, blocking TDP-43 accumulation and exerting crucial activities for MNs function. Methods and analysis: Colchicine in amyotrophic lateral sclerosis (Co-ALS) is a double-blind, placebo-controlled, multicentre, phase II RCT. ALS patients will be enrolled in three groups (placebo, colchicine 0.01 mg/day and colchicine 0.005 mg/day) of 18 subjects treated with riluzole; treatment will last 30 weeks, and follow-up will last 24 weeks. The primary aim is to assess whether colchicine decreases disease progression as measured by ALS Functional Rating Scale - Revised (ALSFRS-R) at baseline and at treatment end. Secondary aims include assessment of (1) safety and tolerability of Colchicine in patiets with ALS; (2) changes in cellular activity (autophagy, protein aggregation, and SG and exosome secretion) and in biomarkers of disease progression (neurofilaments); (3) survival and respiratory function and (4) quality of life. Preclinical studies with a full assessment of autophagy and neuroinflammation biomarkers in fibroblasts, peripheral blood mononuclear cells and lymphoblasts will be conducted in parallel with clinic assessment to optimise time and resources. Ethics and dissemination: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord and by Agenzia Italiana del Farmaco (EUDRACT N.2017-004459-21) based on the Declaration of Helsinki. This research protocol was written without patient involvement. Patients' association will be involved in disseminating the study design and results. Results: will be presented during scientific symposia or published in scientific journals.

2019 - Stereotactic Ablative Radiotherapy as an Alternative to Lobectomy in Patients With Medically Operable Stage I NSCLC: A Retrospective, Multicenter Analysis [Articolo su rivista]
Scotti, Vieri; Bruni, Alessio; Francolini, Giulio; Perna, Marco; Vasilyeva, Polina; Loi, Mauro; Simontacchi, Gabriele; Viggiano, Domenico; Lanfranchi, Biancaluisa; Gonfiotti, Alessandro; Topulli, Juljana; Olmetto, Emanuela; Maragna, Virginia; Ferrari, Katia; Bonti, Viola; Comin, Camilla; Balduzzi, Sara; D'Amico, Roberto; Lohr, Frank Reinhard Heinrich; Voltolini, Luca; Livi, Lorenzo
abstract

Background: Stereotactic ablative body radiation therapy (SBRT) has evolved as the standard treatment for patients with inoperable stage I non–small-cell lung cancer (NSCLC). We report the results of a retrospective analysis conducted on a large, well-controlled cohort of patients with stage I to II NSCLC who underwent lobectomy (LOB) or SBRT. Materials and Methods: One hundred eighty-seven patients with clinical-stage T1a-T2bNoMO NSCLC were treated in 2 academic hospitals between August 2008 and May 2015. Patients underwent LOB or SBRT; those undergoing SBRT were sub-classified as surgical candidates and nonsurgical candidates, according to the presence of surgical contraindications or comorbidities. Results: In univariate analysis, no significant difference was found in local control between patients who underwent SBRT and LOB, with a trend in favor of surgery (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.07-1.01; P <.053). Univariate analysis showed that overall survival (OS) was significantly better in patients who underwent LOB (HR, 0.44; 95% CI, 0.23-0.85) with a 3-year OS of 73.4% versus 65.2% for surgery and radiation therapy patients, respectively (P <.01). However, no difference in OS was observed between operable patients undergoing SBRT and patients who underwent LOB (HR, 1.68; 95% CI, 0.72-3.90). Progression-free survival was comparable between patients who underwent LOB and SBRT (HR, 0.61; P =.09). Conclusion: SBRT is a valid therapeutic approach in early-stage NSCLC. Furthermore, SBRT seems to be very well-tolerated and might lead to the same optimal locoregional control provided by surgery for patients with either operable or inoperable early-stage NSCLC.

2019 - Usefulness of automated breast volume scanner (ABVS) for monitoring tumor response to neoadjuvant treatment in breast cancer patients: preliminary results [Articolo su rivista]
D'Angelo, A; Rinaldi, P; Belli, P; D'Amico, R; Carlino, G; Grippo, C; Giuliani, M; Orlandi, A; Infante, A; Manfredi, R
abstract

OBJECTIVE: We investigated the accuracy of Automated Breast Volume Scanner (ABVS) compared to handheld ultrasound (HHUS) for monitoring tumor response to neoadjuvant treatment (NAT) in breast cancer (BC).PATIENTS AND METHODS: All the patients submitted to biopsy in our Institution, from January 2017 to May 2017, proven invasive BC and eligible for NAT, were enrolled in this prospective study. The participants underwent ABVS, HHUS, dynamic contrast-enhanced Magnetic Resonance Imaging (DCE-MRI) and mammography at the beginning of NAT and ABVS. HHUS and DCE-MRI at the halfway point of therapy and before the surgery. DCE-MRI was considered the standard of reference. Two breast radiologists (R1, R2), with fifteen and five years of experience in breast imaging, independently assigned a visibility score (ordinal 5-point scale) to ABVS, HHUS, and DCE-MRI. Diagnostic performance of ABVS and HHUS as measured by sensitivity, specificity, positive and negative predictive values (PPV and NPV) was calculated. Correlations between ABVS and MRI, and between HHUS and MRI were analyzed using Pearson's correlation test.RESULTS: A total of 21 patients were enrolled. 189 examinations were performed. The comparison between ABVS and DCE-MRI was similar for the both readers: ABVS had a sensitivity of 63,16%, specificity of 83,58%, PPV of 76,60%, NPV of 72,73%, accuracy of 74,19% (R1) and a sensitivity of 54.54%, specificity of 85.51%, PPV of 75%, NPV of 70,24%, accuracy of 71.77% (R2). The comparison between HHUS and DCE-MRI showed that HHUS had a sensitivity of 63,16 %, specificity of 83,58%, PPV of 76,60%, NPV of 72,73%, accuracy of 74,19% (R1) and a sensitivity of 36.84%, specificity of 85.07%, PPV of 67.74%, NPV of 61.29%, accuracy of 62.90% (R2). The calculated Pearson's correlation coefficient r values were 7.8 for HHUS vs. DCE-MRI and 28.5 for ABVS vs. DCE-MRI (R1) and 7.8 for HHUS vs. DCE-MRI and 22.4 for ABVS vs. DCE-MRI (R2). Statistical significance of ABVS and HHUS was p < 0.0001 and 0.005 < p < 0.01, respectively (R1, R2).CONCLUSIONS: DCE-MRI is recommended for the tumor response assessment. ABVS, a product of the biotechnology development, providing reproducible images, in addition to DCE-MRI, can be a potentially useful tool for the monitoring of response to NAT.

2019 - Validation of the AJCC prognostic stage for HER2-positive breast cancer in the ShortHER trial . [Articolo su rivista]
Dieci, Mv; Bisagni, G; Brandes, Aa; Frassoldati, A; Cavanna, L; Giotta, F; Aieta, M; Gebbia, V; Musolino, A; Garrone, O; Donadio, M; Rimanti, A; Beano, A; Zamagni, C; Soto Parra, H; Piacentini, F; Danese, S; Ferro, A; Cagossi, K; Sarti, S; Gambaro, Ar; Romito, S; Bazan, V; Amaducci, L; Moretti, G; Foschini, Mp; Balduzzi, S; Vicini, R; D'Amico, R; Griguolo, G; Guarneri, V; Conte, Pf.
abstract

BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. METHODS: The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. RESULTS: A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P < 0.001). Five-year DDFS according to prognostic stage was as follows: IA 95.7%, IB 91.4%, IIA 86.9%, IIB 85.0%, IIIA 77.6%, IIIC 67.7% (P < 0.001). The C index was similar (0.69209 and 0.69249, P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). CONCLUSIONS: The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment.

2019 - Worse global intellectual and worse neuropsychological functioning in preterm-born children at preschool age: a meta-analysis [Articolo su rivista]
Arpi, Elena; D'Amico, Roberto; Lucaccioni, Laura; Bedetti, Luca; Berardi, Alberto; Ferrari, Fabrizio
abstract

Preterm births (<32 weeks of gestational age) are associated with cognitive problems that are difficult to diagnose in infancy but potentially detectable at preschool age. This review aimed to evaluate the extent to which total intelligence quotient (IQ) and neuropsychological functions at ages three to five years differ between children born at <32 weeks gestational age or <1,500 g birth weight and children born at term. The secondary aim was to determine if cognitive performance differs between extremely preterm (EPT)/extremely low birth weight (ELBW) children and very preterm (VPT) or very low birth weight (VLBW) children.

2018 - 9 weeks versus 1 year adjuvant trastuzumab for HER2+ early breast cancer: Subgroup analysis of the ShortHER trial allows to identify patients for whom a shorter trastuzumab administration may have a favourable risk/benefit ratio [Abstract in Rivista]
Conte, P. F.; Guarneri, V.; Bisagni, G.; Piacentini, F.; Brandes, A. A.; Cavanna, L.; Giotta, F.; Aieta, M.; Gebbia, V.; Frassoldati, A.; Musolino, A.; Garrone, O.; Taverniti, C.; Rimanti, A.; Sarti, S.; Rubino, D.; Bologna, A.; Vicini, R.; Balduzzi, S.; D'Amico, R.
abstract

2018 - 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study. [Articolo su rivista]
Conte, P; Frassoldati, A; Bisagni, G; Brandes, Aa; Donadio, M; Garrone, O; Piacentini, F; Cavanna, L; Giotta, F; Aieta, M; Gebbia, V; Molino, A; Musolino, A; Ferro, A; Maltoni, R; Danese, S; Zamagni, C; Rimanti, A; Cagossi, K; Russo, A; Pronzato, P; Giovanardi, F; Moretti, G; Lombardo, L; Schirone, A; Beano, A; Amaducci, L; Bajardi, Ea; Vicini, R; Balduzzi, Sara; D'Amico, R; Guarneri, Valentina
abstract

BACKGROUND: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment for HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The Short-HER study was aimed to assess the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab combined with chemotherapy. PATIENTS AND METHODS: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT > 2cm, G3, lympho-vascular invasion, Ki-67>20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9-weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end-point. A DFS Hazard Ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary endpoints included 2-year failure rate and cardiac safety. RESULTS: 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR was 1.13 (90%CI 0.89;1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-yr OS is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90%CI0.74;1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95%CI0.22;0.50, p < 0.0001). CONCLUSIONS: This study failed to show the non-inferiority of a shorter trastuzumab administration. 1-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse.

2018 - Bilateral versus single internal mammary artery bypass grafts for coronary arterial atherosclerosis [Articolo su rivista]
Taggart, D. P.; D'Amico, R.; Mussa, S.; Altman, D. G.; Moore, T. H. M.; Burke, M.
abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To review the effects of bilateral versus single internal mammary artery grafts for coronary bypass grafting.

2018 - Breathlessness, but not cough, suggests chronic obstructive pulmonary disease in elderly smokers with stable heart failure. [Articolo su rivista]
Roversi, S; Boschetto, P; Beghè, B; Schito, M; Garofalo, M; Stendardo, M; Ruggieri, V; Tonelli, R; Fucili, A; D'Amico, R; Banchelli, F; Fabbri, Lm; Clini, E.
abstract

Chronic obstructive pulmonary disease (COPD) is a common comorbidity of heart failure (HF), but remains often undiagnosed, and we aimed to identify symptoms predicting COPD in HF. As part of an observational, prospective study, we investigated stable smokers with a confirmed diagnosis of HF, using the 8-item COPD-Assessment-Test (CAT) questionnaire to assess symptoms. All the items were correlated with the presence of COPD, and logistic regression models were used to identify independent predictors. 96 HF patients were included, aged 74, 33% with COPD. Patients with HF and COPD were more symptomatic, but only breathlessness when walking up a hill was an independent predictor of COPD (odds ratio=1.33, p=0.0484). Interestingly, COPD-specific symptoms such as cough and phlegm were not significant. Thus, in elderly smokers with stable HF, significant breathlessness when walking up a hill is most indicative of associated COPD, and may indicate the need for further lung function evaluation.

2018 - Cancer stem cells and their microenvironment. [Capitolo/Saggio]
Masciale, Valentina; Grisendi, Giulia; Banchelli, Federico; D'Amico, Roberto; Morandi, Uliano; Dominici, Massimo; Husnain Haider, Khawaja; Aramini, Beatrice
abstract

2018 - Efficacy and safety of extracranial vein angioplasty in multiple sclerosis: A randomized clinical trial [Articolo su rivista]
Zamboni, P.; Tesio, L.; Galimberti, S.; Massacesi, L.; Salvi, F.; D'Alessandro, R.; Cenni, P.; Galeotti, R.; Papini, D.; D'Amico, R.; Simi, S.; Valsecchi, M. G.; Filippini, G.; Ceruti, S.; Conforti, P.; Malagoni, A. M.; Menegatti, E.; Tessari, M.; Pancaldi, F.; Vanini, M. E.; Barbarossa, E.; Bartolomei, I.; Pellegrino, L.; Piscaglia, M. G.; Rasi, F.; Babini, M.; Drea, A.; Guerrini, E.; Lotti, E. M.; Morelli, A.; Peroni, M.; Zalambani, V.; Zecchini, S.; Patti, F.; Chisari, C.; Chiaramonte, I.; Cimino, V.; Giaquinta, A.; Di Pino, L.; Failla, G.; Veroux, P.; Cantello, R.; Leone, M.; Coppo, L.; Guzzardi, G.; Raymkulova, O.; Ruggerone, S.; Stecco, A.; Vecchio, D.; Confalonieri, P. A.; Campanella, A.; Caldiera, V.; Ciceri, E.; Erbetta, A.; Farago, G.; Parma, L.; Reggiori, B.; Clerici, V. T.; Danni, M.; Arborino, S.; De Berardinis, F.; Di Biagio, L.; Orni, C.; Renzi, R.; Rosettani, P.; Zagaglia, S.; Luccioni, G.; Oncini, L.; Quatrini, C.
abstract

Importance: Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial. Objective: To determine the efficacy and safety of venous PTA in patients with MS and CCSVI. Design, Setting, and Participants: We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat. Interventions: Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham). Main Outcomes and Measures: Two primary end pointswere assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions. Results: Of the included 115 patients with relapsing-remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7%vs 48.7%; odds ratio, 0.75; 95%CI, 0.34-1.68; P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95%CI, 0.15-0.91; P = .03: adjusted P = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95%CI, 0.32-1.63; P = .45; adjusted P = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95%CI, 1.11-6.28; P = .03; adjusted P = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95%CI, 0.81-4.01; P = .15; adjusted P = .30). Conclusion and Relevance: Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS.

2018 - Outpatient parents' views on shared-decision-making at an Italian children's hospital [Articolo su rivista]
Rosati, P.; Di Salvo, V.; D'Amico, R.; Balduzzi, S.; Giampaolo, R.; Rita Marina Mazziotta, M.; Guerra, C.; Menichella, G.; Cosentino, S. P.; Carlino, C.; Di Ciommo, V.
abstract

Information is lacking on what parents in southern European countries know and how they view clinical shared-decision-making (SDM) for their children. This survey assesses general parental views on SDM and patient-physician SDM relationships in an Italian paediatric outpatients' clinic. In a 3-month cross-sectional survey, we enrolled 458 consecutive native and foreign Italian-speaking parents bringing their children to our public hospital for various reasons. Parents completed an anonymous questionnaire exploring their general views on SDM, including what doctor-patient relationship predominates today, and what approach reassures them most. Multivariate logistic regression analysed outcome data from parental questionnaire answers. Results are reported as percentages, odds ratios (OR) and 95% confidence intervals (CI). Multivariate logistic regression showed that 440 parents (96.1%) appreciated SDM, 245 (53.5%) preferred SDM for choosing children's treatment, 126 (27.5%) answered that SDM is the predominant relationship today, and most parents 275 (60.0%) felt reassured by SDM. More native than foreign Italian-speaking parents preferred SDM (97.0 vs 89.7%, OR = 3.8; 95% CI = 1.4-10.8). Highly-educated parents preferred SDM for choosing their child's therapy (57.9 vs 34.1%, OR = 2.7; 95% CI = 1.6-4.4) and this approach reassured them (64.3 vs 41.2%, OR = 2.5; 95% CI = 1.6-4.1). In conclusion, parents bringing children to an Italian outpatient clinic, especially highly-educated parents, wish to be offered SDM and find it reassuring. These findings should encourage paediatricians working in a challenging multicultural environment to change their physician-centred approach and engage parents in tailored SDM strategies.

2018 - Rapamycin treatment for amyotrophic lateral sclerosis protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial) [Articolo su rivista]
Mandrioli, J.; D'Amico, R.; Zucchi, E.; Gessani, A.; Fini, N.; Fasano, A.; Caponnetto, C.; Chio, A.; Bella, E. D.; Lunetta, C.; Mazzini, L.; Marinou, K.; Soraru, G.; De Biasi, S.; Lo Tartaro, D.; Pinti, M.; Nichelli, P.; Vicini, R.; Cabona, C.; Calvo, A.; Moglia, C.; Manera, U.; Fuda, G.; Canosa, A.; Ilardi, A.; Lauria, G.; Dalla Bella, E.; Gerardi, F.; Scognamiglio, A.; De Marchi, F.; Mora, G.; Gizzi, M.; Cossarizza, A.
abstract

Introduction: Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients. Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients. Methods: RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale). Discussion: Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials. Ethics and dissemination: The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.

2018 - Revisione sistematica per valutare l’efficacia, l’accettabilità e la sicurezza degli antipsicotici di seconda generazione per il trattamento della depressione unipolare e bipolare [Systematic review to evaluate the efficacy, acceptability and safety of second-generation antipsychotics for the treatment of unipolar and bipolar depression] [Articolo su rivista]
Amato, Laura; Vecchi, Simona; Barbui, Corrado; Cruciani, Fabio; D'Amico, Roberto; Del Giovane, Cinzia; Minozzi, Silvia; Mitrova, Zuzana; Saulle, Rosella; Davoli, Marina
abstract

Summary. Background. The World Health Organization (WHO) estimates that depression affects about 121 million people in the world and in terms of years of illness, by the year 2020 could become the second most prevalent disease in the world population after cardiovascular diseases. Second-generation antipsychotics (SGAs) seems to induce remission in depression when added to an antidepressant. Aim. To evaluate the efficacy and safety of SGAs for the treatment of depression. Methods. We searched five bibliographic databases. We assessed the quality of evidence using Cochrane and GRADE criteria. Results. We included 42 RCTs. Where possible, we made a statistical synthesis of results. For efficacy outcomes, in direct comparisons in unipolar and bipolar patients with acute depressive episode, and in unipolar patients who did not respond to previous treatments with antidepressants (non-responders), SGAs gave better results than placebo, moderate to low certainty of evidence. In the comparison with antidepressants, in unipolar and bipolar patients with acute depressive episode the evidence was in favour of SGAs high certainty of evidence; while in the non-responder unipolar patients (the included studies considered only this typology of patients) the evidence was in favour of the antidepressants, low certainty of evidence. For safety outcomes, the results were in favour of placebo for patients with at least one adverse event, and in favour of SGAs for the number of patients with serious adverse events, for both comparisons the certainty of evidence was moderate. Comparing the SGAs with antidepressants, no differences were observed for patients with at least one adverse event, high certainty of evidence; while serious adverse events were less acute in patients treated with SGAs, moderate certainty evidence. The results of direct and indirect comparisons made with the network meta-analysis showed no differences for most of the outcomes considered, not showing a clear superiority of a drug compared to the others. Conclusions. These results showed a moderate effect in favour of SGAs compared to antidepressants in patients, unipolar and bipolar, with a new acute depressive episode and confirm that in patients non-responders, antidepressants may remain more effective. © 2018 Il Pensiero Scientifico Editore s.r.l. All rights reserved.

2018 - Selenium for preventing cancer [Articolo su rivista]
Vinceti, Marco; Filippini, Tommaso; Del Giovane, Cinzia; Dennert, Gabriele; Zwahlen, Marcel; Brinkman, Maree; Zeegers, Maurice P. A.; Horneber, Markus; D'Amico, Roberto; Crespi, Catherine M.
abstract

Background: This review is the third update of the Cochrane review "Selenium for preventing cancer". Selenium is a naturally occurring element with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer. Objectives: To gather and present evidence needed to address two research questions: 1. What is the aetiological relationship between selenium exposure and cancer risk in humans?2. Describe the efficacy of selenium supplementation for cancer prevention in humans. Search methods: We updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE (Ovid, 2013 to January 2017, week 4), and Embase (2013 to 2017, week 6), as well as searches of clinical trial registries. Selection criteria: We included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants. Data collection and analysis: We performed random-effects (RE) meta-analyses when two or more RCTs were available for a specific outcome. We conducted RE meta-analyses when five or more observational studies were available for a specific outcome. We assessed risk of bias in RCTs and in observational studies using Cochrane's risk assessment tool and the Newcastle-Ottawa Scale, respectively. We considered in the primary analysis data pooled from RCTs with low risk of bias. We assessed the certainty of evidence by using the GRADE approach. Main results: We included 83 studies in this updated review: two additional RCTs (10 in total) and a few additional trial reports for previously included studies. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. For analyses of RCTs with low risk of bias, the summary risk ratio (RR) for any cancer incidence was 1.01 (95% confidence interval (CI) 0.93 to 1.10; 3 studies, 19,475 participants; high-certainty evidence). The RR for estimated cancer mortality was 1.02 (95% CI 0.80 to 1.30; 1 study, 17,444 participants). For the most frequently investigated site-specific cancers, investigators provided little evidence of any effect of selenium supplementation. Two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43), as were non-melanoma skin cancer (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants), lung cancer (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants), breast cancer (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants), bladder cancer (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants), and prostate cancer (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants). Certainty of the evidence was high for all of these cancer sites, except for breast cancer, which was of moderate certainty owing to imprecision, and non-melanoma skin cancer, which we judged as moderate certainty owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk. Results for most outcomes were similar when we included all RCTs in the meta-analysis, regardless of risk of bias. Selenium supplementation did not reduce overall cancer incidence (RR 0.99, 95% CI 0.86 to 1.14; 5 studies, 21,860 participants) nor mortality (RR 0.81, 95% CI 0.49 to 1.32; 2 studies, 18,698 participants). Summary RRs for site-specific cancers showed limited changes compared with estimates from high-quality studies alone, except for liver cancer, for which results were reversed. In the largest trial, the Selenium and Vitamin E Cancer Trial, selenium supplementation increased risks of alopecia and dermatitis, and for participants with highest background selenium status, supplementation also increased risk of high-grade prostate cancer. RCTs showed a slightly increased risk of type 2 diabetes associated with supplementation. A hypothesis generated by the Nutritional Prevention of Cancer Trial - that individu

2018 - Supplementary Data [Articolo su rivista]
Amato, L.; Vecchi, S.; Barbui, C.; Cruciani, F.; D'Amico, R.; Del Giovane, C.; Minozzi, S.; Mitrova, Z.; Saulle, R.; Davoli, M.
abstract

2018 - Use of adjunctive cardiovascular therapy in patients hospitalized for acute exacerbations of COPD. [Articolo su rivista]
Roversi, S; Tonelli, R; Beghè, Bianca; Banchelli, F; D’Amico, Roberto; Malerba, Mario; Fabbri, Lm; Clini, E.
abstract

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is one of the most frequent diagnoses in patients presenting with acute dyspnea or respiratory failure. According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document, it is defined clinically, as acute worsening of respiratory symptoms that result in additional therapies, being bronchodilators, corticosteroids, and antibiotics the cornerstone of acute management. However, comorbidities in COPD, including cardiac disease, contribute significantly to heterogeneity of the single acute episode in real-life practice. Therefore, we were interested in evaluating how patients admitted to the hospital with a clinical diagnosis of AECOPD were managed at admission, and we analyzed the therapeutic approach at onset of AECOPD in hospitalized patients, aiming at assessing the adjunctive use of diuretic therapy.

2017 - 3* Final analysis of the phase III multicentric Italian study Short-HER: 9 weeks vs 1 year adjuvant trastuzumab for HER2+ early breast cancer [Abstract in Rivista]
Conte, P; Bisagni, G; Frassoldati, A; Brandes, A; Cavanna, L; Giotta, F; Aieta, M; Gebbia, V; Musolino, A; Garrone, O; Donadio, M; Cavazzini, G; Turletti, A; Zamagni, C; Danese, S; Ferro, A; Piacentini, F; Balduzzi, S; D'Amico, R; Guarneri, V
abstract

Introduction: chemotherapy plus 1 year trastuzumab is the standard adjuvant treatment for HER2+ breast cancer patients (pts). The Short-HER study is an independent, non-profit study aimed to test the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab. Methods: HER2+ breast cancer pts were randomized to: Arm A (Long) AC or ECx4 followed by 4 courses of 3-weekly docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel plus weekly trastuzumab for 9 doses followed by FEC x3. When indicated, radiation therapy and hormone therapy were started after the completion of chemotherapy. ShortHER is a non-inferiority trial with disease-free survival (DFS) as primary end-point. The sample size of 1250 pts has been estimated on the basis of an hazard ratio <1.29 for the short arm to be non-inferior. The definitive analysis was planned after 198 DFS events or a 5yr median follow up. Hazard ratio for DFS and OS (90% CI) are estimated according to the Cox model; data are also analyzed by the Bayesian approach. Results: from Dec-2007 to Oct-2013, 1254 pts from 82 centers have been randomized. Pts characteristics are: median age 55 yrs (25-78); pts older than 60 yr 36%; stage I 40.6%, II 43.8%, stage III 15.2%; N0 53.5%, 1-3 positive nodes 30.7%, ≥ 4 15.2%. Sixty-eight% of the pts had ER+ tumors. Characteristics were balanced between the two arms. At the time of the analysis, 189 events have occurred and the median follow up of the study is 5.2 yrs. A total of 109 Grade ≥ 2 cardiac events have been reported, 82 in arm A (long) and 27 in arm B (short) (p < 0.0001); grade 3-4 cardiac events were 13 in arm A and 5 in arm B. Conclusions: Shorter trastuzumab administration significantly reduces the rate of severe cardiac toxicity. Final DFS data will be reported at the time of the meeting. EudraCT: 2007-004326-25.

2017 - 9 weeks vs 1 year adjuvant trastuzumab in combination with chemotherapy: Results of the phase III multicentric Italian study Short-HER [Abstract in Atti di Convegno]
Conte, Pier Franco; Bisagni, Giancarlo; Frassoldati, Antonio; Brandes, Alba Ariela; Anselmi, Elisa; Giotta, Francesco; Aieta, Michele; Gebbia, Vittorio; Musolino, Antonino; Garrone, Ornella; Taverniti, Cristiana; Cavazzini, Giovanna; Turletti, Anna; Rubino, Daniela; Picardo, Elisa; Ferro, Antonella; Piacentini, Federico; Balduzzi, Sara; D'Amico, Roberto; Guarneri, Valentina
abstract

Background: 1-year trastuzumab with chemotherapy is the standard adjuvant treatment for HER2+ breast cancer patients (pts). The efficacy of less extended trastuzumab exposure is still under investigation. The Short-HER study is an independent, non-profit study aimed to test the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab. Methods: This is a phase III, multicenter, Italian trial where pts with HER2+ breast cancer were randomly assigned to: Arm A (Long) AC or ECx4 followed by 4 courses of 3-weekly docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel plus weekly trastuzumab for 9 doses followed by FEC x3. When indicated, radiation therapy was administered after the completion of chemotherapy. Hormonal therapy started at the completion of chemotherapy for pts with hormone receptor positive tumors. This is a non-inferiority trial with disease-free survival (DFS) as primary end-point.Overall survival (OS) is evaluated as second primary analysis outcome. The sample size of 1250 pts has been estimated based on a hazard ratio <1.29 for the short arm to be non-inferior. The definitive analysis will take place after 198 DFS events. Secondary aims include 2-yrs failure rate, cardiac toxicity, correlative biomarkers analyses. Hazard ratio for DFS and OS (90% CI) will be estimated according to the Cox model. Data will also be analyzed by the Bayesian approach. Results: from Dec-2007 to Oct-2013, 1254 pts from 82 centers have been randomized. Pts characteristics are the following: median age 55 yrs (25-78), stage I 37.3%, IIA 40%, IIB 20.6%, III 2.1%. 30% of the pts had 1-3 positive nodes, 16% >=4. Sixty-eight% of the pts had ER+ tumors. Characteristics were balanced between the two arms. At the time of this writing, 95% of the planned DFS events have been reported. 105 Grade ≥2 cardiac events have been reported, 78 in arm A (long) and 27 in arm B (short). Grade 3-4 cardiac events were 20 in arm A and 11 in arm B. Conclusions: Shorter trastuzumab administration almost halves the rate of severe cardiac toxicity. Final DFS data will be available at the time of the meeting.

2017 - Corrigendum to "Are the Two Human Papillomavirus Vaccines Really Similar? A Systematic Review of Available Evidence: Efficacy of the Two Vaccines against HPV" [Articolo su rivista]
Di Mario, Simona; Basevi, Vittorio; Lopalco, Pier Luigi; Balduzzi, Sara; D'Amico, Roberto; Magrini, Nicola
abstract

[This corrects the article DOI: 10.1155/2015/435141.].

2017 - GD2 expression in breast cancer. [Articolo su rivista]
Orsi, Giulia; Barbolini, Monica; Ficarra, G; Tazzioli, Giovanni; Manni, Paola; Petrachi, Tiziana; Mastrolia, Ilenia; Orvieto, E; Spano, Maria Carlotta; Prapa, Malvina; Kaleci, Shaniko; D'Amico, Roberto; Guarneri, V; Dieci, Mv; Cascinu, Stefano; Conte, P; Piacentini, Federico; Dominici, Massimo
abstract

Breast cancer (BC) is a heterogeneous disease, including different subtypes having diverse incidence, drug-sensitivity and survival rates. In particular, claudin-low and basal-like BC have mesenchymal features with a dismal prognosis. Disialoganglioside GD2 is a typical neuroectodermal antigen expressed in a variety of cancers. Despite its potential relevance in cancer diagnostics and therapeutics, the presence and role of GD2 require further investigation, especially in BC. Therefore, we evaluated GD2 expression in a cohort of BC patients and its correlation with clinical-pathological features.Sixty-three patients with BC who underwent surgery without prior chemo- and/or radiotherapy between 2001 and 2014 were considered. Cancer specimens were analyzed by immunohistochemistry and GD2-staining was expressed according to the percentage of positive cells and by a semi-quantitative scoring system.Patient characteristics were heterogeneous by age at diagnosis, histotype, grading, tumor size, Ki-67 and receptor-status. GD2 staining revealed positive cancer cells in 59% of patients. Among them, 26 cases (41%) were labeled with score 1+ and 11 (18%) with score 2+. Notably, the majority of metaplastic carcinoma specimens stained positive for GD2. The univariate regression logistic analysis revealed a significant association of GD2 with triple-receptor negative phenotype and older age (> 78) at diagnosis.We demonstrate for the first time that GD2 is highly prevalent in a cohort of BC patients clustering on very aggressive BC subtypes, such as triple-negative and metaplastic variants.

2017 - Progestogens for Maintenance Tocolysis in Women With a Short Cervix: A Randomized Controlled Trial [Articolo su rivista]
Facchinetti, Fabio; Vergani, Patrizia; Di Tommaso, Mariarosaria; Marozio, Luca; Acaia, Barbara; Vicini, Roberto; Pignatti, Lucrezia; Locatelli, Anna; Spitaleri, Marina; Benedetto, Chiara; Zaina, Barbara; DʼAmico, Roberto
abstract

To assess the efficacy of progestogens for maintenance tocolysis in women undelivered after their first preterm labor episode.

2017 - Systematic review of maternal voice interventions demonstrates increased stability in preterm infants [Articolo su rivista]
Filippa, Manuela; Panza, Costantino; Ferrari, Fabrizio; Frassoldati, Rossella; Kuhn, Pierre; Balduzzi, Sara; D'Amico, Roberto
abstract

We systematically reviewed how effectively maternal voice interventions supported the clinical outcomes and development of preterm infants. A total of 512 preterm infants were included in 15 studies with different designs, from January 2000 to July 2015. Live and recorded maternal voice interventions were associated with the physiologic and behavioural stabilisation of preterm infants, with fewer cardiorespiratory events, but the evidence was insufficient to evaluate the long-term effects. Well-defined determinants and clear setting conditions are needed for such interventions. Conclusion: Further research that investigates the long-term efficacy and effects of live maternal voices on preterm infant development is needed.

2017 - The effect of potassium supplementation on blood pressure in hypertensive subjects: A systematic review and meta-analysis. [Articolo su rivista]
Filippini, Tommaso; Violi, Federica; D'Amico, Roberto; Vinceti, Marco
abstract

BACKGROUND: Several intervention studies have investigated the relation between potassium intake and blood-pressure, particularly in hypertensive subjects. However, uncertainties still exist about the existence and the amount of such an effect, and about the role of some potential effect-modifiers, including the baseline potassium intake and geographical area. METHODS: We carried out a systematic review of the evidence concerning such relation in hypertensive subjects, performing a meta-analysis and a meta-regression of RCT with selective and validated long-term (≥4weeks) potassium supplementation. We also implemented 'unconventional' search strategies in order to identify all potentially interesting studies. RESULTS: Overall, potassium supplementation decreased systolic blood pressure of 4.48mmHg (95% CI 3.07-5.90) and diastolic blood pressure of 2.96mmHg (1.10-4.82). There was little evidence of dose-response relation between blood-pressure decrease and potassium supplementation, as assessed through total achieved potassium intake in the intervention groups, difference in achieved potassium intake, and study duration. However, lower (<90mmol/day) potassium intake at baseline was associated with a higher blood-pressure lowering effect, as were higher sodium intake (particularly ≥4g/day), higher sodium-to-potassium ratio and the absence of any anti-hypertensive drug treatment. Trials conducted in Southern Europe showed the highest blood-pressure lowering effect compared with the remaining regions. CONCLUSIONS: Potassium supplementation in hypertensives was generally associated with decreased blood pressure, particularly in high sodium consumers, subjects not on hypertensive drug treatment, and those in the lowest category of potassium intake. An adequate dietary intake of potassium, in the order of 90mmol/day, should be achieved for blood pressure control.

2016 - Major discrepancies between what clinical trial registries record and paediatric randomised controlled trials publish [Articolo su rivista]
Rosati, Paola; Porzsolt, Franz; Ricciotti, Gabriella; Testa, Giuseppina; Inglese, Rita; Giustini, Ferruccio; Fiscarelli, Ersilia; Zazza, Marco; Carlino, Cecilia; Balassone, Valerio; Fiorito, Roberto; D'Amico, Roberto
abstract

Background: Whether information from clinical trial registries (CTRs) and published randomised controlled trial (RCTs) differs remains unknown. Knowing more about discrepancies should alert those who rely on RCTs for medical decision-making to possible dissemination or reporting bias. To provide help in critically appraising research relevant for clinical practice we sought possible discrepancies between what CTRs record and paediatric RCTs actually publish. For this purpose, after identifying six reporting domains including funding, design, and outcomes, we collected data from 20 consecutive RCTs published in a widely read peer-reviewed paediatric journal and cross-checked reported features with those in the corresponding CTRs. Methods: We collected data for 20 unselected, consecutive paediatric RCTs published in a widely read peer-reviewed journal from July to November 2013. To assess discrepancies, two reviewers identified and scored six reporting domains: funding and conflict of interests; sample size, inclusion and exclusion criteria or crossover; primary and secondary outcomes, early study completion, and main outcome reporting. After applying the Critical Appraisal Skills Programme (CASP) checklist, five reviewer pairs cross-checked CTRs and matching RCTs, then mapped and coded the reporting domains and scored combined discrepancy as low, medium and high. Results: The 20 RCTs were registered in five different CTRs. Even though the 20 RCTs fulfilled the CASP general criteria for assessing internal validity, 19 clinical trials had medium or high combined discrepancy scores for what the 20 RCTs reported and the matched five CTRs stated. All 20 RCTs selectively reported or failed to report main outcomes, 9 had discrepancies in declaring sponsorship, 8 discrepancies in the sample size, 9 failed to respect inclusion or exclusion criteria, 11 downgraded or modified primary outcome or upgraded secondary outcomes, and 13 completed early without justification. The CTRs for seven trials failed to index automatically the URL address or the RCT reference, and for 12 recorded RCT details, but the authors failed to report the results. Conclusions: Major discrepancies between what CTRs record and paediatric RCTs publish raise concern about what clinical trials conclude. Our findings should make clinicians, who rely on RCT results for medical decision-making, aware of dissemination or reporting bias. Trialists need to bring CTR data and reported protocols into line with published data.

2016 - Rethinking on pediatric research in Italy [Articolo su rivista]
Di Mario, S.; Basevi, V.; D'Amico, R.; Gagliotti, C.; Gangemi, M.; Marchetti, F.; Moro, M. L.; Tamburlini, G.
abstract

2016 - Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer [Articolo su rivista]
Mantarro, Stefania; Rossi, Marta; Bonifazi, Martina; D'Amico, Roberto; Blandizzi, Corrado; La Vecchia, Carlo; Negri, Eva; Moja, Lorenzo
abstract

Trastuzumab prolongs survival in women with HER2-positive breast cancer, but may increase the risk of heart disease. The occurrence of severe cardiotoxicity, however, is not defined in real-life settings. We performed a meta-analysis of clinical trials and cohort studies to estimate the frequency of cardiotoxicities following trastuzumab treatment. We searched MEDLINE, EMBASE, and the Cochrane Library (1996-January 2014). The primary outcome was the frequency of severe cardiotoxicities up to 3-years after trastuzumab initiation. Among 58 studies (29,598 patients), severe cardiotoxicity occurred in 3.00 % (95 % CI 2.41-3.64), 2.62 % (95 % CI 1.97-3.35), and 3.14 % (95 % CI 2.12-4.37) of overall, early (EBC) and metastatic (MBC) breast cancer patients, respectively. In EBC, the proportion increased from 2.40 % at the first year to a plateau of approximately 3 % after the second year. In MBC, the proportion increased from 3.00 to 3.68 % when trastuzumab was used as first line or further lines of therapy, respectively. In EBC, cardiotoxicity occurred in 2.90 % of patients treated with taxanes and anthracyclines compared to 0.92 % in patients treated with taxanes without anthracyclines. The occurrence of cardiotoxicity varied according to age, increasing from 2.31 % in individuals <50 years, to 3.46 % in those 50-59 years, to 4.91 % in those >60 years of age. Cardiotoxicity was higher in smokers (5.3 %), dyslipidemic patients (3.9 %), BMI ≥25 (6.5 %), diabetes (6.2 %), hypertension (5.5 %), or positive history of cardiac disease (19.1 %). RCTs consistently report lower cardiac toxicity rates than observational studies (EBC: 1.7 versus 3.2; MBC: 2.8 versus 4.4). Following trastuzumab initiation, approximately three in 100 patients develop severe cardiotoxicity after 2 years. Patients enrolled in cohort studies, who more closely reflect women treated for breast cancer in real-life settings compared to RCTs, are at higher risk of developing cardiac events.

2016 - Short-term and long-term effects of tibolone in postmenopausal women [Articolo su rivista]
Formoso, Giulio; Perrone, Enrica; Maltoni, Susanna; Balduzzi, Sara; Wilkinson, Jack; Basevi, Vittorio; Marata, Anna Maria; Magrini, Nicola; D'Amico, Roberto; Bassi, Chiara; Maestri, Emilio
abstract

Background: Tibolone is a synthetic steroid used for the treatment of menopausal symptoms, on the basis of short-term data suggesting its efficacy. We considered the balance between the benefits and risks of tibolone. Objectives: To evaluate the effectiveness and safety of tibolone for treatment of postmenopausal and perimenopausal women. Search methods: In October 2015, we searched the Gynaecology and Fertility Group (CGF) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO (from inception), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and clinicaltrials.gov. We checked the reference lists in articles retrieved. Selection criteria: We included randomised controlled trials (RCTs) comparing tibolone versus placebo, oestrogens and/or combined hormone therapy (HT) in postmenopausal and perimenopausal women. Data collection and analysis: We used standard methodological procedures of The Cochrane Collaboration. Primary outcomes were vasomotor symptoms, unscheduled vaginal bleeding and long-term adverse events. We evaluated safety outcomes and bleeding in studies including women either with or without menopausal symptoms. Main results: We included 46 RCTs (19,976 women). Most RCTs evaluated tibolone for treating menopausal vasomotor symptoms. Some had other objectives, such as assessment of bleeding patterns, endometrial safety, bone health, sexuality and safety in women with a history of breast cancer. Two included women with uterine leiomyoma or lupus erythematosus. Tibolone versus placebo Vasomotor symptoms Tibolone was more effective than placebo (standard mean difference (SMD) -0.99, 95% confidence interval (CI) -1.10 to -0.89; seven RCTs; 1657 women; moderate-quality evidence), but removing trials at high risk of attrition bias attenuated this effect (SMD -0.61, 95% CI -0.73 to -0.49; odds ratio (OR) 0.33, 85% CI 0.27 to 0.41). This suggests that if 67% of women taking placebo experience vasomotor symptoms, between 35% and 45% of women taking tibolone will do so. Unscheduled bleeding Tibolone was associated with greater likelihood of bleeding (OR 2.79, 95% CI 2.10 to 3.70; nine RCTs; 7814 women; I2 = 43%; moderate-quality evidence). This suggests that if 18% of women taking placebo experience unscheduled bleeding, between 31% and 44% of women taking tibolone will do so. Long-term adverse events Most of the studies reporting these outcomes provided follow-up of two to three years (range three months to three years). Breast cancer We found no evidence of differences between groups among women with no history of breast cancer (OR 0.52, 95% CI 0.21 to 1.25; four RCTs; 5500 women; I2= 17%; very low-quality evidence). Among women with a history of breast cancer, tibolone was associated with increased risk (OR 1.5, 95% CI 1.21 to 1.85; two RCTs; 3165 women; moderate-quality evidence). Cerebrovascular events We found no conclusive evidence of differences between groups in cerebrovascular events (OR 1.74, 95% CI 0.99 to 3.04; four RCTs; 7930 women; I2 = 0%; very low-quality evidence). We obtained most data from a single RCT (n = 4506) of osteoporotic women aged 60 to 85 years, which was stopped prematurely for increased risk of stroke. Other outcomes Evidence on other outcomes was of low or very low quality, with no clear evidence of any differences between the groups. Effect estimates were as follows: • Endometrial cancer: OR 2.04, 95% CI 0.79 to 5.24; nine RCTs; 8504 women; I2 = 0%. • Cardiovascular events: OR 1.38, 95% CI 0.84 to 2.27; four RCTs; 8401 women; I2 = 0%. • Venous thromboembolic events: OR 0.85, 95% CI 0.37 to 1.97; 9176 women; I2 = 0%. • Mortality from any cause: OR 1.06, 95% CI 0.79 to 1.41; four RCTs; 8242 women; I2 = 0%. Tibolone versus combined HT Vasomotor symptoms Combined HT was more effective than tibolone (SMD 0.17, 95% CI 0.06 to 0.28; OR 1.36, 95% CI 1.11 to 1.66; nine studie

2016 - Streptococcus salivarius by nasal spray for recurrent otitis: how good is the evidence? [Articolo su rivista]
Di Mario, S; Basevi, Vittorio; D'Amico, Roberto; Gagliotti, C.; Gangemi, Michele; Marchetti, F.; Moro, M. L.; Tamburlini, G.
abstract

This is a letter published after a paper by Marchisio et al. entitled ‘Streptococcus salivarius 24SMB administered by nasal spray for the prevention of acute otitis media (AOM) in otitis-prone children’ was published. The paper raised some methodological concerns that were expressed in the letter.

2015 - Antibiotic treatment of severe exacerbations of chronic obstructive pulmonary disease with procalcitonin: A randomized noninferiority trial [Articolo su rivista]
Verduri, Alessia; Luppi, Fabrizio; D'Amico, Roberto; Balduzzi, Sara; Vicini, Roberto; Liverani, Anna; Ruggieri, Valentina; Plebani, Mario; Barbaro Foschino, Maria Pia; Spanevello, Antonio; Canonica, Giorgio Walter; Papi, Alberto; Fabbri, Leonardo; Beghe', Bianca
abstract

The duration of antibiotic treatment of exacerbations of COPD (ECOPD) is controversial. Serum procalcitonin (PCT) is a biomarker of bacterial infection used to identify the cause of ECOPD. METHODS AND FINDINGS: We investigated whether a PCT-guided plan would allow a shorter duration of antibiotic treatment in patients with severe ECOPD. For this multicenter, randomized, non-inferiority trial, we enrolled 184 patients hospitalized with ECOPD from 18 hospitals in Italy. Patients were assigned to receive antibiotics for 10 days (standard group) or for either 3 or 10 days (PCT group). The primary outcome was the rate of ECOPD at 6 months. Having planned to recruit 400 patients, we randomized only 183: 93 in the PCT group and 90 in the standard group. Thus, the completed study was underpowered. The ECOPD rate at 6 months between PCT-guided and standard antibiotic treatment was not significant (% difference, 4.04; 90% confidence interval [CI], -7.23 to 15.31), but the CI included the non-inferiority margin of 15. In the PCT-guided group, about 50% of patients were treated for 3 days, and there was no difference in primary or secondary outcomes compared to patients treated for 10 days. CONCLUSIONS: Although the primary and secondary clinical outcomes were no different for patients treated for 3 or 10 days in the PCT group, the conclusion that antibiotics can be safely stopped after 3 days in patients with low serum PCT cannot be substantiated statistically. Thus, the results of this study are inconclusive regarding the noninferiority of the PCT-guided plan compared to the standard antibiotic treatment. The study was funded by Agenzia Italiana del Farmaco (AIFA-FARM58J2XH). Clinical trial registered with www.clinicaltrials.gov (NCT01125098). TRIAL REGISTRATION: ClinicalTrials.gov NCT01125098.

2015 - Are parents of children hospitalized with severe community-acquired pneumonia more satisfied with care when physicians allow them to share decisions on the antibiotic route? [Articolo su rivista]
Rosati, Paola; Di Salvo, Viviana; Crudo, Stefania; D'Amico, Roberto; Carlino, Cecilia; Marchili, Maria Rosaria; Gonfiantini, Michaela; Di Ciommo, Vincenzo
abstract

AIMS Despite convincing evidence that oral and injected amoxicillin have equal efficacy in children with severe community-acquired pneumonia (CAP), hospitalized children often receive injected antibiotics. To investigate whether shared decision-making (choosing the antibiotic route) influences parental satisfaction. DESIGN, SETTING AND PARTICIPANTS: In a one-year questionnaire-based study, we enrolled consecutive children hospitalized for CAP. At admission, all children's parents received a leaflet on CAP. Parents arriving during the daytime were assigned to a shared group and could choose the antibiotic route, those admitted at other times were assigned to an unshared group for whom physicians chose the antibiotic route. Shared group parents answered anonymous questionnaire investigating why they chose a specific route. Parents in both groups answered another anonymous questionnaire at discharge assessing perceived satisfaction with care. MAIN OUTCOME MEASURE: Parents' satisfaction with perceived medical information as assessed by data from a questionnaire. RESULTS: Of the 95 children enrolled, more children's parents were assigned to the unshared than the shared group (77 vs. 18). Of the 18 children's parents in the shared group, 14 chose the oral antibiotic route mainly to avoid painful injections. Doctors explanations were considered better in the shared than in the unshared group (P = 0.02). DISCUSSION AND CONCLUSIONS: The larger number of children's parents assigned to the unshared group reflects paediatricians' reluctance to offer shared-decision making. Well-informed parents prefer oral antibiotic therapy for children with severe CAP. Allowing parents choose the antibiotic route respects parents' wishes, reduces children's pain and improves satisfaction.

2015 - Are the Two Human Papillomavirus Vaccines Really Similar? A Systematic Review of Available Evidence: Efficacy of the Two Vaccines against HPV [Articolo su rivista]
Di Mario, Simona; Basevi, Vittorio; Lopalco, Pier Luigi; Balduzzi, Sara; D'Amico, Roberto; Magrini, Nicola
abstract

When the bivalent and the quadrivalent HPV vaccines were marketed they were presented as having comparable efficacy against cervical cancer. Differences between the vaccines are HPV types included and formulation of the adjuvant. METHOD: A systematic review was conducted to assess the efficacy of the two vaccines against cervical cancer. Outcomes considered were CIN2+, CIN3+, and AIS. RESULTS: Nine reports (38,419 women) were included. At enrollment mean age of women was 20 years, 90% had negative cytology, and 80% were seronegative and/or DNA negative for HPV 16 or 18 (naive women). In the TVC-naive, VE against CIN2+ was 58% (95% CI: 35, 72); heterogeneity was detected, VE being 65% (95% CI: 54, 74) for the bivalent and 43% (95% CI: 23, 57) for the quadrivalent. VE against CIN3+ was 78% (95% CI: <0, 97); heterogeneity was substantial, VE being 93% (95% CI: 77, 98) for the bivalent and 43% (95% CI: 12, 63) for the quadrivalent. VE in the TVC was much lower. No sufficient data were available on AIS. CONCLUSIONS: In naive girls bivalent vaccine shows higher efficacy, even if the number of events detected is low. In women already infected the benefit of the vaccination seems negligible.

2015 - Discordances originated by multiple meta-analyses on interventions for myocardial infarction: a systematic review [Articolo su rivista]
Lucenteforte, Ersilia; Moja, Lorenzo; Pecoraro, Valentina; Conti, Andrea A.; Conti, Antonio; Crudeli, Elena; Galli, Alessio; Gensini, Gian Franco; Minnelli, Martina; Mugelli, Alessandro; Proietti, Riccardo; Shtylla, Jonida; D'Amico, Roberto; Parmelli, Elena; Virgili, Gianni
abstract

To clarify the impact of multiple (covering the same population,intervention, control, and outcomes) systematic reviews (SRs) on interventions for myocardial infarction (MI). STUDY DESIGN AND SETTING: Clinical Evidence (BMJ Group) sections and related search strategies regarding MI were used to identify multiple SRs published between 1997 and 2007. Multiple SRs were classified as discordant if they featured conflicting results or interpretation of them.RESULTS: Thirty-six SRs (23.5% of 153 on the treatment or prevention of MI) were classified as multiple and grouped in 16 clusters [ie, at least two SRs with the same PICO (population, condition/disease, intervention, control) and at least one common outcome] exploring angioplasty, angiotensin-converting enzyme inhibitors,anticoagulants, antiplatelets, beta-blockers, and stents. Complete agreement on statistically significant differences between interventions was found in 7 of 10 clusters with a shared composite outcome. Agreement was reduced when single outcomes were considered. Despite substantial variation and limited agreement in reporting of major outcomes, SRs agreed in their conclusions on the superiority of either the intervention or control in 14 of 16 clusters. Sources of minor discrepancies were found in terms of study and outcome selection, subgroup analyses, and interpretation of findings. CONCLUSION: Multiple SRs agreed in their qualitative conclusions but not on reporting and on analyses of hard outcomes. Discordance on significance of treatment effects was due to a combination of variation in design with inclusion of different studies and lack of precision for single hard outcomes compared with a composite outcome. Such inconsistencies among SRs could potentially slow the translation of SRs' results to clinical and public health decision making and suggest the need for a broader methodological and clinical agreement on their design.

2015 - Erlotinib for advanced pancreatic cancer [Articolo su rivista]
Baldo, P.; Giacomin, E.; Cecco, S.; D'Amico, R.; Cannizzaro, R.; Balduzzi, S.
abstract

This is the protocol for a review and there is no abstract. The objectives are as follows: To evaluate the effectiveness and toxicity profile of erlotinib alone or combined with other therapies for the treatment of advanced pancreatic cancer, as first-line, second-line or palliative treatment.

2015 - Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis [Articolo su rivista]
Tramacere, Irene; DEL GIOVANE, Cinzia; Salanti, Georgia; D'Amico, Roberto; Filippini, Graziella
abstract

Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biologics. Although there is consensus that these therapies reduce the frequency of relapses, their relative benefit in delaying new relapses or disability worsening remains unclear due to the limited number of direct comparison trials.

2015 - Prediction risk chart for scleroderma digital ulcers: A composite predictive model based on capillaroscopic, demographic and clinico-serological parameters [Articolo su rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; Carraro, Valeria; Iudici, Michele; Bocci, Mario; Vukatana, Gentiana; Gerli, Roberto; De Angelis, Rossella; Del Medico, Patrizia; Praino, Emanuela; Lo Monaco, Andrea; D'Amico, Roberto; DEL GIOVANE, Cinzia; Mazzuca, Salvatore; Colaci, Michele; Giuggioli, Dilia; Ferri, Clodoveo
abstract

BACKGROUND: Digital ulcers (DU) affect 50% of systemic sclerosis (SSc) patients, representing a challenging clinical problem. Despite a high negative predictive value, capillaroscopic scores proposed to select patients at risk for DU show an inadequate positive predictive value, especially in patients without previous DU. AIM OF THIS STUDY: To increase the predictive value for DU development of capillaroscopy, through a predictive risk chart taking into account capillaroscopic, demographic, and clinico-serological parameters. PATIENTS AND METHODS: Two hundred and nineteen unselected SSc patients from 8 Italian Rheumatology Centers were consecutively enrolled during a 6-month period. Demographic, clinical, serological and instrumental data and capillaroscopy skin ulcers risk index (CSURI) were collected. RESULTS: A multivariate logistic regression analysis showed a significant positive association between DU appearance and male gender, DU history, altered CSURI, and ESR. A prediction risk chart of the development of DU within 6 months were built on the basis of the above parameters. According to the risk level, four risk classes were identified: low (≤19.3%); medium (>19.3%, ≤58.6%); high (>58.6%, ≤89.2%), and very high risk (>89.2%). CONCLUSIONS: The systematic evaluation of the above parameters can be helpful to identify patients at risk to develop DU optimizing preventive vasoactive therapy.

2015 - Prenatal education for congenital toxoplasmosis [Articolo su rivista]
Di Mario, Simona; Basevi, Vittorio; Gagliotti, Carlo; Spettoli, Daniela; Gori, Gianfranco; D'Amico, Roberto; Magrini, Nicola
abstract

Congenital toxoplasmosis is considered a rare but potentially severe infection. Prenatal education about congenital toxoplasmosis could be the most efficient and least harmful intervention, yet its effectiveness is uncertain.

2015 - Recombinant factor VIIa concentrate versus plasma-derived concentrates for treating acute bleeding episodes in people with haemophilia and inhibitors [Articolo su rivista]
Matino, Davide; Makris, Michael; Dwan, Kerry; D'Amico, Roberto; Iorio, Alfonso
abstract

In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-factor VIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII 'by-passing' agents and used for treatment of bleeding in people with inhibitors.

2015 - Testing treatments interactive (TTi): helping to equip the public to promote better research for better health care [Articolo su rivista]
Chen, Yaolong; Chalmers, Iain; on behalf of the TTi Editorial, Alliance; D'Amico, Roberto
abstract

Testing Treatments is a book written to help everyone understand why testing treatments is so important, why treatment tests have to be fair, and how everyone can help to promote better research for better health care. The book proved to be very popular and its second edition has already been translated into a dozen languages, with more translations in the pipeline. The texts of the original English and all the translations are feely downloadable from Testing Treatments interactive at www.testingtreatments.org. The editors of all the different language websites have established an TTi Editorial Alliance, to share experiences and provide each other with mutual support. The TTi Editorial Alliance seeks to promote a world in which health professionals, patients and the public use reliable research to inform their health decisions. Its missions are (i) To promote a global network, involving members of the public in partnership with professionals, to communicate and discuss basic principles and general knowledge about testing treatments; (ii) to help the public increase critical thinking and skills in accessing, apprehending, appraising and using research evidence; and (iii) to help patients and the public to participate more actively in health research.

2014 - Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: A network meta-analysis [Articolo su rivista]
Tramacere, I.; Del Giovane, C.; Salanti, G.; D'Amico, R.; Pacchetti, I.; Filippini, G.
abstract

This is the protocol for a review and there is no abstract. The objectives are as follows: We aim to compare the efficacy and acceptability of immunomodulators and immunosuppressants to treat participants with RRMS and to generate a clinically useful hierarchy of available immunotherapies according to their efficacy and acceptability.

2014 - Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement [Articolo su rivista]
Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D. G.; Antes, G.; Atkins, D.; Barbour, V.; Barrowman, N.; Berlin, J. A.; Clark, J.; Clarke, M.; Cook, D.; D'Amico, R.; Deeks, J. J.; Devereaux, P. J.; Dickersin, K.; Egger, M.; Ernst, E.; Gotzsche, P. C.; Grimshaw, J.; Guyatt, G.; Higgins, J.; Ioannidis, J. P. A.; Kleijnen, J.; Lang, T.; Magrini, N.; McNamee, D.; Moja, L.; Mulrow, C.; Napoli, M.; Oxman, A.; Pham, B.; Rennie, D.; Sampson, M.; Schulz, K. F.; Shekelle, P. G.; Tovey, D.; Tugwell, P.
abstract

2014 - Prognostic value of diffusion-weighted imaging summation scores or apparent diffusion coefficient maps in newborns with hypoxic-ischemic encephalopathy [Articolo su rivista]
Cavalleri, Francesca; Lugli, Licia; Pugliese, Marisa; D'Amico, Roberto; Todeschini, Alessandra; Della Casa, Elisa; Gallo, Claudio; Frassoldati, Rossella; Ferrari, Fabrizio
abstract

The diagnostic and prognostic assessment of newborn infants with hypoxic-ischemic encephalopathy (HIE) comprises, among other tools, diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps.

2014 - Randomization as an act of altruism [Articolo su rivista]
Amato, L.; Davoli, M.; Parmelli, E.; Ciccone, G.; D'Amico, R.; De Fiore, L.; Filippini, G.; Magrini, N.; Moja, L.; Mosconi, P.
abstract

2014 - Selenium for preventing cancer. [Articolo su rivista]
Vinceti, Marco; Dennert, G; Crespi, Cm; Zwahlen, M; Brinkman, M; Zeegers, Mp; Horneber, M; D'Amico, Roberto; DEL GIOVANE, Cinzia
abstract

BACKGROUND: This review is an update of the first Cochrane publication on selenium for preventing cancer (Dennert 2011).Selenium is a metalloid with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancers. OBJECTIVES: Two research questions were addressed in this review: What is the evidence for:1. an aetiological relation between selenium exposure and cancer risk in humans? and2. the efficacy of selenium supplementation for cancer prevention in humans? SEARCH METHODS: We conducted electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, 2013, Issue 1), MEDLINE (Ovid, 1966 to February 2013 week 1), EMBASE (1980 to 2013 week 6), CancerLit (February 2004) and CCMed (February 2011). As MEDLINE now includes the journals indexed in CancerLit, no further searches were conducted in this database after 2004. SELECTION CRITERIA: We included prospective observational studies (cohort studies including sub-cohort controlled studies and nested case-control studies) and randomised controlled trials (RCTs) with healthy adult participants (18 years of age and older). DATA COLLECTION AND ANALYSIS: For observational studies, we conducted random effects meta-analyses when five or more studies were retrieved for a specific outcome. For RCTs, we performed random effects meta-analyses when two or more studies were available. The risk of bias in observational studies was assessed using forms adapted from the Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies; the criteria specified in the Cochrane Handbook for Systematic Reviews of Interventions were used to evaluate the risk of bias in RCTs. MAIN RESULTS: We included 55 prospective observational studies (including more than 1,100,000 participants) and eight RCTs (with a total of 44,743 participants). For the observational studies, we found lower cancer incidence (summary odds ratio (OR) 0.69, 95% confidence interval (CI) 0.53 to 0.91, N = 8) and cancer mortality (OR 0.60, 95% CI 0.39 to 0.93, N = 6) associated with higher selenium exposure. Gender-specific subgroup analysis provided no clear evidence of different effects in men and women (P value 0.47), although cancer incidence was lower in men (OR 0.66, 95% CI 0.42 to 1.05, N = 6) than in women (OR 0.90, 95% CI 0.45 to 1.77, N = 2). The most pronounced decreases in risk of site-specific cancers were seen for stomach, bladder and prostate cancers. However, these findings have limitations due to study design, quality and heterogeneity that complicate interpretation of the summary statistics. Some studies suggested that genetic factors may modify the relation between selenium and cancer risk-a hypothesis that deserves further investigation.In RCTs, we found no clear evidence that selenium supplementation reduced the risk of any cancer (risk ratio (RR) 0.90, 95% CI 0.70 to 1.17, two studies, N = 4765) or cancer-related mortality (RR 0.81, 95% CI 0.49 to 1.32, two studies, N = 18,698), and this finding was confirmed when the analysis was restricted to studies with low risk of bias. The effect on prostate cancer was imprecise (RR 0.90, 95% CI 0.71 to 1.14, four studies, N = 19,110), and when the analysis was limited to trials with low risk of bias, the interventions showed no effect (RR 1.02, 95% CI 0.90 to 1.14, three studies, N = 18,183). The risk of non-melanoma skin cancer was increased (RR 1.44, 95% CI 0.95 to 1.17, three studies, N = 1900). Results of two trials-the Nutritional Prevention of Cancer Trial (NPCT) and the Selenium and Vitamin E Cancer Trial (SELECT)-also raised concerns about possible increased risk of type 2 diabetes, alopecia and dermatitis due to selenium supplements. An early hypothesis generated by NPCT that individuals with the lowest blood selenium levels at baseline could reduce their risk of cancer, particularly of prostate cancer, by increasing selenium in

2014 - Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration [Articolo su rivista]
Lorenzo, Moja; Ersilia, Lucenteforte; Koren H., Kwag; Vittorio, Bertele; Annalisa, Campomori; Usha, Chakravarthy; D'Amico, Roberto; Kay, Dickersin; Laurent, Kodjikian; Kristina, Lindsley; Yoon, Loke; Maureen, Maguire; Daniel F., Martin; Alessandro, Mugelli; Bernd, Mühlbauer; Isabel, Püntmann; Barnaby, Reeves; Chris, Rogers; Christine, Schmucker; Manju L., Subramanian; Gianni, Virgili
abstract

Neovascular age-related macular degeneration (AMD) is the leading cause of legal blindness in elderly populations of industrialised countries. Bevacizumab (Avastin®) and ranibizumab (Lucentis®) are targeted biological drugs (a monoclonal antibody) that inhibit vascular endothelial growth factor, an angiogenic cytokine that promotes vascular leakage and growth, thereby preventing its pathological angiogenesis. Ranibizumab is approved for intravitreal use to treat neovascular AMD, while bevacizumab is approved for intravenous use as a cancer therapy. However, due to the biological similarity of the two drugs, bevacizumab is widely used off-label to treat neovascular AMD.

2014 - Trastuzumab-containing regimens for metastatic breast cancer [Articolo su rivista]
Balduzzi, Sara; Mantarro, Stefania; Guarneri, Valentina; Tagliabue, Ludovica; Pistotti, Vanna; Moja, Lorenzo; D'Amico, Roberto
abstract

Patients with breast cancer are classified as having cells that over-express the human epidermal growth factor receptor 2 (known as HER2-positive) or not (HER2-negative). Typically, patients with HER2-positive disease have a worse prognosis. Trastuzumab is a selective treatment that targets the HER2 pathway. The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system.

2013 - Capillaroscopic Skin Ulcers Risk Index (CSURI) calculated with different videocapillaroscopy devices: how its predictive values change [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Lo Monaco, A.; Praino, E.; Riccieri, V.; Grattagliano, V.; Bortoluzzi, A.; Stefanantoni, K.; D'Amico, Roberto; Giuggioli, D.; Ferri, Clodoveo
abstract

INTRODUCTION: Digital ulcers (DU) occur in about 50% of systemic sclerosis (SSc) patients. Scleroderma DU are responsible for chronic pain and disability with the need of systemic and local treatments. Recently, capillaroscopic skin ulcer risk index (CSURI) has been validated as useful tool in predicting the appearance of new scleroderma ulcers and/or persistence of non-healing lesions, within 3 months from capillaroscopy evaluation. OBJECTIVES: Since the image length of 1.57 mm might represent a critical factor for CSURI calculation, the present study aimed to evaluate the reliability of CSURI using three different videocapillaroscopy devices with distinct image widths. METHODS: One hundred and seventy-six unselected SSc patients were consecutively enrolled for the study during a six-month period, using three different capillaroscopy devices (image widths of 1.33, 1.57, and 1.70 mm). RESULTS: After a three month-follow-up new DU or persisting non-healing ulcers were observed in 46/176 patients (26.1%). The receiver operating characteristic curve analysis for CSURI showed an area under curve respectively of 0.705 for the image width of 1.33 mm, 0.786 for the image of 1.70 mm, and 0.888 for the image width of 1.57 mm. CONCLUSIONS: The good sensitivity, specificity and positive predictive value of CSURI was confirmed in the whole patients` series, as well as in the three subgroups on different image widths obtained with various available devices. In addition, the negative predictive value of the capillaroscopic index remained very high regardless of the picture length adopted.

2013 - Cerebrospinal fluid oligoclonal IgM bands predict early conversion to clinically definite multiple sclerosis in patients with Clinically Isolated Syndrome. [Articolo su rivista]
Ferraro, Diana; Simone, ANNA MARIA; Bedin, Roberta; Galli, Veronica; Vitetta, F; Federzoni, L; D'Amico, Roberto; Merelli, E; Nichelli, Paolo Frigio; Sola, P.
abstract

We reviewed the records of 391 patients who had presented with a Clinically Isolated Syndrome and selected 205 who had performed a baseline spinal tap and MRI scan. We studied cerebrospinal fluid (CSF) and serum IgM oligoclonal bands (IgMOB) using agarose gel isoelectric focusing and analyzed the impact of baseline clinical, MRI and CSF variables on the risk of conversion to clinically definite multiple sclerosis, i.e. on the risk of a clinical relapse. At survival analysis, a lower age at onset, an onset with optic neuritis and the presence of CSF-restricted IgMOB increased the risk of a relapse. Only the presence of CSF-restricted IgMOB predicted a relapse within one year.

2013 - Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis [Articolo su rivista]
Filippini, Graziella; DEL GIOVANE, Cinzia; Vacchi, Laura; D'Amico, Roberto; Di Pietrantonj, Carlo; Beecher, Deirdre; Salanti, Georgia
abstract

Different therapeutic strategies are available for treatment of multiple sclerosis (MS) including immunosuppressants, immunomodulators, and monoclonal antibodies. Their relative effectiveness in the prevention of relapse or disability progression is unclear due to the limited number of direct comparison trials. A summary of the results, including both direct and indirect comparisons of treatment effects, may help to clarify the above uncertainty.

2013 - Involving patients in setting the research agenda in drug addiction [Articolo su rivista]
Ferri, Marica; Davoli, Marina; D'Amico, Roberto
abstract

Biomedical Research; Humans; Patient Participation; Patient-Centered Care; Substance-Related Disorders

2013 - Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy. [Articolo su rivista]
Ricci, Giulia; Scionti, Isabella; Sera, F; Govi, Monica; D'Amico, Roberto; Frambolli, Ilaria; Mele, Fabiano; Filosto, M; Vercelli, L; Ruggiero, L; Berardinelli, A; Angelini, C; Antonini, G; Bucci, E; Cao, M; Daolio, Jessica; Di Muzio, A; Di Leo, R; Galluzzi, G; Iannaccone, E; Maggi, L; Maruotti, V; Moggio, M; Mongini, T; Morandi, L; Nikolic, Ana; Pastorello, E; Ricci, E; Rodolico, C; Santoro, L; Servida, M; Siciliano, G; Tomelleri, G; Tupler, Rossella
abstract

Facioscapulohumeral muscular dystrophy has been genetically linked to reduced numbers (<8) of D4Z4 repeats at 4q35 combined with 4A(159/161/168) DUX4 polyadenylation signal haplotype. However, we have recently reported that 1.3% of healthy individuals carry this molecular signature and 19% of subjects affected by facioscapulohumeral muscular dystrophy do not carry alleles with eight or fewer D4Z4 repeats. Therefore, prognosis for subjects carrying or at risk of carrying D4Z4 reduced alleles has become more complicated. To test for additional prognostic factors, we measured the degree of motor impairment in a large group of patients affected by facioscapulohumeral muscular dystrophy and their relatives who are carrying D4Z4 reduced alleles. The clinical expression of motor impairment was assessed in 530 subjects, 163 probands and 367 relatives, from 176 unrelated families according to a standardized clinical score. The associations between clinical severity and size of D4Z4 allele, degree of kinship, gender, age and 4q haplotype were evaluated. Overall, 32.2% of relatives did not display any muscle functional impairment. This phenotype was influenced by the degree of relation with proband, because 47.1% of secondthrough fifth-degree relatives were unaffected, whereas only 27.5% of first-degree family members did not show motor impairment. The estimated risk of developing motor impairment by age 50 for relatives carrying a D4Z4 reduced allele with 1-3 repeats or 4-8 repeats was 88.7% and 55%, respectively. Male relatives had a mean score significantly higher than females (5.4 versus 4.0, P = 0.003). No 4q haplotype was exclusively associated with the presence of disease. In 13% of families in which D4Z4 alleles with 4-8 repeats segregate, the diagnosis of facioscapulohumeral muscular dystrophy was reported only in one generation. In conclusion, this large-scale analysis provides further information that should be taken into account when counselling families in which a reduced allele with 4-8 D4Z4 repeats segregates. In addition, the reduced expression of disease observed in distant relatives suggests that a family's genetic background plays a role in the occurrence of facioscapulohumeral muscular dystrophy. These results indicate that the identification of new susceptibility factors for this disease will require an accurate classification of families.

2013 - Novel genetic association of TNF-α-238 and PDCD1-7209 polymorphisms with long-term non-progressive HIV-1 infection. [Articolo su rivista]
Nasi, Milena; Riva, A; Borghi, V; D'Amico, Roberto; DEL GIOVANE, Cinzia; Casoli, C; Galli, M; Vicenzi, E; Gibellini, Lara; DE BIASI, Sara; Clerici, M; Mussini, Cristina; Cossarizza, Andrea; Pinti, Marcello
abstract

About 2-5% of HIV-1-infected subjects, defined as long-term non-progressors (LTNPs), remain immunologically stable for a long time without treatment. The factors governing this condition are known only in part, and include genetic factors. Thus, we studied 20 polymorphisms of 15 genes encoding proinflammatory and immunoregulatory cytokines, chemokines and their receptors, genes involved in apoptosis, and the gene HCP5. METHODS: We analyzed 47 Caucasian LTNPs infected for >9 years, compared with 131 HIV-1-infected Caucasian patients defined as 'usual progressors'. The genotypes were determined by methods based upon PCR, and the statistical analysis was performed by univariate logistic regression. RESULTS: The well-known CCR5Δ32 del32 allele, the cell death-related TNF-α-238 A and PDCD1-7209 T alleles, and HCP5 rs2395029 G, a non-coding protein associated with the HLA-B*5701, were found positively associated with the LTNP condition. No association was observed for other single nucleotide polymorphisms (SDF-1-801, IL-10-592, MCP-1-2518, CX3CR1 V249I, CCR2V64I, RANTES-403, IL-2-330, IL-1β-511, IL-4-590, FASL IVS3nt-169, FAS-670, FAS-1377, FASL IVS2nt-124, PDCD1-7146, MMP-7-181, and MMP7-153). CONCLUSIONS: The novel genetic associations between allelic variants of genes TNF-α-238 and PDCD1-7209 with the LTNP condition underline the importance of host genetic factors in the progression of HIV-1 infection and in immunological preservation.

2013 - Prenatal education for congenital toxoplasmosis [Articolo su rivista]
Di Mario, Simona; Basevi, Vittorio; Gagliotti, Carlo; Spettoli, Daniela; Gori, Gianfranco; D'Amico, Roberto; Magrini, Nicola
abstract

2013 - Prevalence and Risk Factors of PTSD in Children and Adolescents after the 2012 Earthquake in the Emilia Romagna Region: implications for intervention [Abstract in Rivista]
Forresi, Barbara; DEL GIOVANE, Cinzia; Soncini, Francesco; Aggazzotti, Gabriella; D'Amico, Roberto; Parmelli, Elena; Righi, Elena; Caffo, Ernesto
abstract

PTSD is one of the psychological disorders that occurs after natural disasters. Many cases will remit within a few months, however in some estimates nearly one-third of cases have a chronic course. Delay-onset PTSD and progressive increase of symptoms seem to be very common. Given the significant rates of PTSD among children and adolescents after earthquakes and the long-term impact on their mental health, it is of primary importance to identify and treat symptoms effectively. The authors will present preliminary data from a cross-sectional study aimed at evaluating the prevalence of PTSD in a sample of children and adolescents nine months after the 2012 earthquake that hit the Emilia Romagna region in northern Italy. Data concerning risk (e.g., level of trauma exposure and parental psychopathology) and protective factors for the development and the persistence of the disorder will be also presented. Children and adolescents (age range: 9–14 years), randomly selected from schools in the Province of Modena, have been assessed using an exposure questionnaire on objective/subjective experiences during the earthquake, the UCLA PTSD index for DSM-IV (UPID), and the strengths and difficulties questionnaire (SDQ). Parental symptomatology has been also assessed, in order to evaluate the influence of parental psychopathology on offspring's adjustment. Given the few studies conducted in Italy about the long-term psychological impact of natural disaster on children and adolescents, the present research has important implications for the prevention and treatment of traumatized children and adolescents in Italy, as well as for the development of effective posttrauma interventions.

2013 - Prevalence and risk factors of Post-Traumatic Stress Disorder in children and adolescents after the 2012 earthquake affecting the Emilia Romagna Region (Italy). [Abstract in Rivista]
Righi, Elena; Forresi, Barbara; Soncini, Francesco; DEL GIOVANE, Cinzia; D'Amico, Roberto; Caffo, Ernesto; Fantuzzi, Guglielmina; Aggazzotti, Gabriella
abstract

On May 2012, two major earthquakes hit the Province of Modena (Emilia Romagna Region, Northern Italy): the country suffered 27 deaths and several hundred injured citizen; 15000 local resident were left homeless. Post-Traumatic Stress Disorder (PTSD) is a major debilitating psychological disorder that frequently occurs after natural disasters, including earthquakes, with a prevalence ranging, according to different authors, from 28 to 70%. Many cases will remit within 12 months, however about one-third of cases will have a chronic course. Given the high PTSD rates in children and adolescents, the long term impact on their well-being and the relevant social costs of chronic mental disorders, it is of primary importance to recognize and effectively treat cases as soon as possible and to identify potential individual and social risk and protective factors to be addressed in future effective preventive interventions. An epidemiological cross-sectional study has been set up and is on progress in a randomly selected sample of school children and adolescents (9-14 years) exposed to the earthquake with the aim to assess the PTSD prevalence and to explore potential risk (demographic, parental factors and level of trauma exposure) and protective factors (e.g. social support) associated to PTSD development and persistence. The assessment protocol includes the administration of an exposure questionnaire on objective/subjective experiences during the earthquake, the UCLA PTSD Index for DSM-IV questionnaire, and the Strengths and Difficulties Questionnaire. Parental symptomatology will be also assessed using the Symptom Checklist-90-R questionnaire, in order to evaluate the influence of parental psychopathology on children conditions. The present research will have important implications for the prevention in Italy of chronic PTSD, for treatment of traumatized children and adolescents, as well as for the development of effective post-trauma interventions.

2013 - Up-regulation of the canonical Wnt-3A and Sonic hedgehog signaling underlies melanocortin-induced neurogenesis after cerebral ischemia [Articolo su rivista]
Spaccapelo, Luca; Galantucci, Maria; Neri, Laura; Contri, Miranda; R., Pizzala; D'Amico, Roberto; Ottani, Alessandra; Sandrini, Maurizio; Zaffe, Davide; Giuliani, Daniela; Guarini, Salvatore
abstract

In experimental cerebral ischemia, melanocortin MC4 receptor agonists induce neuroprotection and neurogenesis with subsequent long-lasting functional recovery. Here we investigated the molecular mechanisms underlying melanocortin-induced neurogenesis. Gerbils were subjected to transient global cerebral ischemia, then they were treated every 12 h, and until sacrifice, with 5-bromo-2'-deoxyuridine (BrdU; to label proliferating cells), and the melanocortin analog [Nle(4),D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) or saline. NDP-alpha-MSH increased hippocampus dentate gyrus (DG) expression of Wnt-3A, beta-catenin, Sonic hedgehog (Shh), Zif268, interleukin-10 (IL-10) and doublecortin (DCX), as detected at days 3, 6 and 10 after the ischemic insult. Further, an elevated number of BrdU immunoreactive cells was found at days 3 and 10, and an improved histological picture with reduced neuronal loss at day 10, associated with learning and memory recovery. Pharmacological blockade of the Wnt-3A/beta-catenin and Shh pathways, as well as of melanocortin MC4 receptors, prevented all effects of NDP-alpha-MSH. These data indicate that, in experimental brain ischemia, treatment with melanocortins acting at MC4 receptors induces neural stem/progenitor cell proliferation in the DG by promptly and effectively triggering the canonical Wnt-3A/beta-catenin and Shh signaling pathways. Activation of these pathways is associated with up-regulation of the repair factor Zif268 and the neurogenesis facilitating factor IL-10, and it seems to address mainly toward a neuronal fate, as indicated by the increase in DCX positive cells.

2012 - Early visualization and measurement of the pericallosal artery: an indirect sign of corpus callosum development [Articolo su rivista]
M., Pati; C., Cani; Bertucci, Emma; C., Re; S., Latella; D'Amico, Roberto; V., Mazza
abstract

OBJECTIVES:The purpose of this study was to evaluate the feasibility of visualization and measurement of the pericallosal artery during early stages of gestation.METHODS:The study group comprised 80 pregnant women between 12 and 21 weeks' gestation who attended our ultrasound unit. Transabdominal or transvaginal sonography was performed to obtain the optimal angle of a midsagittal section. High-definition flow power Doppler imaging was used to visualize the pericallosal artery. In a sagittal plane, the lengths of the pericallosal artery were measured using a straight line to connect the most anterior and posterior points. All patients were reexamined at a later stage of pregnancy to verify the existence of the corpus callosum and pericallosal artery.RESULTS:Visualization of the pericallosal artery was evident in 71 fetuses, in all of whom the biparietal diameter was greater than 20 mm. We were able to verify normal anatomy and the existence of the pericallosal artery in these fetuses between 30 and 32 weeks' gestation. A positive linear association was found between the length of the pericallosal artery and the gestational age (R(2) = 0.95) and the biparietal diameter at each gestational age (R(2) = 0.99).CONCLUSIONS:Our data show that it is feasible to visualize and measure the pericallosal artery from an early stage of gestation, and this measurement could be an indirect indication of normal corpus callosum development.

2012 - Efficacy and safety of venous angioplasty of the extracranial veins for multiple sclerosis. Brave Dreams Study (Brain Venous Drainage Exploited Against Multiple Sclerosis): study protocol for a randomized controlled trial. [Articolo su rivista]
P., Zamboni; A., Bertolotto; P., Boldrini; P., Cenni; R., D'Alessandro; D'Amico, Roberto; M., Del Sette; R., Galeotti; S., Galimberti; Liberati, Alessandro; L., Massacesi; D., Papini; S., Salvi F; Simi, ; A., Stella; L., Tesio; Mg, Valsecchi; G., Filippini
abstract

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system with a disabling progressive course. Chronic cerebrospinal venous insufficiency (CCSVI) has recently been described as a vascular condition characterized by restricted venous outflow from the brain, mainly due to blockages of the internal jugular and azygos veins. Despite a wide variability among studies, it has been found to be associated with MS. Data from a few small case series suggest possible improvement of the clinical course and quality of life by performing percutaneous balloon angioplasty (PTA) of the stenotic veins.Study design and methodsThis is a multicenter, randomized, parallel group, blinded, sham-controlled trial to assess the efficacy and safety of PTA. Participants with relapsing remitting MS or secondary progressive MS and a sonographic diagnosis of CCSVI will be enrolled after providing their informed consent. Each participant will be centrally randomized to receive catheter venography and PTA or catheter venography and sham PTA. Two primary end points with respect to efficacy at 12 months are (1) a combined end point obtained through the integration of five functional indicators, walking, balance, manual dexterity, bladder control, and visual acuity, objectively measured by instruments; and (2) number of new brain lesions measured by T2-weighted MRI sequences. Secondary end points include annual relapse rate, change in Expanded Disability Status Scale score, proportion of patients with zero, one or two, or more than two relapses; fatigue; anxiety and depression; general cognitive state; memory/attention/calculus; impact of bladder incontinence; and adverse events. Six hundred seventy-nine patients will be recruited. The follow-up is scheduled at 12 months. Patients, treating neurologists, trained outcome assessors, and the statistician in charge of data analysis will be masked to the assigned treatment. DISCUSSION: The study will provide an answer regarding the efficacy of PTA on patients' functional disability in balance, motor, sensory, visual and bladder function, cognitive status, and emotional status, which are meaningful clinical outcomes, beyond investigating the effects on inflammation. In fact, an important part of patients' expectations, sustained and amplified by anecdotal data, has to do precisely with these functional aspects.Trial registrationClinicaltrials.gov NCT01371760.

2012 - Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling. [Articolo su rivista]
I., Scionti; G., Fabbri; C., Fiorillo; G., Ricci; F., Greco; D'Amico, Roberto; A., Termanini; L., Vercelli; G., Tomelleri; M., Cao; L., Santoro; Percesepe, Antonio; Tupler, Rossella
abstract

AbstractBackground Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disease with a prevalence of 1 in 20 000. Almost all patients with FSHD carry deletions of integral copies of tandem 3.3 kb repeats (D4Z4) located on chromosome 4q35. However, FSHD families have been reported in which individuals carrying a D4Z4-reduced allele remain asymptomatic. Recently, it has been proposed that the D4Z4-reduced allele is pathogenic only in association with the permissive haplotype, 4APAS. Methods and results Through the Italian National Registry for FSHD (INRF), genotype-phenotype correlations were extensively studied in 11 non-consanguineous families in which two D4Z4-reduced alleles segregate. Overall, 68 subjects carrying D4Z4-reduced alleles were examined, including 15 compound heterozygotes. It was found that in four families the only FSHD-affected subject was the compound heterozygote for the D4Z4-reduced allele, and 52.6% of subjects carrying a single D4Z4-reduced 4A161PAS haplotype were non-penetrant carriers; moreover, the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was found to be as high as 1.2%. Conclusions This study reveals a high frequency of compound heterozygotes in the Italian population and the presence of D4Z4-reduced alleles with the 4A161PAS pathogenic haplotype in the majority of non-penetrant subjects in FSHD families with compound heterozygosity. These data suggest that carriers of FSHD-sized alleles with 4A161PAS haplotype are more common in the general population than expected on the basis of FSHD prevalence. These findings challenge the notion that FSHD is a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS haplotype, with relevant repercussions for genetic counselling and prenatal diagnosis.

2012 - Multiple systematic reviews: methods for assessing discordances of results. [Articolo su rivista]
L., Moja; MP Fernandez Del, Rio; R., Banzi; C., Cusi; D'Amico, Roberto; A., Liberati; G., Lodi; E., Lucenteforte; S., Minozzi; V., Pecoraro; G., Virgili; E., Parmelli
abstract

BACKGROUND: The process of systematically reviewing research evidence is useful for collecting, assessing and summarizing results from multiple studies planned to answer the same clinical question. The term "systematic" implies that the process, besides being organized and complete, is transparent and fully reported to allow other independent researchers to replicate the results, and therefore come to the same conclusions. Hundreds of new systematic reviews are indexed every year. The growing number increases the likelihood of finding multiple and discordant results. OBJECTIVES: To clarify the impact of multiple and discordant systematic reviews, we designed a program aimed at finding out: (a) how often different systematic reviews are done on the same subject; (b) how often different systematic reviews on the same topic give different results or conclusions; (c) which methods or interpretation characteristics can explain the differences in results or conclusions. METHODS: This paper outlines the method used to explore the frequency and the causes of discordance among multiple systematic reviews on the same topic. These methods were then applied to a few medical fields as case studies. CONCLUSION: This aim is particularly relevant for both clinicians and policy makers. Judgments about evidence and recommendation in health care are complex, and often rely on discordant results, especially when there are no empirical results to help serve as a guideline.

2012 - Predictive role of capillaroscopic skin ulcer risk index in systematic sclerosis: a multicentre validation study [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Vukatana, G; Moscatelli, S; Riato, L; Bocci, M; Iudici, M; Principato, A; Mazzuca, S; Del Medico, P; De Angelis, R; D'Amico, Roberto; Vicini, Roberto; Colaci, Michele; Ferri, Clodoveo
abstract

Introduction The early detection of systemic sclerosis (SSc) patients at high risk of developing digital ulcers could allow preventive treatment, with a reduction of morbidity and social costs. In 2009, a quantitative score, the capillaroscopic skin ulcer risk index (CSURI), calculated according to the formula 'D×M/N(2'), was proposed, which was highly predictive of the appearance of scleroderma digital ulcers within 3 months of capillaroscopic evaluation.OBJECTIVES:This multicentre study aims to validate the predictive value and reproducibility of CSURI in a large population of SSc patients.METHODS:CSURI was analysed in 229 unselected SSc patients by nailfold videocapillaroscopy (NVC). All patients were re-evaluated 3 months later with regard to the persistence and/or appearance of new digital ulcers.RESULTS:57 of 229 patients presented with digital ulcers after 3 months. The receiver operating characteristic curve analysis showed an area under the curve of 0.884 (95% CI 0.835 to 0.922), with specificity and sensitivity of 81.4% (95% CI 74.8 to 86.89) and 92.98% (95% CI 83.0 to 98.0), respectively, at the cut-off value of 2.96. The reproducibility of CSURI was validated on a random sample of 81 patients, with a κ-statistic measure of interrater agreement of 0.8514.CONCLUSIONS:The role of CSURI was confirmed in detecting scleroderma patients with a significantly high risk of developing digital ulcers within the first 3 months from NVC evaluation. CSURI is the only method validated to predict the appearance of digital ulcers and its introduction into routine clinical practice might help optimise the therapeutic strategy of these harmful SSc complications.

2012 - Preoperative chemotherapy plus trastuzumab, lapatinib or both in HER2 positive operable breast cancer: results of the randomized phase II CHER-LOB study [Articolo su rivista]
Guarneri, Valentina; Frassoldati, A; Bottini, A; Cagossi, K; Bisagni, G; Sarti, S; Ravaioli, A; Cavanna, L; Giardina, G; Musolino, A; Untch, M; Orlando, L; Artioli, F; Boni, C; Generali, Dg; Serra, P; Bagnalasta, M; Marini, L; Piacentini, Federico; D'Amico, Roberto; Conte, Pierfranco
abstract

Purposes: This is a non-comparative randomized phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab plus lapatinib in HER2 positive, stage II-IIIA operable breast cancer patients. Primary aim was to estimate the percentage of pathological complete response (pCR; no invasive tumor in breast and axillary nodes).Methods: in the three arms, chemotherapy consisted of weekly paclitaxel (80 mg/sqm) x 12 followed by FE75C x 4 courses q 3 weeks. The patients randomized to arm A received trastuzumab 4 mg loading dose followed by 2 mg weekly; in arm B patients received lapatinib 1500 mg p.o. daily; in arm C, patients received trastuzumab and lapatinib 1000 mg p.o. daily.Results: 121 patients have been randomized. Diarrhea, dermatologic, and hepatic toxicities were observed more frequently in patients receiving lapatinib. No episodes of congestive heart failure were observed. The rates of breast conserving surgery were 66.7%, 57.9% and 68.9% in arm A, B and C, respectively. The pCR rates were 25% (90%CI 13.1 to 36.9) in arm A, 26.3% (90%CI 14.5 to 38.1) in arm B, 46.7% (90%CI 34.4 to 58.9) in arm C (exploratory p= 0.0187).Conclusions: The primary end point of the study was met, with a relative increase of 80% in the pCR rate achieved with chemotherapy plus trastuzumab and lapatinib compared to chemotherapy plus either trastuzumab or lapatinib. These data add further evidence supporting the superiority of a dual-HER2 inhibition for the treatment of HER2 positive breast cancer.

2012 - Pro-Calcitonin guided antibiotic treatment of acute exacerbations of Chrnic Obstructive Pulmonary Disease [Poster]
A., Veduri; D'Amico, Roberto; Ruggieri, Valentina; P., Vicini; A., Liverani; M., Plebani; A., Papi; Fabbri, Leonardo; Beghe', Bianca
abstract

non presente

2012 - Short and long term effects of tibolone in postmenopausal women [Articolo su rivista]
G., Formoso; E., Perrone; S., Maltoni; Balduzzi, Sara; D'Amico, Roberto; C., Bassi; V., Basevi; Am, Marata; N., Magrini; E., Maestri
abstract

BACKGROUND:Tibolone is an option available for the treatment of menopausal symptoms, based on short-term data on its efficacy. However, there is a need to consider the balance between the benefits and risks of tibolone as there are concerns about breast and endometrial cancer as well as stroke.OBJECTIVES:To evaluate the effectiveness and safety of tibolone in treating postmenopausal women.SEARCH METHODS:We searched the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register (19 April 2011), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, 2nd Quarter), MEDLINE (from inception to 19 April 2011), EMBASE (1980 to week 3 April 2011), PsycINFO (1806 to week 3 April 2011), Clinical Trials.gov (30 April 2011). Individual researchers and the current manufacturer of tibolone were contacted to identify unpublished and ongoing trials.SELECTION CRITERIA:Randomised controlled trials (RCTs) that compared tibolone versus placebo, estrogens or combined hormone replacement therapy (HT) by assessing the percentage of women with menopausal symptoms, the severity of those symptoms and the occurrence of safety outcomes in postmenopausal women.DATA COLLECTION AND ANALYSIS:Four review authors independently extracted information from the articles, resolving discrepancies by consensus. All outcomes studied were dichotomous. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using the random-effects model. Heterogeneity of studies was taken into account before deciding to combine the data.MAIN RESULTS:When compared to placebo, tibolone was more effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 847; OR 0.42, 95% CI 0.25 to 0.69), although only the 2.5 mg/day dose of tibolone was significantly better than placebo; but with increased vaginal bleeding (seven RCTs, n = 7462; OR 2.75, 95% CI 1.99 to 3.80). When compared to equipotent doses of combined HT, tibolone reduced vaginal bleeding (15 RCTs, n = 6342; OR 0.32, 95% CI 0.24 to 0.42) but was less effective in relieving the frequency of vasomotor symptoms (two RCTs, n = 545; OR 4.16, 95% CI 1.50 to 11.58).As for long term safety, two major RCTs of tibolone versus placebo provided the most relevant data. An RCT of 3098 women with breast cancer and menopausal symptoms was halted after 3.1 years because of increased tumour recurrence (OR 1.50; 95% CI 1.21 to 1.85). However, in another RCT that selected osteoporotic women with negative mammograms (n = 4506) tibolone was associated with a reduction in breast cancer compared to placebo after 2.8 years (OR 0.32, 95% CI 0.13 to 0.79) although the trial was not specifically designed to assess that outcome and the number of overall events was low. In the same RCT, an excess risk of stroke was observed (OR 2.18, 95% CI 1.12 to 4.21). There was no clear evidence of a tibolone effect on endometrial cancer compared with placebo given the low number of events (seven RCTs, n = 8152; OR 1.98, 95% CI 0.73 to 5.32).There was no evidence of a difference in long term safety between tibolone and combined HT.AUTHORS' CONCLUSIONS:Tibolone, used at the daily dose of 2.5 mg, may be less effective than combined HT in alleviating menopausal symptoms although it reduced the incidence of vaginal bleeding. There was evidence that treatment with combined HT was more effective in managing menopausal symptoms than was tibolone. Available data on the long term safety of tibolone is concerning given the increase in the risk of breast cancer in women who had already suffered from breast cancer in the past and in a separate trial the increase in the risk of stroke in women whose mean age was over 60 years. Similar concerns may exist for estroprogestins but their overall benefit-risk profile is better known and is more directly related to women with menopausal symptoms.

2012 - Trastuzumab containing regimens for early breast cancer. [Articolo su rivista]
L., Moja; L., Tagliabue; Balduzzi, Sara; E., Parmelli; V., Pistotti; Guarneri, Valentina; D'Amico, Roberto
abstract

Approximately one-fifth of women who develop early breast cancer have HER2-positive tumours, which if untreated, have a worse prognosis than HER2-negative tumours. Trastuzumab is a selective treatment targeting the HER2 pathway. Although the results on efficacy seem to support its use, there are potential cardiac toxicities which need to be considered, especially for women at lower risk of recurrence, or those at increased cardiovascular risk. OBJECTIVES: To assess the evidence on the efficacy and safety of therapy with trastuzumab, overall and in relation to its duration, concurrent or sequential administration with the standard chemotherapy regimen in patients with HER2-positive early breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's (CBCGs) Specialised Trials Register, and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, EMBASE, BIOSIS, TOXNET, and the WHO ICTRP search portal (up to February 2010). SELECTION CRITERIA: RCTs comparing the efficacy and safety of trastuzumab alone, or in combination with chemotherapy, or no treatment, or standard chemotherapy alone, in women with HER2-positive early breast cancer including women with locally advanced breast cancer. DATA COLLECTION AND ANALYSIS: We collected data from published and unpublished trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included duration (less or greater than six months) and concurrent or sequential trastuzumab administration. MAIN RESULTS: We included eight studies involving 11,991 patients. The combined HRs for overall survival (OS) and disease-free survival (DFS) significantly favoured the trastuzumab-containing regimens (HR 0.66; 95% confidence interval (CI) 0.57 to 0.77, P < 0.00001; and HR 0.60; 95% CI 0.50 to 0.71, P < 0.00001, respectively). Trastuzumab significantly increased the risk of congestive heart failure (CHF: RR 5.11; 90% CI 3.00 to 8.72, P < 0.00001); and left ventricular ejection fraction decline (LVEF: RR 1.83; 90% CI 1.36 to 2.47, P = 0.0008). For haematological toxicities, risks did not differ. The two small trials that administered trastuzumab for less than six months did not differ in efficacy from longer studies, but found fewer cardiac toxicities. Studies with concurrent administration gave similar efficacy and toxicity results to sequential studies. AUTHORS' CONCLUSIONS: Trastuzumab significantly improves OS and DFS in HER2-positive women with early and locally advanced breast cancer, although it also significantly increases the risk of CHF and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab concurrently or sequentially did not differ significantly in efficacy. Shorter duration of therapy may reduce cardiotoxicity and maintain efficacy, however there is insufficient evidence at present to conclude this due to small numbers of patients in these trials.

2011 - Analgesia and endocrine surgical stress: effect of two analgesia protocols on cortisol and prolactin levels during abdominal aortic aneurysm endovascular repair. [Articolo su rivista]
Barbieri, Alberto; Giuliani, Enrico; Genazzani, Alessandro; Baraldi, E; Ferrari, Anna; D'Amico, Roberto; Coppi, Gioachino
abstract

OBJECTIVES:Endovascular abdominal aortic aneurysm (AAA) repair was performed with local anaesthesia and intravenous analgesia. The objective of the study was to evaluate how two analgesia protocols affected stress response, measured as cortisol, 17-OH progesterone (17OHP) and prolactin (PRL) concentration during the procedure.METHODS:44 patients undergoing elective AAA endovascular repair were included to either receive regular boluses of fentanyl midazolam or remifentanil continuous infusion, analgesia was monitored by Visual Analogue Scale (VAS) measurement; cortisol, 17OHP and PRL were sampled preoperatively, at skin incision, endovascular prosthesis release and skin suture.RESULTS:42 patients were included. Mean VAS values were lower in the remifentanil group 0.50±0.68 vs 1.48±1.20, p=0.002 at incision, 0.24±0.58 vs 1.45±1.18, p<0.001 prosthesis release, 0.51±0.90 vs 1.73±1.45, p=0.002 suture. No statistically significant difference was found among cortisol and 17OHP levels; PRL was significantly lower in the fentanyl-midazolam group (23.83±16.92 ng/ml vs 40.81±22.45 p=0.009 at prosthesis release and 28.23±15.05 vs 41.37±14.54, p=0.007 at suture).CONCLUSIONS:Although statistically significant VAS difference had a limited clinical impact due to its small entity. The group that experienced less pain showed a more intense PRL response, while cortisol and 17OHP did not reach statistical significance.

2011 - Anti-Müllerian hormone-based prediction model for a live birth in assisted reproduction [Articolo su rivista]
LA MARCA, Antonio; S. M., Nelson; G., Sighinolfi; M., Manno; E., Baraldi; L., Roli; S., Xella; T., Marsella; D., Tagliasacchi; D'Amico, Roberto; Volpe, Annibale
abstract

Prediction of assisted reproduction treatment outcome has been the focus of clinical research for many years, with a variety of prognostic models describing the probability of an ongoing pregnancy or a live birth. This study assessed whether serum anti-Müllerian hormone (AMH) concentrations may be incorporated into a model to enhance the prediction of a live birth in women undergoing their first IVF cycle, by analysing a database containing clinical and laboratory information on IVF cycles carried out between 2005 and 2008 at the Mother-Infant Department of University Hospital, Modena. Logistic regression was used to examine the association of live birth with baseline patient characteristics. Only AMH and age were demonstrated in regression analysis to predict live birth, so a model solely based on these two criteria was generated. The model permitted the identification of live birth with a sensitivity of 79.2\% and a specificity of only 44.2\%. In the prediction of a live birth following IVF, a distinction, however moderate, can be made between couples with a good and a poor prognosis. The success of IVF was found to mainly depend on maternal age and serum AMH concentrations, one of the most relevant and valuable markers of ovarian reserve.

2011 - BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph(+) acute lymphoblastic leukemia during second-generation tyrosine-kinase inhibitor therapy. [Articolo su rivista]
Riva, Giovanni; Luppi, Mario; Quadrelli, Chiara; Barozzi, Patrizia; Basso, S; Vallerini, Daniela; Zanetti, E; Morselli, M; Forghieri, Fabio; Maccaferri, M; Paolini, Ambra; DEL GIOVANE, Cinzia; D'Amico, Roberto; Marasca, Roberto; Narni, Franco; Iacobucci, I; Martinelli, G; Baccarani, M; Comoli, P; Potenza, Leonardo
abstract

BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during second-generation tyrosine-kinase inhibitor therapy

2011 - CD4+ T-cell differentiation, regulatory T cells and gag-specific T lymphocytes are unaffected by CD4-guided treatment interruption and therapy resumption. [Articolo su rivista]
Nemes, Elisa; Lugli, Enrico; Bertoncelli, Linda; Nasi, Milena; Pinti, Marcello; Manzini, S; Prati, Francesca; Manzini, Lisa; DEL GIOVANE, Cinzia; D'Amico, Roberto; Cossarizza, Andrea; Mussini, Cristina
abstract

OBJECTIVES:Despite limiting exposure to antiretroviral drugs, structured treatment interruptions can influence multiple aspects of T-cell immunity, particularly those regarding CD4(+) T lymphocytes. We evaluated the impact of CD4-guided treatment interruption (CD4-GTI) and treatment resumption on regulatory T cells (Tregs), T-lymphocyte activation, differentiation and polyfunctional gag-specific response.METHODS:Patients were analyzed just prior to treatment interruption, at 2 and 6 months after treatment interruption, just prior to treatment resumption and at 2 and 6 months after treatment resumption. Thawed peripheral blood mononuclear cells were stained immediately for phenotype analysis or stimulated with HIV-gag peptides and analyzed by polychromatic flow cytometry.RESULTS:Treatment interruption resulted in a CD4(+) cell count decrease and plasma viral load (pVL) increase, but did not preclude a good immune reconstitution and a complete suppression of pVL after treatment resumption. Treatment interruption did not influence CD4(+) T-cell differentiation and Treg subsets. During treatment interruption, gag-specific CD4(+) T cells were not lost, although the frequency of HIV-specific CD8(+) cells increased. Most gag-specific CD4(+) T cells were potentially cytotoxic (CD107a(+)) and were not influenced by pVL or by HAART. Most helper (CD154(+)) gag-specific CD4(+) T lymphocytes did not produce interferon-γ or interleukin-2.CONCLUSION:CD4-GTI did not cause depletion of memory cells, Tregs or HIV-specific CD4(+) cells and, on the contrary, could induce HIV-specific responses. If guided by CD4(+) T-cell count, treatment interruption does not provoke irreversible immune damages.

2011 - Decreased mitochondrial DNA content in subcutaneous fat from HIV-infected women taking antiretroviral therapy as measured at delivery. [Articolo su rivista]
Nasi, Milena; Pinti, Marcello; Chiesa, E; Fiore, S; Manzini, S; DEL GIOVANE, Cinzia; D'Amico, Roberto; Palai, N; Campatelli, C; Sabbatini, F; Roccio, M; Tibaldi, C; Masuelli, G; Mussini, Cristina; Ferrazzi, E; d'Arminio Monforte, A; Cossarizza, Andrea
abstract

BACKGROUND: Increasing numbers of pregnant HIV-positive women are receiving combination antiretroviral regimens for preventing mother-to-child virus transmission or for treating the infection itself. Several studies have demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxicity by several mechanisms, including depletion of mitochondrial DNA (mtDNA). By the quantification of mtDNA levels, we studied mitochondrial toxicity in HIV-positive women at delivery and the possible correlations with antiretroviral regimens, viroimmunological and metabolic parameters.METHODS: We analysed 68 HIV-positive women enrolled in the Italian Prospective Cohort Study on Efficacy and Toxicity of Antiretroviral in Pregnancy (TARGET Study); all were taking ≥1 NRTI. We quantified mtDNA copies per cell in subcutaneous fat samples collected during delivery. At the 3rd, 6th and 9th month of pregnancy, we collected data concerning CD4(+) T-cell count, plasma HIV RNA, total and high-density lipoprotein (HDL) cholesterol, fasting plasma glucose and triglycerides. As a control, we analysed mtDNA levels in abdominal subcutaneous fat samples from 23 HIV-seronegative women at delivery.RESULTS: mtDNA content was significantly lower in HIV-infected women when compared with HIV-negative controls. mtDNA content varied independently from viroimmunological, lipid and glucose parameters at the different months, with the exceptions of triglycerides at the 9th month and of HDL at the 6th month of pregnancy.CONCLUSIONS: In subcutaneous tissue from women taking NRTI-based antiretroviral regimens, we observed a significant decrease of mtDNA content, compared with uninfected women not on antiviral treatment. Moreover, a significant correlation was noted between mtDNA content and HDL cholesterol and triglycerides.

2011 - Double-blind, placebo-controlled, multicentric randomized phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal HER2-negative, hormone receptor-positive operable breast cancer [Abstract in Rivista]
Conte, Pierfranco; Guarneri, Valentina; D. G., Generali; A., Bottini; L., Bazzola; Piacentini, Federico; F., Artioli; K., Cagossi; G., Bisagni; M., Bagnalasta; Tagliafico, Enrico; Barbieri, Elena; L., Cavanna; A., Ravaioli; D'Amico, Roberto; Vicini, Roberto; A., Frassoldati
abstract

Background: The crosstalk between the ER pathway and erbB receptor family is emerging as a mechanism of resistance to hormonal therapy. The combination of lapatinib-letrozole might prevent or delay the development of endocrine resistance. On these premises we have designed a multicentric phase IIb randomized, double-blind, placebo controlled study to evaluate the clinical and biological effects of combined letrozole+lapatinib/placebo as neoadjuvant therapy in previously untreated ER+ve/HER2-ve breast cancer patients. Primary aim is the percentage of breast clinical response, as measured by ultrasonography (US). Secondary aims include pathologic response, percentage of breast conserving surgery, modulation of Ki67 and HER2/EGFR pathways, and gene expression analysis. Methods: After diagnostic core biopsy, patients were randomized to letrozole 2.5 mg continuous daily dosing (CDD) + lapatinib 1500mg CDD or to letrozole- placebo, given for 24 weeks before surgery. Results: As of October 2010, the planned accrual has been completed. Ninety-two postmenopausal women have been randomized. Patient characteristics were as follows: median age 68 yrs (range 48-89 yrs); stage at diagnosis: IIA 49%; IIB 41%, IIIA 10%. Median ER expression 95% (range 30-100%); median PgR expression 68% (range 0-100%). At diagnosis, mean US tumor size was 3 cm (range 1.2-8 cm). Seventy-one patients are evaluable so far. The ORR (PR + CR) by US at the completion of therapy was 61%; SD was observed in 27% of the patients. Four patients experienced PD. Five patients prematurely discontinued therapy due to toxicity (n=1), consent withdrawal (n=3) or lost to follow up (n=1). No change in mean LVEF was observed at the 3- and 6-month evaluations. The data will be unblinded by April 2011. Conclusions: Preliminary blinded results suggest that the combination of letrozole+lapatinib/placebo is associated with clear tumor downstaging. Final unblinded results per treatment arm, including pathologic response, clinical response by centralized review and biomarker analyses will be presented at the meeting.

2011 - Final results of a phase II randomized trial of neoadjuvant anthracycline-taxane chemotherapy plus lapatinib, trastuzumab, or both in HER2-positive breast cancer (CHER-LOB trial). [Abstract in Rivista]
Guarneri, Valentina; A., Frassoldati; A., Bottini; D. G., Generali; K., Cagossi; F., Artioli; G., Bisagni; C., Boni; A., Ravaioli; D., Amadori; A., Musolino; L., Cavanna; M., Untch; L., Orlando; G., Giardina; Piacentini, Federico; Tagliafico, Enrico; M., Bagnalasta; D'Amico, Roberto; Conte, Pierfranco
abstract

Background: This is a randomized phase II trial of preoperative taxane-anthracycline in combination with trastuzumab, lapatinib, or combined trastuzumab and lapatinib in HER2 positive, stage II-IIIA breast cancer patients. Primary aim of the study is the percentage pathological complete response (pCR), defined as complete disappearance of invasive tumor in breast and axillary nodes. Methods: chemotherapy (CT) consists of weekly paclitaxel x 12 followed by FE75C x 4. Pts randomized to arm A receive CT plus weekly trastuzumab; in arm B pts receive CT plus lapatinib 1250 mg po daily; in arm C pts receive CT plus weekly trastuzumab and lapatinib 750 mg po daily. The study sample size has been calculated according to the two-step Simon’s design. The overall planned accrual was 120 pts. P95HER2 expression will be measured by bioTheranostics, Inc (San Diego) to explore if there is a clinically relevant difference in the pCR rate according to p-95 status. Gene expression profile analysis to identify a predictive signature is ongoing. Results: 121 pts have been randomized as of November 2010. Pts characteristics are the following: median age 49 yrs (26-68 yrs); stage IIA 32%, IIB 50%; IIIA 18%; ER and or PgR positivity: 59%. Eighty pts have completed surgery and are evaluable for response: 50 pts (62.5%) received breast conservation (BCS). A conversion from mastectomy to BCS was observed in 23/44 pts initially candidate to mastectomy (conversion rate: 52%). The pCR rate is 36.2% (28% in arm A, 32% in arm B, and 48% in arm C). By using a 30% cutoff for p95 positivity, in a preliminary analysis on 48 cases, 57% resulted as p-95 positive. In this preliminary analysis, the pCR rate in 15 trastuzumab treated pts is 86% in p-95-negative and 13% in p-95-positive cases. Mean Left ventricular ejection fraction (range) at baseline was 62% (52%-77%), 61% (44%-78%) after 12-13 weeks, and 61% (44%-74%) at the end of therapy. No patient had symptomatic cardiac events. Conclusions: Preliminary activity data are promising, and cardiac safety data are reassuring. Final results per treatment arm, along with definitive biomarker correlations will be presented at the meeting.

2011 - Identification and characterization of Aspergillus-specific immune responses to diagnose invasive aspergillosis in high risk patients: a multicenter study [Abstract in Rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Maertens, J; Candoni, A; Beauvais, A; Zanetti, Eleonora; Quadrelli, C; Morselli, M; Forghieri, Fabio; Maccaferri, M; Paolini, Ambra; Marasca, Roberto; DEL GIOVANE, Cinzia; D'Amico, Roberto; Ciceri, F; Comoli, P; Cesaro, S; Caira, M; Pagano, L; Romani, L; Narni, Franco; Latgè, Jp; Luppi, Mario
abstract

Background. The mortality of Invasive Aspergillosis (IA) still affects from 27% to 55% of high risk hematologic patients. The reasons of such a poor outcome also rely on several drawbacks limiting the di- agnostic accuracy of non cultural based diagnostic methods (NCBDM) and hampering the opportunities for an early intervention. Studies in mice model of IA and in healthy subjects have shown that Aspergillus-specific T-cells producing interferon-gamma (IFN- gamma-T1) are protective, while Aspergillus-specific T-cells pro- ducing interleukin-10 (IL-10-T2) are non-protective to IA. Aims. We have investigated whether the identification of Aspergillus-specific IFN-gamma-T1 and/or IL-10-T2 through an ex-vivo enzyme linked immunospot (ELISPOT) assay may be effective in the diagnosis of IA in high risk patients. Furthermore, in the proven IA patients, we have functionally and phenotipically characterized such T cells through the cytokine secretion assay (CSA). Methods. 180 patients (168 hemato- logic and 12 solid organ transplant patients) have been enrolled. They were classified, according the revised EORTC/MSG criteria, as fol- lows: 18 proven, 35 probable, 17 possible IA cases and 110 controls. The control patients were divided in two groups: group 1 included 86 (78.2%) patients with hystological and/or cultural verified infec- tious/inflammatory/neoplastic diseases, but other than IA; group 2 in- cluded 24 (21.8%) patients without clinical and/or microbiological features of IA. ELISPOT has been performed, as described [Potenza et al. Leukemia 2007; 21: 578-81], by using as antigens Aspergillus either conidia or recombinant antigens, namely CRF1p, GEL1p, PEP1p, SOD1p, α1-3 glucan, β1-3 glucan and galactomannan (GM). Results. The patient and sample positivity rates were 94.4%/89.5% in proven, 45.7%/35.3% in probable, 35.3%/50% in possible IA cases and 1.8%/4.5% in the controls, respectively. The sensitivity and speci- ficity of ELISPOT for the diagnosis of IA resulted 94.4% (95% CI, 73%-99%) and 98.2% (95% CI, 93%-99%), respectively. The PPV of the test was 89.5% (95% CI, 67%-99%), the NPV was 99.1% (95% CI, 94%-100%) and the efficiency was 97.6% (95% CI, 92.3%- 99.4%). The positive likelihood ratio (LR) resulted 51.89, the negative LR was 0.06 (Table 1A,B). In proven IA patients, CSA demonstrated that Aspergillus-specific IL-10-T2 were predominantly central memory (CM) CD4+ T cells (median frequency 0.37%/0.22%), while Aspergillus-specific IFN-gamma-T1 were either CD4+ or CD8+ cells of either effector memory (EM) or CM phenotype (median frequen- cies 0.24%/0.20%). Also lower frequencies of Aspergillus-specific ei- ther CD4+ or CD8+ T cells producing IL-4 (0.11%/0.19%) of EM phenotype, and EM CD8+ cells producing IL-17 (0.18%), were de- tected. Moreover, although CRF1p, GEL1p, α1-3 glucan and SOD1p resulted the antigens eliciting the highest number of Aspergillus-spe- cific IFN-gamma-T1, only GEL1p and α1-3 glucan were those most constantly targeted by protective immune responses along the entire course of the IA. Conclusions. Our findings demonstrate the potential of ELISPOT in the diagnosis of IA, suggesting that it may comple- ment the other NCBDM, enabling a more consistent diagnosis of IA. Furthermore, this study describes for the first time the Aspergillus- specific immune responses in patients with proven IA, identifying also the antigens predominantly targeted by protective IFN-gamma- T1, with possible consequences in designing strategies of either adoptive cell infusion or vaccine therapies.

2011 - Intrapartum translabial three-dimensional ultrasound visualization of levator trauma. [Articolo su rivista]
Blasi, I; Fuchs, I; D'Amico, Roberto; Vinci, V; LA SALA, Giovanni Battista; Mazza, V; Henrich, W.
abstract

OBJECTIVES: The aim of this study was to visualize levator trauma by three-dimensional (3D) ultrasound performed during labor and soon after the crowning of the fetal head and to determine how often levator trauma occurs. METHODS: This was a prospective, observational study of 66 women enrolled during the first stage of labor. The women underwent intrapartum 3D transperineal ultrasound examination during the first and second stages of labor and within 12 h after delivery. Volume datasets were acquired and analyzed to determine the presence of levator trauma. RESULTS: Data from 10 of the 66 women were excluded from analysis-nine because they underwent Cesarean section in the first or second stage of labor and one because she underwent hysterectomy and no postpartum volumes were collected. Thus our study group comprised 56 women-35 nulliparous and 21 parous. A total of 504 volumes were collected in the 56 women (three volumes for each stage of labor). One hundred and twenty levator volumes were excluded from analysis, but volumes of acceptable quality were available for all three stages of labor in all women. Eleven (31.4%) of the 35 nulliparae had levator lesions detected postpartum and none of them had levator lesions before delivery. Five (23.8%) of the 21 parous women had a levator tear detected in their postpartum volumes. In two of these five women the levator tear was also present in both volumes taken during labor. CONCLUSIONS: Visualization of the levator ani during labor by 3D ultrasound examination is feasible. Comparison of volumes obtained during labor and within the first 2 h after delivery supports the theory that crowning of the head is the immediate cause of avulsion of the levator ani muscle.

2011 - Magnetic Resonance Imaging and Ultrasonography in Predicting Infiltrating Residual Disease after Preoperative Chemotherapy in Stage II-III Breast Cancer [Articolo su rivista]
Guarneri, Valentina; Pecchi, A; Piacentini, Federico; Barbieri, Elena; Dieci, Mv; Ficarra, G; Tazzioli, Giovanni; Frassoldati, A; Battista, R; Canossi, Barbara; Mauri, C; D'Amico, Roberto; Conte, Pierfranco; Torricelli, Pietro
abstract

BACKGROUND: This study was designed to evaluate the accuracy of breast magnetic resonance imaging (MRI) and ultrasonography (US) in predicting the extent of breast residual disease after preoperative chemotherapy. METHODS: Patients withstage II-III invasive breast tumors who received preoperative chemotherapy and were imaged with post-treatment MRI were included. Histopathological verification was available for all patients. The longest diameter of residual tumor measuredwith MRI and US has been compared with the infiltrating residual tumor size at pathologic evaluation. RESULTS: A total of 108 patients were enrolled: 59 were imaged with both MRI and US (MRI group), and 49 were imaged with US only (non-MRI group). The non-MRI group was enrolled as an external control to avoid possible bias in the selection of patients. In the MRI group, the means of the deltas between MRI residual tumor size and pathologic size and between US and pathologic size were 0.16 cm and -0.06 cm respectively (P = not significant). Overall, a discrepancy limited in the interval from -0.5 cm to +0.5 cm compared with the pathologic size was observed in 54% and 51% of the patients with MRI and US, respectively (P = not significant). The linear correlation between the radiological measurement and pathologic tumor size was r = 0.53 for MRI and r = 0.66 for breast US. In the non-MRI group, the mean of the deltas between US residual tumor size and pathologic size was 0.06 cm, and the linear correlation was r = 0.79. CONCLUSIONS: In this series of patients, MRI and US do not show significant differences in predicting the breast residual infiltrating tumor after preoperative chemotherapy.

2011 - Mucorles-specific T cells emerge in the course of invasive mucormucosis and may be used as a surrogate diagnostic marker in high-risk patients [Articolo su rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Forghieri, Fabio; Zanetti, Eleonora; Quadrelli, Chiara; Candoni, A; Maertens, J; Rossi, Giulio; Morselli, M; Codeluppi, M; Paolini, Ambra; Maccaferri, Monica; DEL GIOVANE, Cinzia; D'Amico, Roberto; Rumpianesi, F; Pecorari, M; Cavalleri, F; Marasca, Roberto; Narni, Franco; Luppi, Mario
abstract

Mucorales-specific T cells have been investigated in 28 hematologic patients during the course of their treatment. Three developed proven invasive mucormycosis (IM), 17 infections of known etiologies but other than IM, and 8 never showed fever upon the period of observation. The Mucorales-specific T cells may be detected only in patients with IM, at diagnosis and along the entire course of the IM, but neither before nor long time after the resolution of the infection. Such T cells produced predominantly interleukin-4, interferon-gamma (IFN-γ), interleukin-10, and to a lesser extent also interleukin-17, and belonged to either CD4+ or CD8+ subsets. The specific T cells producing IFN-γ were able to directly induce damage of Mucorales hyphae. None of the 25 patients without IM showed Mucorales-specific T cells. Specific T cells contribute to human immune responses against fungi of the order Mucorales and could be evaluated as a surrogate diagnostic marker of IM.

2011 - Prevention of Digital Ulcers in Systemic Sclerosis Patients: A Proposal of Risk Chart. [Abstract in Rivista]
Manfredi, Andreina Teresa; Sebastiani, Marco; D'Amico, Roberto; Carraro, V.; Bocci, M.; Moscatelli, S.; Iudici, M.; Colaci, Michele; Giuggioli, D.; Ferri, Clodoveo
abstract

Background/Purpose: Systemic sclerosis (SSc) is a connective tissue disease mainly characterized by fibrosis of skin and internal organs and by diffuse microangiopathy, responsible for digital ulcers (DU) in about 50% of patients. Management of DU is very challenging; it includes combined systemic and local treatments. Risk factors for the appearance of scleroderma DU are not defined and data from literature are discordant.Recently, our group proposed a capillaroscopic index (CSURI: Capillaroscopic Skin Ulcer Risk Index), able to identify patients with high risk to develop DU within 3 months from capillaroscopic evaluation, with a positive and negative predictive value of 62.3% and 97.2%, respectively.Aim of the study was to develop a predictive model, including CSURI, demographic, and clinico-serological parameters, in order to estimate the total risk of developing DU over next six months.Methods: One hundred and seventy-two unselected SSc patients (male/female 19/153, limited/diffuse cutaneous SSc 121/51, mean age 53.4 years ± 13.8 SD, mean SSc duration 108.2 months ± 97.8 SD) from 5 Italian Rheumatology Centers were consecutively enrolled. Capillaroscopic parameters were defined and collected according to our previous study. All patients underwent videocapillaroscopy at baseline; 3 and 6 months later patients were investigated for the development of DU.The main demographic, clinical, and serologic features were evaluated for the possible association with the occurrence of DU. Possible correlations among the variables and DU were investigated by multivariate logistic regression.Results: The development of DU was significantly associated with CSURI (Odds Ratio [OR] - 66.8, confidence interval [CI] 17.9 to 248.7; p <0.001), history of previous DU within the last year (OR 5.1, CI 1.7 to 14.9; p= 0.003), and male gender (OR 6.2, CI 1.1 to 34.5; p= 0.039). The proposed risk chart based on these three parameters is reported in the figure (the percentages are referred to the cumulative risk for DU). Conclusion: Among different SSc parameters CSURI, recent history of DU, and male gender showed to be strictly associated with the appearance of DU within the next six months from baseline. Our composite predictive model, which must be opportunely validated, represents an attempt to classify patients with different risk levels to develop DU; a correct patient's classification may optimize the needed pre-emptive and therapeutical strategies.

2011 - Risk for cardiovascular events in an Italian population of patients with type 2 diabetes [Articolo su rivista]
E., Pellegrini; M., Maurantonio; I. M., Giannico; M. S., Simonini; Ganazzi, Dorval; Carulli, Lucia; D'Amico, Roberto; A., Baldini; Loria, Paola; Bertolotti, Marco; Carulli, Nicola
abstract

BACKGROUND AND AIM:This study aims to analyse the risk of cardiovascular events in a local cohort of patients with type 2 diabetes, and to evaluate the prognostic accuracy of four algorithms used to estimate cardiovascular risk: the Framingham study, United Kingdom Prospective Diabetes Study (UKPDS), Riskard study and Progetto Cuore.METHOD AND RESULTS:We analysed clinical charts of the Diabetes Clinics of Modena for the period 1991-95. Patients in the age range of 35-65 with type 2 diabetes and no previous cardiovascular disease were eligible. The incidence of new cardiovascular disease was compared with estimated rates deriving from the different functions. A stratification was obtained in subgroups at different cardiovascular risk, allowing comparison between the algorithms. A total of 1532 patients were eligible; women presented a worse cardiovascular risk profile. An absolute 10-year rate of cardiovascular events of 14.9% was observed. Comparing patients with events with event-free subjects, we found significant differences in systolic blood pressure, age at visit, smoking, high-density lipoprotein (HDL)-cholesterol, duration of diabetes, glycosylated haemoglobin (HbA1c) and co-morbidities. Comparing the estimated risk rate according to the different functions, Italian algorithms were more consistent with observed data; however, Progetto Cuore and Riskard show underestimation of events when applied to females.CONCLUSIONS:Estimation of cardiovascular risk is dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population, including risk variables peculiar for diabetes, should be adopted to increase the performance of such functions which is clearly unsatisfactory at present.

2011 - Role Of The QFT-IT Assay For The Diagnosis Of Latent Tuberculosis Infection Among Adult Immigrants [Abstract in Rivista]
Losi, Monica; Dal Monte, Paola; Cagarelli, Roberto; Meacci, Marisa; DEL GIOVANE, Cinzia; Luppi, Fabrizio; Lombardi, Giulia; Spagnolo, Paolo; D'Amico, Roberto; Roversi, Pietro; Cerri, Stefania; Rumpianesi, Fabio; Fabbri, Leonardo; Richeldi, Luca
abstract

Background. Accurate identification and treatment of contacts with latent tuberculosis infection (LTBI) is a desirable goal to achieve effective tuberculosis (TB) control in areas with low prevalence of disease. In immigrants from high prevalence countries, especially in those who are close contacts of active TB cases, the low specificity of the tuberculin skin test (TST) represents an obstacle to the identification of truly infected BCG-vaccinated individuals. The Interferon-Gamma (IFN-g) Release Assays (IGRAs), based on M. tuberculosis -specific antigens, might improve LTBI diagnosis in this population. Methods. In a retrospective study, we assess the performance of the QuantiFERON-TB Gold In-Tube (QFT-IT, Cellestis Ltd., Victoria, Australia) assay and the TST in 84 adult immigrants from high prevalence countries: 68 (80.9%) of those individuals were close contacts of active TB cases. Results. In 84 immigrants (mean age 37.7 ± 11.6 years, 46.3 % were males, 46.3% were BCG-vaccinated) TST was positive in 68 (80.9%) individuals: among these TST-positive individuals, 26 (38.2%) were negative with QFT-IT. QFT-IT assay tested positive in 44 (52.4%) subjects (TST vs QFT-IT: 80.9% vs 52.4%, p< 0.001). Two (2.4%) subjects tested QFT-IT-indeterminate and was TST-positive. Diagnostic overall agreement between TST and QFT-IT was 63.4% (k=0.23). Conclusions. These preliminary data suggest that the rate of LTBI among adult immigrants from TB endemic countries, in our study most of them also close contacts of active TB cases, is significantly lower when detected by QFT-IT, than by TST. Moreover, our findings suggest that using an IGRA test for LTBI screening in this high risk population might reduce the number of candidates to preventive treatment and can provide potential substantial benefits for TB control.

2011 - The diagnostic reliability of urinary cytology: A retrospective study. [Articolo su rivista]
O., Raisi; C., Magnani; N., Bigiani; E., Cianciavicchia; D'Amico, Roberto; U., Muscatello; C., Ghirardini
abstract

The aim of this study was twofold. The first aim was to estimate the diagnostic reliability of urinary cytology for detection and management of urothelial neoplasms by using a specific preserving fluid for sample collection, and the liquid-based thin layer method for specimen preparation, the estimate was based on the correlation between the cytological findings of 10,000 non-hospitalized patients, and their histological diagnoses. A second aim was to compare the reliability of two instruments for thin-layer preparation, i.e., TP2000, TP3000, capable of processing the specimens at very different rates. The preservation of cell structure is ameliorated by the procedure of sample collection and treatment here described. This allows a more accurate reading of LBC slides as shown by: (a) the significant concordance between cytological and histological diagnosis (92%); (b) the significant number of low-grade urothelial carcinomas (20.5%) revealed by urinary cytology and validated by histologic diagnosis; (c) the low rate (8%) of misjudgement of cytological diagnosis reached in this study. The quality of performances of the two instruments tested for thin-layer preparation, i.e., TP2000 and TP3000, is statistically comparable. We recommend the procedure that makes use of preserving fluid for sample collection (cytolyt™) and treatment (preservcyt ™) as here described. We also recommend the use of thin-layer method for specimen preparation since it allows a more uniform distribution of the cells on the support with reduction of overlapping phenomena. Finally, economic considerations suggest the preferential use of Thin Prep 3000. Diagn. Cytopathol. 2011;. © 2011 Wiley-Liss, Inc.

2011 - Transesophageal echocardiographic scoring for transcatheter aortic valve implantation: impact of aortic cusp calcification on postoperative aortic regurgitation. [Articolo su rivista]
A., Colli; D'Amico, Roberto; J., Kempfert; Ma, Borger; Fw, Mohr; T., Walther
abstract

OBJECTIVE: Transcatheter aortic valve implantation is an emerging technique for the treatment of aortic valve stenosis in high-risk patients. Detailed knowledge of aortic root anatomy, including specific information on the extent of native cusp calcifications, is required. The aim of this study was to evaluate whether echocardiographic assessment of aortic stenosis using a calcification score is useful to predict outcomes of transcatheter aortic valve implantation in elderly high-risk patients.METHODS: Detailed preoperative digitalized transesophageal echocardiographic images were available from 103 patients treated by transapical transcatheter aortic valve implantation between February 2006 and February 2009. On the basisof a previously published study, an index score was developed to describe the extent of valve calcification ranging from 0 to 8 (normal to diffuse calcification).RESULTS: The median age of patients was 82.2 ± 5.9 years. The mean logistic European System for Cardiac Operative Risk Evaluation was 33.0% ± 16.3%. Mild paravalvular leak was present in 43 patients (42.2%), and a moderate paravalvularleak was observed in 5 patients (4.9%). Severe regurgitation was not observed in any patient. Logistic regression analysis revealed that the transcatheter aortic valve implantation echocardiographic calcification score is associated with thepresence of moderate paravalvular aortic regurgitation (odds ratio, 8.5; 95% confidence interval, 1.2-58.9; P = .0001) and overall moderate aortic regurgitation (odds ratio, 3.6; 95% confidence interval, 1.2-10.4; P = .0006).CONCLUSIONS: Transesophageal echocardiography demonstrates detailed anatomic information of the calcification patterns of the aortic valve and root and thus plays an important role in the screening of patients undergoing transcatheteraortic valve implantation. The transcatheter aortic valve implantation echocardiographic calcification score allowed prediction of the risk of postoperative paravalvular and overall aortic regurgitation.

2010 - 9 Weeks vs 1 Year Adjuvant Trastuzumab in Combination with Chemotherapy: Preliminary Cardiac Safety Data of the Phase III Multicentric Italian Study Short-HER. [Abstract in Rivista]
Guarneri, Valentina; Frassoldati, A; Gebbia, V; Bisagni, G; Cavanna, L; Donadio, M; Lelli, G; Musolino, A; Colucci, G; Banna, Gl; Degli Esposti, R; Ferro, A; Grasso, F; Zamagni, C; Amadori, D; Aieta, M; Molino, A; Garrone, O; Aitini, E; Fornari, G; Cascinu, Stefano; Rossi, G; D'Amico, Roberto; Conte, Pierfranco
abstract

Introduction: Several large randomized trials have shown the superiority of combining trastuzumab with chemotherapy versus chemotherapy alone as adjuvant treatment for HER2+ breast cancer patients. We are running a large phase III trial comparing two different trastuzumab durations (Short-HER study). We are reporting the preliminary cardiac safety data. Methods: The Short-HER study is a phase III, multicentric, Italian trial where 2500 HER2+ breast cancer patients will be randomized to: Arm A (Long) 4 courses of anthracycline based chemotherapy (AC or EC) followed by 4 courses of docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel in combination with weekly trastuzumab followed by FEC x3. this is a non-inferiority trial with DFS and OS as primary end points, and 2-yr failure rate and incidence of cardiac events as secondary end points. Left ventricular ejection fraction (LVEF) is measured at baseline, at the end of each sequence of chemotherapy in both arms, and after 9 and 12 months since randomization thereafter. A cardiac event (CE) was defined as the occurrence of any of the followings: 1) LVEF decrease of more than 15 percentage points from baseline ; 2) LVEF decrease of more than 10 percentage points with absolute value below 50%; 3) symptomatic cardiac failure; 4) other cardiac side effects of grade 2 or more. Results: 510 patients from 69 Italian centers have been randomized so far, 251 in arm A (long) and 259 in Arm B (Short). 146 patients enrolled in arm A and 150 patients enrolled in arm B have received at least 3 months of therapy, and are eligible for the present analysis. In arm A (long), 20 patients (13.7%) experienced a CE: 12 patients experienced a LVEF decline of > 15 percentage points (5 patients with LVEF below 50%, one patient with concomitant atrial fibrillation); 3 patients had a LVEF decline of >10 percentage points with an absolute value below 50%. One patient had symptomatic cardiac failure. Two patients developed Grade 2 hypertension. Two patients developed Grade 2 arrhythmia. In arm B (short), 11 patients (7.3%) experienced a CE: 7 patients had a LVEF decline of > 15 percentage points; one patient had a LVEF decline of > 10 percentage points with an absolute value below 50%. Three patients developed Grade 2 arrhythmia Conclusions: This is a non-inferiority study designed on the assumption that a shorter treatment duration is associated with a significantly lower incidence of cardiac events. With 9 clinically relevant CEs (symptomatic cardiac failure or LVEF below 50%) in arm A (Long) and 1 in arm B (Short), these preliminary data support the assumption, and recruitment is ongoing. Supported by Agenzia Italiana del FArmaco (AIFA).

2010 - A standardized clinical evaluation of patients affected by facioscapulohumeral muscular dystrophy: The FSHD clinical score [Articolo su rivista]
Costanza, Lamperti; Greta, Fabbri; Liliana, Vercelli; D'Amico, Roberto; Roberto, Frusciante; Bonifazi, Emanuela; Chiara, Fiorillo; Carlo, Borsato; Michelangelo, Cao; Maura, Servida; Greco, Francesca; Rita Di, Leo; Leda, Volpi; Claudia, Manzoli; Paola, Cudia; Ebe, Pastorello; Leopoldo, Ricciardi; Gabriele, Siciliano; Giuliana, Galluzzi; Carmelo, Rodolico; Lucio, Santoro; Giuliano, Tomelleri; Corrado, Angelini; Enzo, Ricci; Laura, Palmucci; Maurizio, Moggio; Tupler, Rossella
abstract

To define numerically the clinical severity of facioscapulohumeral muscular dystrophy (FSHD), we developed a protocol that quantifies muscle weakness by combining the functional evaluation of six muscle groups affected in this disease. To validate reproducibility of the protocol, 69 patients were recruited. Each patient was evaluated by at least five neurologists, and an FSHD severity score was given by each examiner. The degree of agreement among clinicians' evaluations was measured by kappa-statistics. Nineteen subjects received a score between 0 and 1, 9 had a score between 2 and 4, 20 received a score between 5 and 10, and 8 had a score between 11 and 15. Of the 13 subjects with D4Z4 alleles within the normal range (ranging from 10 to 150 repeats), 12 obtained a score of 0 and only 1 had a score of 1. Kappa-statistics showed a very high concordance for all muscle groups. We developed a simple, reliable, easily used tool to define the clinical expression of FSHD. Longitudinal studies will assess its sensitivity and utility in measuring changes for widespread use.

2010 - Commentary: The debate on non-inferiority trials: ' when meta-analysis alone is not helpful' [Articolo su rivista]
Liberati, Alessandro; D'Amico, Roberto
abstract

no abstract available

2010 - Common vascular endothelial growth factor variants and risk for posttransplant Kaposi sarcoma. [Articolo su rivista]
Zanetti, E; Barozzi, Patrizia; Brown, Ee; Bosco, R; Vallerini, Daniela; Riva, Giovanni; Quadrelli, Chiara; Potenza, Leonardo; Forghieri, Fabio; Montagnani, G; D'Amico, Roberto; Del Giovane, Cinzia; Duraes, C; Whitby, D; Machado, Jc; Schulz, Tf; Torelli, G; Luppi, Mario
abstract

No abstract available

2010 - Emergence of BCR-ABL-specific cytotoxic T cells in the bone marrow of patients with Ph+ acute lymphoblastic leukemia during long-term Imatinib mesylate treatment. [Articolo su rivista]
Riva, Giovanni; Luppi, Mario; Barozzi, Patrizia; Quadrelli, Chiara; Basso, S; Vallerini, Daniela; Zanetti, Eleonora; Morselli, M; Forghieri, Fabio; Maccaferri, M; Volzone, F; DEL GIOVANE, Cinzia; D'Amico, Roberto; Locatelli, F; Torelli, Giuseppe; Comoli, P; Potenza, Leonardo
abstract

Imatinib mesylate (IM) has been demonstrated to be permissive for the emergence of T cells directed against chronic myeloid leukemia cells. Ten Philadelphia chromosome-positive acute lymphoblastic leukemia patients, receiving high dose IM maintenance, underwent a long-term immunological monitoring (range 2-65 months) of (p190)BCR-ABL-specific T cells in the bone marrow (BM) and peripheral blood (PB). (p190)BCR-ABL-specific T lymphocytes were detected in all patients, more frequently in BM than in PB samples (67% vs 25%, p<0.01), and resulted significantly associated with lower minimal residual disease values (p<0.001), while absent at leukemia relapse. Specific T cells were mainly effector memory CD8+ and CD4+ T cells, producing IFNgamma, TNFalpha and IL-2 (median % positive cells: 3.34, 3.04, 3.58, respectively). Cytotoxic subsets able to lyse BCR-ABL-positive leukemia blasts were also detectable. Whether these autologous (p190)BCR-ABL-specific T cells may be detectable under other tyrosine-kinase inhibitors, expanded ex vivo and exploited for immunotherapy remains to be addressed.

2010 - Erratum: Does needle calibre affect pain and complication rates in patients undergoing transperineal prostate biopsy? A prospective, randomized trial by Giovanni Saredi et al. (Asian Journal of Andrology (2009) 11 (678-682) DOI: 10.1038/aja.2009.43) [Articolo su rivista]
Saredi, Giovanni; Sighinolfi, Maria Chiara; Fidanza, Francesco Antonio; DE STEFANI, Stefano; Micali, Salvatore; Maurizio, Paterlini; D'Amico, Roberto; Bianchi, Giampaolo
abstract

[No abstract available]

2010 - Is early antithrombotic therapy necessary after tissue mitral valve replacement? [Articolo su rivista]
A., Colli; D'Amico, Roberto; Ca, Mestres; Jl, Pomar; Ml, Camara; X., Ruyra; J., Mulet
abstract

BACKGROUND AND AIM OF THE STUDY:Patients with prosthetic heart valves have a higher risk of developing valve thrombosis and arterial thromboembolism. Antithrombotic therapy during the early postoperative period after biologic mitral valve replacement (MVR) is controversial. Hence, a retrospective study was conducted to investigate the efficacy of different antithrombotic therapies in patients after MVR with bioprostheses.METHODS:Between January 2000 and January 2006, a total of 99 patients presenting with preoperative sinus rhythm underwent isolated bioprosthetic MVR. Of these patients, 59 (58%) received a bovine pericardial xenograft, and 40 (42%) a porcine bioprosthesis. The postoperative antithrombotic therapy was prescribed according to the surgeon's preference.RESULTS:Fifty-one (51%) patients received acetylsalicylic acid (ASA group, 100 mg/day), 12 (13%) did not receive any specific antithrombotic therapy (NT group), and 36 (36%) received a vitamin K antagonist (VKA group, INR 2-3). The primary endpoints were the rate of cerebral ischemic events, bleeding events, and survival. The mean follow up was 23 months (range: 3-68 months). There were five early deaths (5%), and eight late deaths (8%). There were five episodes of cerebral ischemic events; these included three patients (8.3%) in the VKA group, one patient (2.0%) in ASA group, and one patient (8.3%) in the NT group (p = 0.351). Of these episodes, two occurred between 24 h and three months after surgery. Only one (2.8%) episode of major bleeding occurred (in the VKA group), due to poor anticoagulation management.CONCLUSION:Each of the antithrombotic therapies evaluated appeared to be safe. There was no evidence to suggest that any specific antithrombotic therapy would be superior in preventing valve thrombosis in patients undergoing bioprosthetic MVR.

2010 - Non-steroid agents for idiopathic pulmonary fibrosis [Articolo su rivista]
Spagnolo, Paolo; Del Giovane, C.; Luppi, F.; Cerri, Stefania; Balduzzi, Sara; Walters, Eh; D'Amico, Roberto; Richeldi, Luca
abstract

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive lung disease with poor outcome and no effective treatment to date. This is an update of a Cochrane Review first published in 2003.OBJECTIVES: To assess the efficacy of non-steroid agents in adults with idiopathic pulmonary fibrosis.SEARCH STRATEGY: We searched the Cochrane Airways Group Register (30 March 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2010), Ovid MEDLINE to March week 5, 2010, EMBASE to week 13, 2010 and PubMed to April 2010, with additional handsearching, including abstracts of international conferences. We also contacted pharmaceutical companies and researchers in the field.SELECTION CRITERIA: Randomised studies comparing non-steroid drugs with placebo or steroids in adults with idiopathic pulmonary fibrosis.DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality, extracted data and assessed risk of bias. We contacted pharmaceutical companies to obtain missing information, if any. We combined survival outcomes using Peto odds ratios or hazard ratios (HR).MAIN RESULTS: Fifteen trials involving 10 different drugs were included. Two trials enrolling 1156 patients compared interferon gamma-1beta with placebo: interferon gamma-1beta did not significantly improve survival (HR 0.88, 95% CI 0.47 to 1.64; P = 0.68). Four trials involving 1155 patients compared pirfenidone with placebo. Three trials, conducted in 1046 patients, provided data on progression-free survival: pirfenidone significantly reduced the risk of disease progression by 30% (HR 0.70, 95% CI 0.56 to 0.88, P = 0.002). Data on the effect of pirfenidone on pulmonary function could only be assessed for two studies analysing 314 patients. Forced vital capacity or vital capacity was significantly improved by pirfenidone (mean difference 0.08 L, 95% CI 0.03 to 0.13, P = 0.0006).AUTHORS' CONCLUSIONS: Based on available data, partly still unpublished, pirfenidone appears to improve progression-free survival and, to a lesser extent, pulmonary function in patients with idiopathic pulmonary fibrosis. More data are needed on overall survival and quality of life on treatment. From the studies in this review, interferon gamma-1beta has not been shown to affect survival. Other agents evaluated in single studies either failed to provide evidence for a benefit or need to be assessed in larger randomised controlled trials.

2010 - PREVALENCE OF NODE NEGATIVE AND SMALL SIZE TUMORS IN A NATIONAL, RANDOMISED, PHASE III ADJUVANT TRIAL IN HER2 + EARLY BREAST CANCER (SHORT-HER STUDY) [Abstract in Atti di Convegno]
Conte, Pf.; Agostara, B.; Aieta, M.; Banna, G.; Barbieri, E.; Belfiglio, M.; Boni, C.; Boni, L.; Brandes, A.; Cascinu, S.; Cavanna, L.; Colucci, G.; D’Amico, R.; Donadio, M.; Fornari, G.; Frassoldati, A.; Galligioni, E.; Garrone, O.; Gebbia, V.; Grasso, F.; Grisolia, Immacolata Deborah; Guarneri, V.; Lelli, G.; Molino, A.; Musolino, A.; Nanni, Oriana; Piacentini, F.; Pronzato, P.; Vicini, R.; Zamagni, C.
abstract

Introduction: Several large randomized trials have shown the superiority of combining trastuzumab with chemotherapy versus chemotherapy alone as adjuvant treatment for HER2+ breast cancer patients. Unfortunately, only a minority of the patients enrolled in these trials were node negative, and virtually none had pT1a,bN0 disease, even though recent data have demonstrated a worse outcome for these small HER2+ tumors versus HER2- cases. It is therefore of interest to know the prevalence of N0 disease and of pT1a,b in patients with HER2+ early breast cancer. We are running a large phase III trial comparing two different trastuzumab durations (Short-HER study). We are reporting the characteristics of patients randomized as of April 2010. Methods: The Short-HER study is phase III, multicentric, Italian trial where 2500 HER2+ breast cancer patients will be randomized to: Arm A (Long) 4 courses of anthracycline based chemotherapy (AC or EC) followed by 4 courses of docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel in combination with weekly trastuzumab followed by FEC x3. Results: 470 patients from 66 Italian centers have been randomized, 229 in arm A (long) and 241 in Arm B (Short). Mean age is 54 years (29 to 76); 68% of the cases have ER+ disease. Regarding stage distribution, among 400 evaluable patients, 34.7% have stage I, 37.3% have stage IIA, 10.5% have stage IIB, and 17.5% have stage III disease. In particular, 51% of the patients have node negative disease, and 6.7% have stage pT1a,bN0 disease. Conclusions: In the largest Italian series of HER2+ patients enrolled in a phase III trial, more than 50% have node negative disease, and around 7% have pT1a,bN0 disease. Given the prevalence of low stage disease, these data reinforce the importance of exploring less intensive, and possibly less toxic, adjuvant trastuzumab regimens. Supported by Agenzia Italiana del FArmaco (AIFA).

2010 - Pain and emotional distress in leukemia patients at diagnosis. [Articolo su rivista]
Morselli, M; Bandieri, E; Zanin, R; Buonaccorso, L; D'Amico, Roberto; Forghieri, Fabio; Pietramaggiori, A; Potenza, Leonardo; Berti, A; Cacciapaglia, G; Molitierno, A; Galli, L; Artioli, F; Ripamonti, C; Bruera, E; Torelli, Giuseppe; Luppi, Mario
abstract

Pain and emotional distress in leukemia patients at diagnosis.

2010 - Predictive Value of Intracellular HIV-1 DNA Levels During CD4-Guided Treatment Interruption in HIV(+) Patients [Articolo su rivista]
Nasi, Milena; Pinti, Marcello; Manzini, S; Gibellini, Lara; Manzini, Lisa; Bisi, Luca; DE BIASI, Sara; DEL GIOVANE, Cinzia; D'Amico, Roberto; Borghi, V; Mussini, Cristina; Cossarizza, Andrea
abstract

The amount of HIV-1 DNA within peripheral blood mononuclear cells is an important marker of viral activity. We studied intracellular HIV-1 DNA content in purified CD4(+) T cells from 28 chronically HIV-1-infected adults with sustained CD4(+) T cell counts (>500 cells/microl) and undetectable plasma viral load (<50 copies/ml), who underwent CD4-guided treatment interruption (TI). Patients were followed up for 18 months during TI, and for 6 months after treatment resumption (TR). Six naïve HIV(+) patients starting therapy were also enrolled and followed up for 6 months. All patients were studied every 2 months; HIV-1 DNA copy number was quantified with real-time PCR. Considering all patients remaining off-treatment, in the first 18 months of TI, intracellular HIV-1 DNA levels (expressed as Log(10) copies/million cells) remained stable (mean, 3.82 and 3.77 at time 0 and after 18 months, respectively). Similarly, HIV-1 DNA values, either in patients who restarted treatment after TI (time 0, 4.90) or in naïve patients who started treatment for the first time (time 0, 4.37), did not change significantly in the first 6 months of therapy (4.42 and 3.67, respectively). Evaluating HIV-1 DNA variations during the first 2 months of TI, we found that patients with a stable level had a lower risk to reach a CD4(+) T cell count <350 cells/microl, and thus to restart therapy, whereas this risk was significantly higher in those with a marked increase of HIV-1 DNA. In conclusion, intracellular HIV-1 DNA is a predictive marker for the length of CD4-guided TI.

2010 - Predictive and prognostic role of p53 according to tumor phenotype in breast cancer patients treated with preoperative chemotherapy: a single-institution analysis [Articolo su rivista]
Guarneri, Valentina; Barbieri, Elena; Piacentini, Federico; Giovannelli, Simona; Ficarra, G; Frassoldati, A; Maiorana, Antonino; D'Amico, Roberto; Conte, Pierfranco
abstract

Introduction and aims: The p53 protein is a mediator of the cellular response to DNA damage. The aim of this study was to evaluate the predictive and/or prognostic value of p53 expression in relation to the molecular subtypes of breast cancer in patients treated with preoperative chemotherapy. Patients and methods: Patients with stage II-III breast cancer were included in the study. The expression of p53 was evaluated by immunohistochemistry on the diagnostic core biopsy specimen. Patients received 4-6 courses of preoperative chemotherapy. Pathological complete response (pCR) was defined as complete disappearance of invasive tumor in the breast and axillary lymph nodes. Results: 154 patients were included in the study and the molecular subtypes of their tumors were classified as follows: triple negative 18.2%, hormone receptor positive 60.4%, and HER2 positive 21.4%. p53 was expressed in 43.5% of the patients. A significant association between p53 expression and breast cancer molecular subtypes, tumor differentiation, and proliferation was observed. pCR was achieved in 8 patients (5.2%). p53 expression, molecular subtype, and nuclear grading were significant predictors of pCR (odds ratio for pCR in patients with p53-expressing tumors 10.03, p=0.0077). In univariate analysis, the expression of p53 as well as high proliferation and lymph node involvement after preoperative chemotherapy were predictors of a worse disease-free survival. Patients with p53 positivity also had a worse overall survival. In multivariate analysis, both p53 expression and nodal status after preoperative chemotherapy were significantly associated with disease-free and overall survival: the hazard ratios for relapse and death in patients with p53-expressing versus non-p53-expressing tumors were 2.29 (p=0.015) and 7.74 (p=0.002), respectively. The hazard ratios for relapse and death in node-positive versus node-negative patients were 3.63 (p=0.003) and 3.64 (p=0.041), respectively. Conclusions: In this series of patients, p53 expression was significantly associated with markers of aggressive tumor biology, and with a higher likelihood of attaining pCR. p53 expression was a negative prognostic parameter for diseasefree and overall survival in univariate and multivariate analysis.

2010 - Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors. [Articolo su rivista]
A., Iorio; D., Matino; D'Amico, Roberto; M., Makris
abstract

BACKGROUND:In people with haemophilia, therapeutic clotting agents might be recognised as a foreign protein and induce anti-FVIII antibodies, known as 'inhibitors'. Drugs insensitive to such antibodies, either recombinant or plasma-derived, are called factor VIII "by-passing" agents and used for treatment of bleeding in people with inhibitors.OBJECTIVES:To determine the clinical effectiveness of recombinant FVIIa concentrate in comparison to plasma-derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors.SEARCH STRATEGY:We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Coagulopathies Trials Register which comprises references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Trials Register: 07 July 2010.SELECTION CRITERIA:Randomised (RCTs) and quasi-randomised controlled clinical trials comparing recombinant FVIIa concentrate (rFVIIa) to human plasma-derived concentrates (high-dose human or recombinant FVIII or FIX concentrate; prothrombin complex concentrates (PCCs); activated prothrombin complex concentrate (aPCC)) in persons with haemophilia. Comparisons with animal derived products were excluded.DATA COLLECTION AND ANALYSIS:Two authors independently assessed trials (eligibility and risk of bias) and extracted data. No meta-analysis was performed due to unavailability of outcomes and comparisons common to the included studies.MAIN RESULTS:A total of ten trials were identified, two of which (total of 69 participants) were eligible for analysis. Both trials showed methodological flaws and did not show superiority of one treatment over the other. Both the treatments showed that (rFVIIa and aPCC appeared to have a similar haemostatic effect in both studies, without increasing thromboembolic risk.AUTHORS' CONCLUSIONS:Although the main conclusion should be the need for further randomised controlled trials, we conclude that both rFVIIa and aPCC can be used to treat bleeding in haemophiliacs with inhibitors.

2010 - Sonographic assessment of fetal spine and head position during the first and second stages of labor for the diagnosis of persistent occiput posterior position: a pilot study [Articolo su rivista]
I., Blasi; D'Amico, Roberto; V., Fenu; A., Volpe; I., Fuchs; W., Henrich; V., Mazza
abstract

OBJECTIVES:The aim of this pilot study was to perform a preliminary investigation into the predictive values of the position of the fetal spine and of the occiput measured during the first and second stages of labor by intrapartum ultrasound for persistent occiput posterior (OP) position.METHODS:This was a prospective, cohort study, in which 100 women with singleton pregnancies were enrolled during the first or second stage of labor. The women underwent intrapartum transabdominal sonography and the positions of the fetal head and spine were recorded. The women were followed up until delivery and occiput position at birth was assessed.RESULTS:Eighty-four pregnancies were evaluated in the second stage of labor, with 74 of these also evaluated in the first stage. Fifty-one percent of fetuses were found to be in an OP position during the first stage of labor, but the majority of these rotated to an anterior position before delivery. There were six cases of OP at delivery, and all of these were among the 23 fetuses that were found to be in an OP position on ultrasound evaluation during the second stage of labor. All six were also found to have a posterior spine position during the second stage of labor, with this finding observed in only one fetus with occiput anterior position at delivery.CONCLUSIONS:The results of this study suggest that the position of the head and spine during the second stage of labor could be useful indicators for predicting the OP position at delivery. The results also suggest that the OP position at delivery results from a failure of rotation from the OP position, rather than a malrotation from the anterior position. Studies with larger sample sizes are needed to confirm these results.

2009 - A prognostic model based on nodal status and Ki-67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy. [Articolo su rivista]
Guarneri, Valentina; Piacentini, Federico; Ficarra, G; Frassoldati, A; D'Amico, Roberto; Giovannelli, Simona; Maiorana, Antonino; Jovic, Gordana; Conte, Pierfranco
abstract

BACKGROUND: Preoperative chemotherapy (PCT) allows for in vivo testing of treatment effects on tumor and its microenvironment. Aim of this analysis was to evaluate the effect of PCT on tumor biomarker expression and to evaluate the prognostic role of treatment-induced variation of these biomarkers (molecular response). METHODS: Two hundred and twenty-one stage II-III breast cancer patients were included. The following parameters were evaluated at baseline and on surgical specimens after PCT: estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki-67, p53, human epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and apoptosis. RESULTS: A pathological complete response was observed in 8.8% of the patients. PCT induced a significant reduction in the expression of ER, PgR, Ki-67, and apoptosis. As by multivariable model, Ki-67 > or = 15% and nodal positivity after preoperative chemotherapy (PCT) were significant predictors of worse disease-free survival [hazard ratio (HR) 3.79, P < 0.0001 and HR 2.31, P = 0.037, respectively]. Ki-67 > or = 15% after PCT was also a significant predictor of overall survival (HR 3.75, P = 0.013). On the basis of these two parameters, patients were classified into three groups: (i) low risk (negative nodes and Ki-67 <15%), (ii) intermediate risk (nodal positivity or Ki-67 > or = 15%), and (iii) high risk (nodal positivity and Ki-67 > or = 15%). As compared with the low-risk group, the HRs for recurrence were 3.1 and 9.3 for the intermediate- and high-risk group, respectively (P = 0.0001); the HRs for death were 2.4 and 6.5 for the intermediate- and high-risk group, respectively (P = 0.042). CONCLUSIONS: Ki-67 and nodal status have been used to generate a simple and easily reproducible prognostic model, able to discriminate patients with worse prognosis among the heterogeneous group of women with residual disease after PCT.

2009 - Analgesia during abdominal aortic aneurysm endovascular repair: remifentanil vs fentanyl-midazolam - a randomized controlled trial [Articolo su rivista]
Giuliani, Enrico; D'Amico, Roberto; Barbieri, Alberto; Bonfreschi, V.; Malagnino, F. C.; Navi, A.; Coppi, Gioachino; Silingardi, R.
abstract

BACKGROUND AND OBJECTIVE: Endovascular repair offers a less surgically invasive procedure for abdominal aortic aneurysms but nevertheless, still requires analgesic sedative cover to ensure an acceptable level of patient comfort and cardiorespiratory stability. The peculiarity of this kind of operation is that painful stimuli are concentrated in specific moments separated by intervals devoid of pain, so the insurgence of pain can be predicted and prevented with a bolus of analgesic, making a continuous infusion not essential, but potentially useful in achieving a better analgesic stability. The primary objective of the study was pain control measured by Visual Analogue Scale; secondary endpoints were cardiorespiratory stability and an acceptable level of sedation. METHODS: The sedative analgesic protocols of two groups of randomly allocated patients, undergoing abdominal aortic aneurysm endovascular repair, were compared. The experimental group received remifentanil infusion (0.03-0.1 microg kg min) and the control group received intravenous doses of fentanyl and midazolam (1-3 microg kg and 0.05-0.1 mg kg, respectively). RESULTS: Fifty patients were investigated out of 60 enrolled. There were no relevant differences concerning cardiorespiratory stability and level of sedation, but pain levels were significantly lower in the experimental group: mean Visual Analogue Scale 0.35+/-0.40 vs. 1.49+/-0.62 (P<0.001) and area under the curve 17.48+/-5.09 vs. 33.05+/-8.19 (P<0.001). CONCLUSION: Both techniques were shown to be safe and most importantly effective in offering cardiovascular stability and analgesia for American Society of Anaesthesiologists III-IV patients undergoing endovascular abdominal aortic aneurysm repair. However, remifentanil continuous infusion proved to offer significantly more stable pain control compared with the currently used combination fentanyl-midazolam.

2009 - Antibiotic Prophylaxis to Reduce Respiratory Tract Infections and Mortality in Adults Receiving Intensive Care [Articolo su rivista]
A., Liberati; D'Amico, Roberto; S., Pifferi; V., Torri; L., Brazzi; E., Parmelli
abstract

BACKGROUND: Pneumonia is an important cause of mortality in intensive care units (ICUs). The incidence of pneumonia in ICU patients ranges between 7% and 40%, and the crude mortality from ventilator-associated pneumonia may exceed 50%. Although not all deaths in patients with this form of pneumonia are directly attributable to pneumonia, it has been shown to contribute to mortality in ICUs independently of other factors that are also strongly associated with such deaths. OBJECTIVES: To assess the effects of prophylactic antibiotic regimens, such as selective decontamination of the digestive tract (SDD) for the prevention of respiratory tract infections (RTIs) and overall mortality in adults receiving intensive care. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 1), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register; MEDLINE (January 1966 to March 2009); and EMBASE (January 1990 to March 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs) of antibiotic prophylaxis for RTIs and deaths among adult ICU patients. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data and assessed trial quality. MAIN RESULTS: We included 36 trials involving 6914 people. There was variation in the antibiotics used, patient characteristics and risk of RTIs and mortality in the control groups. In trials comparing a combination of topical and systemic antibiotics, there was a significant reduction in both RTIs (number of studies = 16, odds ratio (OR) 0.28, 95% confidence interval (CI) 0.20 to 0.38) and total mortality (number of studies = 17, OR 0.75, 95% CI 0.65 to 0.87) in the treated group. In trials comparing topical antimicrobials alone (or comparing topical plus systemic versus systemic alone) there was a significant reduction in RTIs (number of studies = 17, OR 0.44, 95% CI 0.31 to 0.63) but not in total mortality (number of studies = 19, OR 0.97, 95% CI 0.82 to 1.16) in the treated group. AUTHORS' CONCLUSIONS: A combination of topical and systemic prophylactic antibiotics reduces RTIs and overall mortality in adult patients receiving intensive care. Treatment based on the use of topical prophylaxis alone reduces respiratory infections but not mortality. The risk of resistance occurring as a negative consequence of antibiotic use was appropriately explored only in one trial which did not show any such effect.

2009 - Antithrombin plasma levels decrease is associated with preeclampsia worsening. [Articolo su rivista]
M., Marietta; L., Simoni; P., Pedrazzi; L., Facchini; D'Amico, Roberto; Facchinetti, Fabio
abstract

Antithrombin plasma levels (AT) have been found decreased in women with preeclampsia (PE), but little is known about the trend of AT during the course of this disease. We prospectively investigated AT in consecutive women admitted to our hospital with a diagnosis of PE, to assess if AT fluctuations could be associated with the evolution of the disease. AT, platelet count and D-dimer levels were determined every other day. In the 73 patients studied, AT, platelet count and fibrinogen progressively reduced during the observational period, reaching a nadir on the day of delivery, whereas D-dimer progressively increased over time. Statistical analysis was restricted to the 39 women that had an AT measurement performed on each of days -1, 0 and +1, with respect to the day of delivery. These subjects showed a significant decrease in AT on the day of delivery compared to the day just before (77.8 +/- 15.1\%vs. 85.4 +/- 14.2\%, P = 0.027), followed by a recovery on the first day after delivery (87.6 +/- 21.3\% from 77.8 +/- 15.1\%, P = 0.005). Our study demonstrates that a significant drop in AT levels is associated with the clinical worsening of PE, regardless of its severity.

2009 - Capillaroscopic skin ulcer risk index: a new prognostic tool for digital skin ulcer development in systemic sclerosis patients. [Articolo su rivista]
Sebastiani, Marco; Manfredi, Andreina Teresa; Colaci, Michele; D'Amico, Roberto; Malagoli, V; Giuggioli, D; Ferri, Clodoveo
abstract

Objective. Digital ulcerations are one of the most frequent manifestations of microangiopathy in patients with systemicsclerosis (SSc; scleroderma). The early detection of SSc patients who are at high risk to develop digital ulcers could allowa preventive treatment of these complications with reduction of morbidity and social costs. The aim of our study was todevelop a capillaroscopic skin ulcer risk index (CSURI) that can predict the onset of new digital ulcers by using nailfoldvideocapillaroscopy (NVC) in patients with SSc.Methods. We performed NVC in 120 consecutive unselected patients with SSc (13 men, 107 women, mean SD age56.1 13.4 years, mean SD SSc duration 44.7 60.7 months) to assess the total number of capillaries in the distal row(N), maximum loop diameter (D), number of megacapillaries (M), and the M:N ratio.Results. Within 3 months since NVC examination, 35 of 120 patients experienced digital ulcers. A significant associationbetween ischemic lesions and the M:N ratio, N, and D was observed; the combination of these parameters allowed us todevelop the CSURI, which is characterized by the formula D M:N2. A receiver operating characteristic curve analysisshowed an area under the curve of 0.926 for ulcer appearance, with specificity and sensitivity of 85.9% and 94.3%,respectively, at the cutoff value of 2.94. Interestingly, 33 of 35 patients with new skin ulcers had a CSURI >2.94, but only2 of 35 had a CSURI <2.94.Conclusion. The proposed CSURI may represent a novel tool with the ability to predict the development of digital ulcersin patients with scleroderma.

2009 - Chronic total coronary occlusion in patients with intermediate viability: value of low-dose dobutamine and contrast-enhanced 3-T MRI in predicting functional recovery in patients undergoing percutaneous revascularisation with drug-eluting stent. [Articolo su rivista]
Fiocchi, F; Sgura, F; Di Girolamo, A; Ligabue, Guido; Ferraresi, S; Rossi, Rosario; D'Amico, Roberto; Modena, Maria Grazia; Torricelli, Pietro
abstract

PURPOSE: Myocardial viability was evaluated by magnetic resonance imaging (MRI) in patients with chronic total coronary occlusion (CTO) treated with a drug-eluting stent. Change in left ventricular ejection fraction (LVEF) was analysed. MATERIALS AND METHODS: Twenty-three patients with CTO underwent delayed-enhancement (DE) and low-dose dobutamine MRI (LD). Diastolic wall thickness (DWT), dobutamine-induced systolic wall thickening (SWT) and DE transmural extension were quantitatively assessed in vessel-related segments, calculating the contribution of viable tissue to SWT, expressed as viability index (VI)=[SWTx(100 - DE)]/100. Patients with transmural enhancement were excluded from revascularisation. At 6 months follow-up, patients underwent coronary angiography (CA) and MRI. Functional recovery was defined as a 2-mm increase in SWT. RESULTS: Transmural enhancement (mean DE 62.88+/-37.18] was present in three patients. Mean DWT, SWT, VI and DE of recanalised patients were 8.03+/-2.35, 2.64+/-1.56, 1.77+/-1.48 mm and 41.97+/-30.32. Revascularisation was successful in 14/16. Follow-up CA showed patency of treated vessels. Functional recovery was achieved in 13 patients. Functional recovery showed significant correlation with SWT (beta 1,779, p=0.015), and even higher correlation with VI (beta 2.032, p=0.011). LVEF improved significantly [Delta 95% confidence interval (CI) -4.47, p=0.0203). CONCLUSIONS: Invasive CTO treatment has beneficial effects on myocardial contractility that can be predicted by VI, and on LVEF.

2009 - Does needle calibre affect pain and complication rates in patients undergoing transperineal prostate biopsy? A prospective, randomized trial [Articolo su rivista]
Sighinolfi, Maria Chiara; Fidanza, Francesco Antonio; DE STEFANI, Stefano; Micali, Salvatore; M., Paterlini; D'Amico, Roberto; Bianchi, Giampaolo; Saredi, G
abstract

Transperineal prostate biopsy is a procedure that can be used to obtain histological samples from the prostate. To improve both the quality of the biopsy core samples and prostate cancer detection, we are currently performing a prospective, randomized trial comparing prostate biopsy samples obtained using an 18 G-needle to those obtained using a 16 G needle. The aim of this preliminary study was to evaluate pain and complication rates in both groups in order to assess whether performing a prostate biopsy with a larger calibre needle is a feasible procedure. One hundred and eighty-seven patients undergoing transperineal prostate biopsy were prospectively evaluated and divided into two groups. The first group (94 patients, Group A) received a transperineal prostate biopsy using a 16 G-needle and the second group (93 patients, Group B) underwent transperineal prostate biopsy with an 18 G-needle. Anaesthesia was obtained with a single perineal injection at the prostatic apex in all subjects. A visual analogue scale (VAS) and facial expression scale (FES) were used to assess pain during multiple steps of the procedure in each group. A detailed questionnaire was used to obtain information about drug use because it could potentially influence the pain and complications that patients experienced. Two weeks after the procedure, early and late complications were evaluated. Statistical analysis was carried out using non-parametric tests. Prostate Specific Antigen (PSA) and drug use were similar at baseline between the two groups. Pain during prostate biopsy, which was measured with both the VAS and FES instruments, did not differ significantly between the 18- and 16 G-needle groups, and no significant differences were found in early or late complication rates between the groups. Transperineal prostate biopsy with a 16 G-needle is a feasible procedure in terms of pain and complication rates. Further studies with larger patient populations are required to assess whether or not this procedure can improve prostate cancer detection rates.

2009 - Endogenous blood maximal interferon-gamma production may predict response to interferon-gamma 1beta treatment in patients with idiopathic pulmonary fibrosis. [Articolo su rivista]
F., Luppi; M., Losi; D'Amico, Roberto; Lm, Fabbri; Richeldi, Luca
abstract

BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is an untreatable lung disorder with a mean survival of 3 years after diagnosis. Treatment with interferon-gamma (IFN-gamma) 1beta has been reported to significantly improve lung function and arterial oxygen saturation in a first randomized controlled trial; unexpectedly, these findings have not been confirmed in a subsequent large placebo-controlled randomized study. Another larger placebo-controlled randomized trial has been stopped because data analyzed at interim analysis excluded the possibility that treatment with IFN-gamma 1beta would cause a significant reduction in the risk of death.METHODS:Seven Italian male patients diagnosed with IPF were treated with IFN-gamma 1beta (200 microg/die subcutaneously three times a week), accordingly to the indications of the Italian Drug Agency. Based on available studies the response to treatment was pre-defined as changes in either lung function (FVC and DLCO) or oxygen arterial saturation. All patients consented to provide a peripheral blood sample for endogenous IFN-gamma production measurement with the ELISpot assay before treatment and 6 months thereafter.RESULTS:Four of 7 patients improved or stabilized their lung function after 6 months treatment. Using the ELISpot assay to quantify the maximal production of endogenous IFN-gamma on peripheral blood samples, these 4 patients had a significantly higher endogenous IFN-gamma production before therapy, as compared to the 3 patients who deteriorated (91.3 +/- 49.6 vs. 277.8 +/- 34.2 spot forming cells, p = 0.023). No significant differences were observed after 6 months of treatment.DISCUSSION:These preliminary results suggest that some IPF patients might benefit from treatment with IFN-gamma 1beta and may help to interpret the results of large randomized trials, suggesting that individual susceptibility could determine clinical response to treatment.

2009 - Epidermal growth factor receptor gene copy number, K-ras mutation and pathological response to preoperative cetuximab, 5-FU and radiation therapy in locally advanced rectal cancer.. [Articolo su rivista]
Bengala, C; Bettelli, Stefania Raffaella; Salvi, S; Chiara, S; Sonaglio, C; Losi, Lorena; Bigiani, N; Sartori, G; Dealis, Cristina; Malavasi, Norma; D'Amico, Roberto; Luppi, G; Gatteschi, B; Maiorana, Antonino; Conte, Pierfranco
abstract

Cetuximab improves activity of chemotherapy in metastatic colorectal cancer (mCRC). Gene copy number (GCN) of epidermal growth factor receptor (EGFR) has been suggested to be a predictive factor of response to cetuximab in patients (pts) with mCRC; on the contrary, K-ras mutation has been associated with cetuximab resistance. PATIENTS AND METHODS: We have conducted a phase II study with cetuximab administered weekly for 3 weeks as single agent and then with 5-fluorouracil and radiation therapy as neo-adjuvant treatment for locally advanced rectal cancer (LARC). EGFR immunohistochemistry expression, EGFR GCN and K-ras mutation were evaluated on diagnostic tumor biopsy. Dworak's tumor regression grade (TRG) was evaluated on surgical specimens. RESULTS: Forty pts have been treated; 39 pts are assessable. TRG 3 and 4 were achieved in nine (23.1%) and three pts (7.7%) respectively; TRG 3-4 rate was 55% and 5.3% in case of high and low GCN, respectively (P 0.0016). Pts with K-ras mutated tumors had lower rate of high TRG: 11% versus 36.7% (P 0.12). In pts with wild-type K-ras, TRG 3-4 rate was 58.8% versus 7.7% in case of high or low GCN, respectively (P 0.0012). CONCLUSIONS: In pts with LARC, EGFR GCN is predictive of high TRG to cetuximab plus 5-FU radiotherapy. Moreover, our data suggest that a wild-type K-ras associated with a high EGFR GCN can predict sensitivity to cetuximab-based treatment.PMID: 19095777 [PubMed - indexed for MEDLINE]Related articlesNeoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2009 Feb 1; 73(2):466-72. Epub 2008 Nov 10. [Int J Radiat Oncol Biol Phys. 2009]Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007 Aug 1; 25(22):3230-7. [J Clin Oncol. 2007]A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment. BMC Cancer. 2008 Jun 10; 8:169. Epub 2008 Jun 10. [BMC Cancer. 2008]Review[The RAS paradox of the EGFR-targeted therapy in colorectal cancer] Magy Onkol. 2008 Jun; 52(2):185-91. [Magy Onkol. 2008]ReviewAssessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer. Lancet Oncol. 2008 Oct; 9(10):962-72. Epub 2008 Sep 17. [Lancet Oncol. 2008]» See reviews... | » See all... Patient Drug InformationFluorouracil (Adrucil®) Your doctor has ordered the drug fluorouracil to help treat your illness. The drug is given by injection into a vein. Source: AHFS Consumer Medication Information

2009 - Interferon-gamma-release assays detect tuberculosis re-infection in elderly contacts [Articolo su rivista]
G., Ferrara; M., Losi; D'Amico, Roberto; R., Cagarelli; Am, Pezzi; M., Meacci; B., Meccugni; I., Dori Marchetti; F., Rumpianesi; P., Roversi; L., Casali; Lm, Fabbri; Richeldi, Luca
abstract

The tuberculin skin test (TST) does not discriminate between recent and remote latent tuberculosis infection (LTBI). This study was carried out to test two interferon-gamma-based blood assays in recent contacts with high prevalence of remote LTBI. We performed a contact tracing investigation in a nursing home for the elderly, where elderly patients were exposed to a case of pulmonary tuberculosis. TST, QuantiFERON-TB Gold (QFT-G) and T-SPOT.TB (TS.TB) were performed 8 weeks after the end of potential exposure. IFN-gamma measurements were recorded and correlation with exposure was evaluated. Twenty-seven (37.5%), 32 (44.4%) and 16 (22.2%) subjects were TST, TS.TB and QFT-G positive, respectively; agreement between TS.TB and QFT-G was good among exposed subjects only (K=0.915, 0.218 in unexposed, p<0.001). When amounts of IFN-gamma were corrected for the number of producing T cells, specific IFN-gamma production was significantly different between exposed and unexposed individuals (16.75+/-5.40 vs 2.33+/-0.71 IFN-gamma IU/1000 SFC, p=0.0001). QFT-G and TS.TB provided discordant results among elderly contacts. Unlike TST, the specific IFN-gamma response might discriminate between recent and long-lasting tuberculosis infection.

2009 - Migraine is a risk factor for hypertensive disorders in pregnancy: a prospective cohort study [Articolo su rivista]
Facchinetti, Fabio; G., Allais; R. E., Nappi; D'Amico, Roberto; L., Marozio; L., Bertozzi; A., Ornati; C., Benedetto
abstract

The aim was to assess whether women suffering from migraine are at higher risk of developing hypertensive disorders in pregnancy. In a prospective cohort study, performed at antenatal clinics in three maternity units in Northern Italy, 702 normotensive women with singleton pregnancy at 11-16 weeks' gestation were enrolled. Women with a history of hypertensive disorders in pregnancy or presenting chronic hypertension were excluded. The presence of migraine was investigated according to International Headache Society criteria. The main outcome measure was the onset of hypertension in pregnancy, defined as the occurrence of either gestational hypertension or preeclampsia. Two hundred and seventy women (38.5%) were diagnosed with migraine. The majority (68.1%) suffered from migraine without aura. The risk of developing hypertensive disorders in pregnancy was higher in migraineurs (9.1%) compared with non-migraineurs (3.1%) [odds ratio (OR) adjusted for age, family history of hypertension and smoking 2.85, 95% confidence interval (CI) 1.40, 5.81]. Women with migraine also showed a trend to increased risk for low birth weight infants with respect to women without migraine (OR 1.97, 95% CI 0.98, 3.98). Women with migraine are to be considered at increased risk of developing hypertensive disorders in pregnancy. The diagnosis of primary headaches should be taken into account at antenatal examination.

2009 - P53 EXPRESSION IS A SIGNIFICANT PREDICTOR OF RESPONSE AND PROGNOSIS IN STAGE II-III BREAST CANCER PATIENTS TREATED WITH PREOPERATIVE CHEMOTHERAPY [Abstract in Atti di Convegno]
Guarneri, V.; Piacentini, F.; Barbieri, E.; Frassoldati, A.; Ficarra, G.; D’Amico, R.; Conte, Pf.
abstract

Introduction and Aims: p53 protein is a mediator of the cellular response to DNA damage. Mutation in p53 genes has been reported in breast cancer (BC) , and has been suggested as potential marker of chemoresistance. Aim of this study is to evaluate the predictive and/or prognostic role of p53 expression in a consecutive series of BC patients (pts) treated with preoperative chemotherapy (PCT). Patients and Methods: pts with stage II-III BC were included. The expression of p53 was evaluated by IHC on the diagnostic core biopsy, (Cellmar D07Ab, cut off: staining in ³ 10% of cells). Pts received 4-6 courses of PCT before surgery. Pathologic complete response (pCR) was defined as complete disappearance of invasive tumor in breast and axillary nodes. The association between biomarkers and pCR was assessed by Pearson chi square test. Survival was estimated with the Kaplan-Meier method. Results: 155 BC pts were included. Median age was 52 yrs (range: 29-76). Clinical stage at diagnosis: II A-B in 80% of the pts, IIIA-B in 20% of the pts. The majority of the pts (72%) had ER+ tumors; 22% of the pts were HER2 +. 68 pts (44%) showed p53 overexpression (mean expression 24%: range 0-99%). p53 overexpressing tumors were significantly less ER +(63% vs 79%, p=0.02). p53 expression was also positively correlated with higher levels of ki67 (87 vs 70%, p=0.012). PCT consisted of anthracycline-based regimens in 40 pts; anthra/taxanes combinations in 110 pts; a taxane regimen in 4 cases. After PCT, 43% of the pts underwent conservative surgery. A pCR was observed in 5.3% of the pts. The probability of pCR was significantly higher in case of p53 overexpression (10.8% vs 1%, p=0.009), ER negativity (11.6% vs 2.8%, p=0.028), HER2 positivity (12 vs 3.4%, p=0.04), and nuclear grade 3 (9% vs 0, p=0.02). The overall 5-yr DFS and OS were 70% and 85%. The 5-yr DFS in case of p53 <10% was 82% vs 55% in p53 >/= 10% (p=0.0038). The 5-yr OS in case of p53 <10% was 99% vs 67% in p53 >/= 10% (p<0.0001). Conclusions: the expression of p53 is significantly associated with a higher probability of achieving a pCR to PCT including anthracyclines +/- taxanes. However, inspite of the greater chemosensitivity, in our study p53 overexpression is a negative prognostic parameter. The role of p53 in patients receiving PCT warrants further studies. Supported in part by a Ministry of Health Research grant (Progetti Integrati Oncologia # 04/07)

2009 - Performance of commerical blood tests for the diagnosis of latent tuberculosis infection in children and adolescents [Articolo su rivista]
Bergamini, Barbara Maria; M., Losi; F., Vaienti; D'Amico, Roberto; B., Meccugni; M., Meacci; D., De Giovanni; F., Rumpianesi; Fabbri, Leonardo; F., Balli; Richeldi, Luca
abstract

BACKGROUND: The accurate diagnosis of latent tuberculosis infection reduces the risk of progression to severe disseminated disease. However, in young children, a major limitation of the standard tuberculin skin test is that false-negative results cannot be detected. The new interferon-gamma release assays QuantiFERON-TB Gold (Cellestis Carnegie Victoria, Australia), QuantiFERON-TB In-Tube (Cellestis), and T-SPOT.TB (Oxford Immunotec, Abingdon, United Kingdom) show promise of greater accuracy, but they may also be affected by impaired cellular immunity, resulting in indeterminate results (ie, insufficient response in positive-control wells).OBJECTIVE:To evaluate the impact of age on the performance of interferon-gamma release assays when used in a routine hospital setting among children tested for suspected active or latent TB infection.METHODS:We retrospectively studied 496 children 0 to 19 years of age who had been tested with the tuberculin skin test and at least 1 interferon-gamma release assay: 181 with QuantiFERON-TB Gold and 315 with QuantiFERON-TB In-Tube. In 154 of the children, paired interferon-gamma release assay testing was available: 87 with QuantiFERON-TB Gold/T-SPOT.TB and 67 with QuantiFERON-TB In-Tube/T-SPOT.TB.RESULTS:Compared with T-SPOT.TB, the rates of indeterminate results were significantly higher for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube. QuantiFERON-TB Gold and QuantiFERON-TB In-Tube also gave indeterminate results more frequently in children <4 years of age than in those >/=4 years of age. Indeterminate results were associated with younger age for both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube but not for T-SPOT.TB. Considering age as a binary variable (<4 and >/=4 years of age), a significantly higher concentration of phytohaemagglutinin-produced interferon-gamma was observed in older children with both QuantiFERON-TB Gold and QuantiFERON-TB In-Tube.CONCLUSIONS:Different blood tests for the diagnosis of latent tuberculosis infection in children seem to perform differently, because both QuantiFERON-TB tests were more likely than T-SPOT.TB to give indeterminate results in children <4 years of age.

2009 - Performance of tests for latent tuberculosis in different groups of immunocompromised patients. [Articolo su rivista]
Richeldi, Luca; Losi, M; D'Amico, Roberto; Luppi, M; Ferrari, A; Mussini, Cristina; Codeluppi, M; Cocchi, S; Prati, F; Paci, V; Meacci, M; Meccugni, B; Rumpianesi, F; Roversi, P; Cerri, Stefania; Luppi, F; Ferrara, G; Latorre, I; Gerunda, Giorgio Enrico; Torelli, G; Esposito, R; Fabbri, Leonardo
abstract

BACKGROUND: Immunocompromised persons infected with Mycobacterium tuberculosis (MTB) have increased risk of tuberculosis (TB) reactivation, but their managementis hampered by the occurrence of false-negative results of the tuberculin skin test (TST). The T-cell interferon (IFN)-gamma release blood assays T-SPOT.TB(TS.TB) [Oxford Immunotec; Abingdon, UK] and QuantiFERON-TB Gold In-Tube (QFT-IT) [Cellestis Ltd; Carnegie, VIC, Australia] might improve diagnostic accuracy forlatent TB infection (LTBI) in high-risk persons, although their performance in different groups of immunocompromised patients is largely unknown.METHODS AND RESULTS: Over a 1-year period, we prospectively enrolled patients in three different immunosuppressed groups, as follows: 120 liver transplantation candidates (LTCs); 116 chronically HIV-infected persons; and 95 patients with hematologic malignancies (HMs). TST, TS.TB, and QFT-IT were simultaneouslyperformed, their results were compared, and intertest agreement was evaluated.Overall, TST provided fewer positive results (10.9%) than TS.TB (18.4%; p <0.001) and QFT-IT (15.1%; p = 0.033). Significantly fewer HIV-infected individuals had at least one positive test (9.5%) compared with LTCs (35.8%; p < 0.001) and patients with HMs (29.5%; p < 0.001). Diagnostic agreement between tests was moderate (kappa = 0.40 to 0.65) and decreased in the HIV-infected group when the results of the TS.TB were compared with either TST (kappa = 0.16) orQFT-IT (kappa = 0.19). Indeterminate blood test results due to low positive control values were significantly more frequent with QFT-IT (7.2%) than with TS.TB (0.6%; p < 0.001).CONCLUSIONS: Blood tests identified significantly more patients as being infected with MTB than TST, although diagnostic agreement varied across groups. Based onthese results, we recommend tailoring application of the new blood IFN-gamma assays for LTBI in different high-risk groups and advise caution in their current use in immunosuppressed patients.

2009 - Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement (Chinese edition) [Articolo su rivista]
Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D. G.; Altman, D.; Antes, G.; Atkins, D.; Barbour, V.; Barrowman, N.; Berlin, J. A.; Clark, J.; Clarke, M.; Cook, D.; D'Amico, R.; Deeks, J. J.; Devereaux, P. J.; Dickersin, K.; Egger, M.; Ernst, E.; Gotzsche, P. C.; Grimshaw, J.; Guyatt, G.; Higgins, J.; Ioannidis, J. P. A.; Kleijnen, J.; Lang, T.; Magrini, N.; Mcnamee, D.; Moja, L.; Mulrow, C.; Napoli, M.; Oxman, A.; Pham, B.; Rennie, D.; Sampson, M.; Schulz, K. F.; Shekelle, P. G.; Tovey, D.; Tugwell, P.
abstract

2009 - Prenatal education for congenital toxoplasmosis [Articolo su rivista]
DI MARIO, S; Basevi, V; Gagliotti, C; Spettoli, D; Gori, G; D'Amico, Roberto; Magrini, N.
abstract

BACKGROUND: Congenital toxoplasmosis is considered a rare but potentially severe infection. Prenatal education about congenital toxoplasmosis could be the most efficient and least harmful intervention, yet its effectiveness is uncertain. OBJECTIVES: To assess the effects of prenatal education for preventing congenital toxoplasmosis. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (November 2007), CENTRAL (The Cochrane Library 2007, Issue 3), MEDLINE (1966 to November 2007), EMBASE (1980 to November 2007), CINAHL (1982 to November 2007), LILACS (1982 to November 2007) IMEMR (1984 to November 2007), and reference lists of relevant papers, reviews and websites. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials (RCT) of all types of prenatal education on toxoplasmosis infection during pregnancy. DATA COLLECTION AND ANALYSIS: Three authors independently assessed study quality and extracted data. MAIN RESULTS: One cluster-randomized controlled trial (432 women) met the inclusion criteria. However, the overall methodological quality was poor. The authors did not report measure of association but only provided P values (P less than 0.05) for all outcomes. The authors concluded that prenatal education can effectively change pregnant women's behavior as it increased pet, personal and food hygiene. There are no randomized trials on the effect of prenatal education on congenital toxoplasmosis rate, or toxoplasmosis seroconversion rate during pregnancy, but three observational studies consistently suggest that prenatal education might have a positive impact on these outcomes. AUTHORS' CONCLUSIONS: Even though primary prevention of congenital toxoplasmosis is considered a desirable intervention, given the lack of related risks compared to secondary and tertiary prevention, its effectiveness has not been adequately evaluated. There is very little evidence from RCTs that prenatal education is effective in reducing congenital toxoplasmosis even though evidence from observational studies suggests it is. Given the lack of good evidence supporting prenatal education for congenital toxoplasmosis prevention, further RCTs are needed to confirm any potential benefits and to further quantify the impact of different sets of educational intervention.

2009 - Preplanned first-step analysis of LET-LOB neoadjuvant study: A double-blind randomized phase IIb trial of letrozole (L) plus lapatinib (Lp) or placebo (P) in postmenopausal HER2-ve, HR+ve operable breast cancer. [Abstract in Rivista]
A., Frassoldati; Guarneri, Valentina; A., Bottini; K., Cagossi; L., Cavanna; G., Bisagni; D'Amico, Roberto; Piacentini, Federico; C., Oliva; Conte, Pierfranco
abstract

Background: In HR+ve BC, the simultaneous blockade of ER and HER-related pathways could prevent the hormone-resistance due to activation of EGFR-family signalling, as shows the high activity of the combination of letrozole and lapatinib in HR+ve/HER2+ve advanced BC. The LET-LOB trial evaluates the clinical and biological effects of the combined inhibitory strategy with letrozole + lapatinib in untreated ER+ve/HER2-ve BC patients suitable for hormonal neoadjuvant therapy. Methods: Postmenopausal women with stage II-IIIa, HR+ve/HER2-ve BC are randomized to L (2.5 mg/d) + Lp (1500 mg/d) or L + P, given continuously for 24 weeks before surgery. Primary end point is the clinical RR (with ultrasonography, US); secondary endpoints are the pathological RR, the safety, and HR/EGFR-related biomarker evaluation. According to the "two step Simon's design" of the study, at least 20 cORs (8 in L+P and 12 in L+Lp) must be observed in the first 43 patients; then, additional 48 patients will be recruited to demonstrate a 40% increase in cOR with L+Lp, assuming a cOR of 50% with L+P. Results: Since April 2007, 39/55 randomized patients completed the preoperative treatment. Median age was 68 yrs. At diagnosis, mean US tumor size was 3 cm. All patients were HER2-ve, and either ER+ve or PR+ve (both +ve: 76%). After 3 and 6 months of therapy, a 29% and 41% reduction from baseline mean US longest tumor diameter was observed. No change in mean LVEF has been reported at the 3- and 6-month evaluations. 5 episodes of G3 toxicity have occured (skin rash, 1; liver function parameters, 4). So far 31 women underwent surgery (conservative in 65 %). The efficacy results according to the first step Simon's analysis will be performed by the IDMC on march 2009, and will be presented at the meeting along with updated clinical and safety data. Conclusions: Preliminary blinded results suggest that the combination of L+Lp in ER+ve/HER2-ve operable BC is feasible, without early cardiac events or other severe toxicities, and associated with clear tumor downstaging. Biological correlative studies will clarify the relationship between the double inhibition strategy and the clinical response. Supported by GlaxoSmithKline.

2009 - Risk stratification of non-traumatic headache in the emergency department [Articolo su rivista]
D., Grimaldi; F., Nonino; S., Cevoli; A., Vandelli; D'Amico, Roberto; P., Cortelli; Mandrioli, Jessica
abstract

OBJECTIVE: To determine the diagnostic accuracy of an algorithm structured in four clinical scenarios to discriminate benign primary headaches from serious secondary non-traumatic headaches (NTH) in the emergency department (ED). BACKGROUND: NTH is usually a benign symptom but can occasionally result in serious outcome making the disposition of patients with NTH difficult in the ED. DESIGN AND METHODS: Consecutive adults patients referring to 8 EDs of the Emilia-Romagna region in Italy for NTH as the chief complaint were recruited in the study for a 30-day period. ED physicians attributed to each patient one of the four clinical scenarios (1, 2 and 3 identifying serious secondary headaches and scenario 4 identifying benign primary headaches) or an undetermined scenario when none of the four scenarios applied. Reference standards of the study were the head CT scan and a follow-up telephone interview after three months by the ED admission. RESULTS: The test was administered to 256 out of 302 (85%) eligible patients. The analysis (scenario 1,2,3 vs scenario 4) was based on 180 patients who completed the follow-up showing a sensitivity of 100% (95% confidence interval, 81% to 100%) and a specificity of 64% (56% to 71%). The likelihood ratio for a positive test was 2.67 (2.15 to 3.31) and the likelihood ratio for a negative test was 0.04 (0.003 to 0.64). CONCLUSIONS: An algorithm based on four clinical scenarios can be administered to the majority of patients presenting to the ED with the chief complaint of NTH. The algorithm showed a good accuracy in identifying patients with non-life threatening causes of headache and could be used as a risk stratification tool to improve clinical decision- making. Further studies are required to validate this diagnostic algorithm.

2009 - Short-Term Efficacy of Upper-Extremity Exercise Training in Patients With Chronic Airway Obstruction: A Systematic Review. [Articolo su rivista]
Costi, Stefania; M., Di Bari; P., Pillastrini; D'Amico, Roberto; E., Crisafulli; C., Arletti; Fabbri, Leonardo; Clini, Enrico
abstract

Background, Objectives, and Measurements Patients with chronic airway obstruction (CAO) frequently experience dyspnea and fatigue during activities performed by accessory muscles of ventilation, which competitively participate in arm elevation. This systematic review of randomized controlled trials (RCTs) concerning patients with CAO addresses the effects of upper-extremity exercise training (UEET), added to lower-extremity training or comprehensive pulmonary rehabilitation, on the following patient-centered outcomes: exercise capacity, symptoms, ability to perform daily activities, and health-related quality of life. METHODS:/b> Studies were retrieved using comprehensive database and hand-search strategies. Two independent reviewers determined study eligibility based on inclusion criteria. A detailed description of treatments was mandatory. Reviewers rated study quality and extracted information on study methods, design, intervention, and results. RESULTS: /b> Forty publications were evaluated. Four RCTs met the inclusion criteria but had serious methodological limitations, which introduce possible biases that reduce their internal validity. The outcomes measured were heterogeneous, and the results were inconsistent regarding maximal exercise capacity, dyspnea, and health-related quality of life. No effect of UEET was demonstrated for measures of arm fatigue. Limitations and CONCLUSIONS:/b> The limited methodological quality of the studies retrieved prevented us from performing a meta-analysis, the results of which could be misleading. This systematic review shows that there is limited evidence examining UEET and that the evidence available is of poor quality. Therefore, a recommendation for the inclusion or exclusion of UEET in pulmonary rehabilitation programs for individuals with CAO is not possible. Further research is needed to definitively ascertain the effects of this training modality on patient-centered outcomes.

2009 - rates of latent tuberculosis infection using different diagnostica test [Abstract in Rivista]
Losi, M; Piro, Roberto; D'Amico, Roberto; Luppi, Francesco; Bergamini, Barbara Maria; Ferrari, D; Miglietta, Roberta; Codeluppi, M; Luppi, M; Fantini, R.
abstract

Background.The interferon−g−release assays (IGRA) are emerging as an attractive alternative to the tuberculin skin test (TST) for the diagnosis of latent tuberculosis infection (LTBI).The absence of a gold standard for LTBI hampers the assessment of any diagnostic test. Methods.In a prospective study,229 patients (mean age 35.5±24.6 y) from different ward of the Hospital (Respiratory Diseases,Dermatology, Rheumatology, Pediatrics, Infectious Diseases, Hematology and Transplant Unit) were simultaneously tested for a suspect of either LTBI or active tuberculosis using all commercially available diagnostics: TST,QuantiFERON−TB Gold (QFT−2G), QuantiFERON−TB Gold In−Tube(QFT−3G) and T−SPOT.TB(TS.TB). Results. 42(18.3%),37(16.2%),59(25.8%) and 79(34.5%) patients were positive with TST,QFT−2G,QFT−3G and TS.TB, respectively.TS.TB(p<0.001) and QFT−3G(p=0.016) provided more positive results than TST, while no difference was found for TST and QFT−2G(p=0.53).All IGRA showed a good overall agreement (TS.TB vs QFT−2G,k=0.55; TS.TB vs QFT−3G,k=0.72;QFT−2G vs QFT−3G, k=0.62). In 22 subjects (9.6%) QFT−3G was positive and QFT−2G negative. Indeterminate results were more frequent with QFT−2G(18.3%) and QFT−3G (12.7%) than with TS.TB(1.3%,p<0.0001). Conclusion. Rates of LTBI as detected by different diagnostic tests may have significant variations. Performances of various IGRA formats were variable in this population.

2008 - "Endocrine NAFLD": a hormonocentric perspective of Non-Alcoholic Liver Disease (NAFLD) pathogenesis in HIV-infected patients [Abstract in Atti di Convegno]
C., Stentarelli; S., Zona; V., Rochira; G., Caffagni; L., Zirilli; S., Ballestri; A., Lonardo; D'Amico, Roberto; N., Squillace; G., Orlando; P., Loria; Guaraldi, Giovanni
abstract

We assessed endocrine system involvement in a multifactorial pathogenesis hypothesis of NAFLD in HIV-infected patients.

2008 - A prognostic model based on nodal status and Ki 67 predicts the risk of recurrence and death in breast cancer patients with residual disease after preoperative chemotherapy [Abstract in Rivista]
Guarneri, Valentina; Piacentini, Federico; A., Frassoldati; G., Ficarra; D'Amico, Roberto; Giovannelli, Simona; Conte, Pierfranco
abstract

Introduction and Aims: The achievement of a pathologic complete response (pCR) after preoperative chemotherapy (PCT) is a validated surrogate end point for long term outcome. On the other side, patients with residual disease in the breast and/or axilla are an heterogeneous group with very different prognosis, including both patients with truly chemo-resistant disease as well as patients with an important tumor downstaging even if not in pCR. Aim of this analysis is to identify, in patients with residual disease, potential markers able to discriminate patients at higher risk of relapse. Patients and Methods:. The following parameters were evaluated on the surgical specimen in patients with less than pCR following PCT: residual breast disease, number of involved nodes, proliferation (Ki 67), hormone receptor, HER2, p53, EGFR, VEGFR2. Survival curves were estimated with the Kaplan-Meier method and the log rank test was used to test for differences between groups. Hazard Ratios and their confidence intervals were estimated by using Cox model. Results: 195 breast cancer patients were included. Median age 51 yrs (range: 27-73); 71% of the patients had ER+ tumors at diagnosis, 20% were HER2+. After PCT, 55% of the patients received mastectomy, 45% underwent conservative surgery. 57% of the patients had residual breast disease < 2 cm; 38% between 2-5 cm; 35% had no involved nodes, 30% 1-3 nodes, 19% 4-9 nodes, and 16% > 10 nodes; 50% of the patients had Ki 67 >/= 15%. Among the examined parameters, nodal positivity and Ki 67>/=15% were significantly related with a higher risk of relapse (HR 2.5 , p=0.014 and HR 3.4, p <0.0001 respectively). Ki 67 >/=15% was also predictive of a higher risk of death (HR 4.1, p=0.007). On the basis of these two parameters, patients were classified in three groups: 1) low risk (negative nodes and Ki 67<15%): 14.4% of the patients ; 2) intermediate risk (nodal positivity or Ki67 >/= 15%): 54.4% of the patients; 3) high risk (nodal positivity and Ki 67>/= 15%): 31.2% of the patients. Five-year DFS rates were 90%, 72%, and 43% respectively (log rank test p<0.0001); as compared with the low risk group, the HRs for recurrence were 3.1 and 9.3 for the intermediate and high risk group respectively (p=0.0001). Five-year OS rates were 86%, 88%, and 64% respectively (log rank test p=0.035); as compared with the low risk group, the HRs for death were 2.4 and 6.5 for the intermediate and high risk group respectively (p=0.042). Conclusions: In this series of patients, Ki 67 and nodal status have been used to generate a simple and easily reproducible prognostic model, able to discriminate patients with worse prognosis among the heterogeneous group of women with residual disease after PCT. In the era of customized treatment strategies, patients at higher risk are the optimal candidates to study the efficacy of additional postoperative treatments.

2008 - Comparison of HER-2 and hormone receptor expression in primary breast cancers and asynchronous paired metastases: impact on patient management [Articolo su rivista]
Guarneri, Valentina; Giovannelli, Simona; Ficarra, G; Bettelli, Stefania Raffaella; Maiorana, Antonino; Piacentini, Federico; Barbieri, Elena; Dieci, Maria Vittoria; D'Amico, Roberto; Jovic, Gordana; Conte, Pierfranco
abstract

The assessment of hormone receptors (HRs) and human epidermal growth factor receptor (HER)-2 is necessary to select patients who are candidates for hormonal and anti-HER-2 therapy. The evaluation of these parameters is generally carried out in primary tumors and it is not clear if reassessment in metastatic lesions might have an impact on patient management. The primary aim of this analysis was to compare HER-2 and HR status in primary tumors versus metastatic sites in breast cancer patients. PATIENTS AND METHODS: Seventy-five patients with available samples from primary tumors and paired metastases were included. HER-2 status was evaluated by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH); HR status was assessed by IHC. RESULTS: Nineteen percent of primary tumors were HER-2 positive; 77% were HR positive. Sites of biopsied or resected metastases were: locoregional soft tissues (n = 30), liver (n = 20), central nervous system (n = 5), bone (n = 5), pleura (n = 4), distant soft tissues (n = 3), abdomen (stomach, colon, peritoneum) (n = 3), bronchus (n = 3), and bone marrow (n = 2). For paired metastases, the HER-2 status was unchanged in 84% of cases; two patients changed from positive to negative, while 10 patients converted from negative to positive (agreement, 84%; kappa = 0.5681). A change in HR status was observed in 16 cases (21%): nine cases from positive to negative and seven cases from negative to positive (agreement, 78.7%; kappa = 0.4158). CONCLUSIONS: Further studies are necessary to better define the level of discordance in HER-2 or HR status between primary tumors and paired metastases. However, a biopsy of metastatic disease can be recommended, if feasible with minimal invasiveness, because treatment options might change for a significant proportion of patients

2008 - ESTIMATION OF CARDIOVASCULAR RISK IN TYPE 2 DIABETES [Abstract in Rivista]
E., Pellegrini; Simonini, M. S.; M., Maurantonio; I. M., Giannico; D'Amico, Roberto; Ganazzi, Dorval; Carulli, Lucia; Loria, Paola; Bertolotti, Marco; Carulli, Nicola
abstract

Diabetes mellitus is a major risk factor for cardiovascular (CV) events. Many algorithms have been devised to assess CV risk, some of which specific for diabetics. Most of them, however, can hardly be extrapolated to Mediterranean countries. AIM of this study was to analyze CV risk and the incidence of CV events in a local cohort of patients with type 2 diabetes. METHODS. Clinical charts of the Diabetes Clinics of Modena in the period 1991-1995 were analyzed. Patients aged 35-65 with type 2 diabetes and no previous CV disease were eligible. Global CV risk was computed according to Framingham, RISCARD, Progetto Cuore and UKPDS algorithms and compared with the actual rate of CV events over the following 10 years. RESULTS. 2416 patients were screened; 1532 of them (63.4%) were eligible on the basis of predefined criteria and completeness of data. In such population an absolute 10-yr risk rate of 14.6% was observed. When looking at the characteristics of the patients who developed a cardiovascular event compared to those who did not, we found a significant difference in the prevalence of risk factors as systolic blood pressure, age at visit, smoke, duration of diabetic disease and HbA1c. COPD and chronic heart failure also display a higher prevalence in patients with events, suggesting a possible role of these chronic conditions in developing cardiovascular disease. Interestingly, most of the subjects presenting with a CV event had a low to moderate risk estimate at the beginning; this was particularly evident with the Progetto Cuore algorithm. CONCLUSIONS. Estimation of CV risk is largely dependent on the algorithm adopted and on the baseline risk of the reference cohort. Equations designed for a specific population should be adopted. The overall performance of presently available functions is however low. Inclusion of additional risk parameters might hopefully increase the performance of such algorithms, which is presently clearly unsatisfactory. The algorithm derived from the present study will be utilized for a prospective evaluation of CV risk in our local cohort.

2008 - Evolution of Non-alcoholic Fatty Liver Disease in HIV-infected Patients: Incidence, Characteristics, and Predictors [Abstract in Atti di Convegno]
Guaraldi, Giovanni; N., Squillace; C., Stentarelli; G., Orlando; D'Amico, Roberto; Ligabue, Guido; F., Fiocchi; S., Zona; Esposito, Roberto; F., Palella
abstract

Non-alcoholic fatty liver disease (NAFLD) occurs among persons without chronic viral hepatitis or significant alcohol consumption. It presents often in the context of cardiovascular risk factors. Our objectives were to assess the incidence and predictors of NAFLD in HIV-infected HAART-experienced patients.

2008 - Magnetic resonance imaging and ultrasonography in predicting pathologic extent after preoperative chemotherapy in stage II-III breast cancer [Abstract in Rivista]
Guarneri, Valentina; Pecchi, Annarita; Torricelli, Pietro; Piacentini, Federico; A., Frassoldati; C., Mauri; R., Battista; B., Canossi; D'Amico, Roberto; Conte, Pierfranco
abstract

Introduction and aims: the main advantage of preoperative chemotherapy (PCT) is tumor down-staging, that can allow either mastectomy in large, inoperable primaries, or breast conserving surgery (BCS) for patients initially candidate to mastectomy. Therefore, an accurate measurement of residual disease after PCT is critical in the optimal surgical planning. Aim of this study is to evaluate the accuracy of breast magnetic resonance imaging (MRI) and ultrasonography (USG) in predicting the extent of breast residual disease. Patients and Methods: patients with stage II-III invasive breast tumor receiving PST and imaged with post-treatment MRI, USG or both were included; deltas were calculated as differences between the longest tumor diameter as measured by MRI and USG and the pathologic size of residual breast tumor. Differences between deltas were tested by using T test for paired data. Results: 45 patients treated with PCT in our Institution were eligible. Patients characteristics were as follows: mean age 50 yrs (range 30-70 yrs); stage IIA 31%, IIB 49%, IIIA-B: 20%. Eighty-nine % of the cases had ductal histology, 69% had ER positivity, and 24% had HER2 over-expression. The mean T size at diagnosis was 3.8 cm (range 1.5-8 cm). PCT type was anthracycline-based (24%) or anthracycline-taxane combination (76%). Forty-four patients have been evaluated after PCT by MRI, 41 by USG, 40 patients by both MRI and USG. The mean T size (range) after PCT was 2 cm (0-6.5 cm) and 1.7cm (0-5cm) as measured by MRI and USG respectively. The mean interval between breast imaging and surgery was 20 days (range 1-63). Type of surgery was mastectomy in 45% and BCS in 55% of the cases; 6 patients (13%) achieved a pathologic complete response (pCR). The mean pathologic T size was 1.98 cm (range 0-6 cm). The mean of the deltas were 0.04 (SD 1.91) and -0.19 (SD 1.53) for MRI and USG respectively (p=0.22). A complete response by MRI was observed in 9 cases: 3 cases were confirmed as pCRs; 2 cases presented with scattered microscopic residual disease. An USG complete response was observed in 8 cases (4 confirmed pCRs). Conclusion: in this series of patients, MRI and USG do not show significant differences in predicting the breast residual tumor after PCT. The major challenge for breast imaging after PCT is represented by scattered residual disease.

2008 - Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER2- positive breast cancer (Short-HER Trial; NCT00629278) [Articolo su rivista]
Guarneri, V.; Frassoldati, A.; Bruzzi, P.; D'Amico, R.; Belfiglio, M.; Molino, A.; Bertetto, O.; Cascinu, S.; Cognetti, F.; Di Leo, A.; Pronzato, P.; Crino, L.; Agostara, B.; Conte, P.
abstract

Trastuzumab, a monoclonal antibody against the HER2 receptor, is currently approved as a part of adjuvant therapy for patients with HER2-overexpressing breast tumors. The Short-HER study is a phase III randomized, multicentric Italian trial aimed at testing the optimal duration of adjuvant trastuzumab. In this trial, 2500 patients with HER2-positive breast cancer will be randomized to receive the following: (arm A, long) 4 courses of anthracycline- based chemotherapy (doxorubicin/cyclophosphamide or epidoxorubicin/cyclophosphamide) followed by 4 courses of docetaxel or paclitaxel in combination with trastuzumab, followed by 14 additional courses of trastuzumab administered every 3 weeks (for a total of 18 3-weekly doses of trastuzumab); or (arm B, short) 3 courses of 3-weekly docetaxel in combination with weekly trastuzumab (for a total of 9 weekly doses of trastuzumab) followed by 3 courses of 5-fluorouracil/epirubicin/cyclophosphamide. The primary objective is disease-free survival.

2008 - Nonalcoholic Fatty Liver Disease in HIV-Infected Patients Referred to a Metabolic Clinic: Prevalence, Characteristics, and Predictors [Articolo su rivista]
Guaraldi, Giovanni; Squillace, N.; Stentarelli, Chiara; Orlando, Gabriella; D'Amico, Roberto; Ligabue, Guido; Fiocchi, Federica; Zona, Stefano; Loria, Paola; Esposito, Roberto; Palella, F.
abstract

BACKGROUND: The prevalence and predictors of nonalcoholic fatty liver disease (NAFLD) in human immunodeficiency virus (HIV)-infected highly active antiretroviral therapy-experienced patients and the association of NAFLD with risk of cardiovascular disease and subclinical atherosclerosis are unknown. METHODS: We performed a cross-sectional observational study. NAFLD was defined by liver-spleen attenuation values of <1.1 on computed tomography in persons who had neither evidence of chronic viral hepatitis nor a significant history of alcohol consumption. RESULTS: We enrolled 225 patients; 163 (72.4%) were men. Mean (+/-SD) HIV infection duration was 145 +/- 60 months, and mean (+/-SD) body mass index (calculated as weight in kilograms divided by the square of height in meters) was 23.75 +/- 3.59. NAFLD was diagnosed in 83 patients (36.9% of the total cohort). The following variables were significantly associated with NAFLD in univariate analyses: sex, waist circumference, body mass index, cumulative exposure to nucleoside reverse-transcriptase inhibitors, visceral adipose tissue, homeostasis model assessment of insulin resistance index, serum alanine and aspartate aminotransferase levels, and ratios of total serum cholesterol to high-density lipoprotein cholesterol. Coronary artery calcium scores and a diagnosis of diabetes were not associated with NAFLD. In multivariable logistic regression analyses, factors associated (P<0.001) with NAFLD were higher serum alanine to aspartate ratio (odds ratio, 4.59; 95% confidence interval, 2.09-10.08), male sex (odds ratio, 2.49; 95% confidence interval, 1.07-5.81), greater waist circumference (odds ratio, 1.07; 95% confidence interval, 1.03-1.11), and longer nucleoside reverse-transcriptase inhibitor exposure (odds ratio, 1.12 per year of exposure; 95% confidence interval, 1.03-1.22). CONCLUSIONS: NAFLD is common among HIV-infected persons who have the traditional risk factors for NAFLD (elevations in serum alanine level, male sex, and increased waist circumference) apparent. Exposure to nucleoside reverse-transcriptase inhibitors was an independent risk factor for NAFLD, with an 11% increase in the odds ratio for each year of use.

2008 - Statistical agreement between ATPIII, IDF, EGIR, AACE metabolic syndrome classifications in HIV-infected patients and association with lipodystrophy [Abstract in Atti di Convegno]
Guaraldi, Giovanni; S., Zona; D'Amico, Roberto; N., Squillace; G., Orlando; C., Stentarelli; Esposito, Roberto
abstract

Purpose of the studyTo assess statistical agreement of metabolic syndrome (MS) ATPIII, IDF, EGIR and AACE classification in HIV-infected patients and association with body fat redistribution.MethodsCross-sectional observational study that included all consecutive HIV-infected patients seen at a metabolic clinic who were screened for MS and had a clinical and radiological lipodystrophy (LD) evaluation. Cohen's Kappa statistic was calculated to assess statistical agreement between different MS classifications. Logistic regression models were performed to identify factors associated with different MS classifications. (Tables 1 and 2.)Table 1. K of Cohen shows a low level of agreement between MS classifications.Summary of results1,348 pts were included in the analysis.Figure 1 depicts prevalence of metabolic syndrome according to different definition.ConclusionConcordance between MS classification is less than ideal. After adjusting for BMI strata, lipodystrophy phenotypes and central fat accumulation are associated with for MS diagnosis.

2008 - Statistical agreement between metabolic syndrome ATP-III, IDF, EGIR and ACE classification in HIV-infected patients and association with body fat redistribution [Abstract in Rivista]
Squillace, N.; Zona, S.; Guaraldi, Giovanni; Stentarelli, C.; D'Amico, Roberto; Mazeu, I.; Esposito, Roberto
abstract

The aim of our study is to assess K statistic of Metabolic Syndrome (MS) Adult Treatment Panel III (ATP-III), International Diabetic Federation (IDF), European Group for the study of Insulin Resistance (EGIR) and America College of Endocrinology (ACE) classificationin in HIV-infected patients and association with body fat reditribution.

2008 - Statistical agreement between ultrasound (US) and computerized tomography (CT) for non-alcoholic liver disease (NAFLD) diagnosis [Abstract in Rivista]
Stentarelli, C.; Ballestri, S.; Zona, S.; Amedeo, L.; D'Amico, Roberto; Squillace, N.; Orlando, G.; Loria, P.; Guaraldi, Giovanni
abstract

To assess the Cohen's Kappa statistic of non invasive imaging evaluations to diagnose non-alcoholic liver disease (NAFLD) by means of ultrasound (US) fatty liver index score and liver-to-spleen attenuation ratio (L/S) by computerized tomography (CT)

2008 - Systematic reviews of diagnostic test accuracy [Articolo su rivista]
Mm, Leeflang; Jj, Deeks; C., Gatsonis; Pm, Bossuyt; D'Amico, Roberto; Cochrane Diagnostic Test Accuracy Working, Group
abstract

More and more systematic reviews of diagnostic test accuracy studies are being published, but they can be methodologically challenging. In this paper, the authors present some of the recent developments in the methodology for conducting systematic reviews of diagnostic test accuracy studies. Restrictive electronic search filters are discouraged, as is the use of summary quality scores. Methods for meta-analysis should take into account the paired nature of the estimates and their dependence on threshold. Authors of these reviews are advised to use the hierarchical summary receiver-operating characteristic or the bivariate model for the data analysis. Challenges that remain are the poor reporting of original diagnostic test accuracy studies and difficulties with the interpretation of the results of diagnostic test accuracy research.

2008 - TYPE 2 DIABETES AND CARDIOVASCULAR EVENTS : STUDY OF THE AMIN RISK FACTORS IN A LOCAL POPULATION OF PATIENTS [Abstract in Rivista]
Elisa, Pellegrini; M., Sole Simonini; Mauro, Maurantonio; Iolanda M., Giannico; Carulli, Lucia; D'Amico, Roberto; Dorval, Ganazzi; Loria, Paola; Bertolotti, Marco; Carulli, Nicola
abstract

Background and aim. The aim of this study is to analyze the risk of cardiovascular events in a local cohort of patients with type 2 diabetes, and to evaluate the prognostic accuracy of four algorithms used to estimate cardiovascular risk: Framingham study, UKPDS study, Riskard study and Progetto Cuore. Method and results. We analyzed clinical charts of the Diabetes Clinics of Modena during the period 1991-1995. Patients aged 35-65 with type 2 diabetes and no previous cardiovascular disease were eligible. The incidence of new cardiovascular disease was compared with estimated rates deriving from the different functions. A stratification was obtained in subgroups at different cardiovascular risk, allowing comparison between the algorithms. The presence of heart failure and chronic obstructive pulmonary disease was also recorded. 1532 patients were eligible; women presented a worse cardiovascular risk profile. An absolute 10-yr rate of cardiovascular events of 14.9% was observed. Comparing patients with events with event-free subjects we found significant differences in systolic blood pressure, age at visit, smoke, HDL-cholesterol, duration of diabetes, HbA1c and comorbidities. Comparing the estimated risk rate according to the different functions, Italian algorithms were more consistent with observed data; however, Progetto Cuore shows underestimation of events, particularly when applied to females.Conclusions. Estimation of cardiovascular risk is dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population, including risk variables peculiar for diabetes should be adopted to increase the performance of such functions which is presently clearly unsatisfactory.

2008 - VALORE PROGNOSTICO E PREDITTIVO DI p53 NEL CARCINOMA MAMMARIO TRATTATO CON CHEMIOTERAPIA NEOADIUVANTE [Abstract in Atti di Convegno]
Piacentini, F.; Guarneri, V.; Ficarra, G.; Frassoldati, A.; D’Amico, R.; Giovannelli, S.; Maiorana, A.; Conte, Pf.
abstract

Introduzione: p53 gioca un ruolo chiave nel meccanismo di risposta della cellula a vari stress: agendo infatti come fattore di trascrizione multifunzionale, regola una serie di geni implicati nella proliferazione cellulare, apoptosi, angiogenesi e riparo di danni al DNA. Una sua mutazione si verifica in una minoranza di carcinomi mammari, mentre in altri casi sono le alterazioni dei geni target o di altri componenti regolatori a ridurre in qualche modo la capacità di p53 di reagire agli insulti cellulari. L’espressione di p53 descritta dall’immunoistochimica non necessariamente correla con le possibili mutazioni di questa oncoproteina. Il potere predittivo e prognostico di p53 nel carcinoma mammario rimane dibattuto. Pazienti e metodi: sono state incluse nella presente analisi pazienti con carcinoma mammario in stadio I-III trattate con chemioterapia primaria (TP). Sono stati valutati con metodica ICH i seguenti parametri: ER, PgR, HER2, Ki-67/MIB1, p53, EGFR. Risultati: sono state analizzate 91 pazienti, età mediana (range): 52 anni (29-73). Le caratteristiche biologiche alla diagnosi bioptica sono risultate le seguenti: recettori ormonali (ER e/o PgR) positivi, 78%; HER2+, 22%; grado 3, 57%; EGFR >/= 1%, 11%. Nel 42% dei casi si è osservata una iperespressione di p53 >/=10%. Le pazienti hanno ricevuto 4-6 cicli di TP (45% antraciclina-based; 53% antraciclina-taxani). Dopo TP, il 64% delle pazienti è stato sottoposto a mastectomia; in tutte è stata eseguita linfoadenectomia ascellare. Una risposta patologica completa (pCR) si è osservata in sei casi (6.7%). Nelle pazienti con p53>/=10% il tasso di pCR è risultato significativamente maggiore (p=0.003). p53 è stata misurata anche sul residuo tumorale dopo TP, senza osservare significative variazioni. A 5 anni la sopravvivenza libera da malattia (DFS) risulta 80% (95%CI 64;89) per le pazienti con p53 <10% e 45% (95%CI 26;62) per quelle con p53>/=10% (p=0.0018). Nei due gruppi la sopravvivenza globale (OS) a 5 anni è pari a 98% (95%CI 87;99) e a 53% (95%CI 32;91) rispettivamente (p<0.001). In analisi multivariata, le pazienti con p53>/=10% e linfonodi positivi dopo TP hanno un maggior rischio di recidiva (HR 2.93, p=0.003 e HR 3.07, p=0.022, rispettivamente). Conclusioni: nella presente analisi, l’iperespressione di p53 si è dimostrata predittiva di risposta alla TP; in particolare il tasso di pRC è risultato significativamente più elevato nei casi con p53>/=10% alla diagnosi. Tuttavia, l’overespressione di p53 è risultato un fattore prognostico negativo, sia in termini sia di DFS che di OS. Sono in corso ulteriori analisi che permetteranno, ampliando la casistica, di chiarire l’implicazione clinica di questi dati.

2007 - Amantadine for fatigue in multiple sclerosis [Articolo su rivista]
D'Amico, Roberto; Pucci, E; Branãs, P; Giuliani, G; Solari, A; Taus, C.
abstract

BACKGROUND:Fatigue is one of the most common and disabling symptoms of people with Multiple Sclerosis (MS). The effective management of fatigue has an important impact on the patient's functioning, abilities, and quality of life. Although a number of strategies have been devised for reducing fatigue, treatment recommendations are based on a limited amount of scientific evidence. Many textbooks report amantadine as a first-choice drug for MS-related fatigue because of published randomised controlled trials (RCTs) showing some benefit.OBJECTIVES:To determine the effectiveness and safety of amantadine in treating fatigue in people with MS.SEARCH STRATEGY:We searched The Cochrane MS Group Trials Register (July 2006), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 1, 2006), MEDLINE (January 1966 to July 2006), EMBASE (January 1974 to July 2006), bibliographies of relevant articles and handsearched relevant journals. We also contacted drug companies and researchers in the field.SELECTION CRITERIA:Randomised, placebo or other drugs-controlled, double-blind trials of amantadine in MS people with fatigue.DATA COLLECTION AND ANALYSIS:Three reviewers selected studies for inclusion in the review and they extracted the data reported in the original articles. We requested missing and unclear data by correspondence with the trial's principal investigator. A meta-analysis was not performed due to the inadequacy of available data and heterogeneity of outcome measures.MAIN RESULTS:Out of 13 pertinent publications, 5 trials met the criteria for inclusion in this review: one study was a parallel arms study, and 4 were crossover trials. The number of randomised participants ranged between 10 and 115, and a total of 272 MS patients were studied. Overall the quality of the studies considered was poor and all trials were open to bias. All studies reported small and inconsistent improvements in fatigue, whereas the clinical relevance of these findings and the impact on patient's functioning and health related quality of life remained undetermined. The number of participants reporting side effects during amantadine therapy ranged from 10% to 57%.AUTHORS' CONCLUSIONS:The efficacy of amantadine in reducing fatigue in people with MS is poorly documented, as well as its tolerability. It is advisable to: (1) improve knowledge on the underlying mechanisms of MS-related fatigue; (2) achieve anagreement on accurate, reliable and responsive outcome measures of fatigue; (3) perform good quality RCTs.

2007 - Cyclophosphamide for multiple sclerosis [Articolo su rivista]
LA MANTIA, L; Milanese, C; Mascoli, N; D'Amico, Roberto; WEINSTOCK GUTTMAN, B.
abstract

BACKGROUND:Multiple sclerosis is a presumed cell-mediated autoimmune disease of the central nervous system. Cyclophosphamide (CFX) is a cytotoxic and immunosuppressive agent, used in systemic autoimmune diseases. Controversial results have been reported on its efficacy in MS. We conducted a systematic review of all relevant trials, evaluating the efficacy of CFX in patients with progressive MS.OBJECTIVES:The main objective was to determine whether CFX slows the progression of MS.SEARCH STRATEGY:We searched the Cochrane MS Group Trials Register (searched June 2006), Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3 2006), MEDLINE (January 1966 to June 2006), EMBASE (January 1988 to June 2006) and reference lists of articles. We also contacted researchers in the field.SELECTION CRITERIA:Randomised controlled trials (RCTs) evaluating the clinical effect of CFX treatment in patients affected by clinically definite progressive MS.CFX had to be administered alone or in combination with adrenocorticotropic hormone (ACTH) or steroids. The comparison group had to be placebo or no treatment or the same co-intervention (ACTH or steroids)DATA COLLECTION AND ANALYSIS:Two reviewers independently decided the eligibility of the study, assessed the trial quality and extracted data. We also contacted study authors for original data.MAIN RESULTS:Of the 461 identified references, we initially selected 70: only four RCTs were included for the final analysis. Intensive immunosuppression with CFX (alone or associated with ACTH or prednisone) in patients with progressive MS compared to placebo or no treatment (152 participants) did not prevent the long-term (12, 18, 24 months) clinical disability progression as defined as evolution to a next step of Expanded Disability Status Scale (EDSS) score. However, the mean change in disability (final disability subtracted from the baseline) significantly favoured the treated group at 12 (effect size - 0.21, 95% confidence interval - 0.25 to -0.17) and 18 months (- 0.19, 95% confidence interval - 0.24 to - 0.14) but favoured the control group at 24 months (0.14, CI 0.07 to 0.21). We were unable to verify the efficacy of other schedules. Five patients died; sepsis and amenorrhea frequently occurred in treated patients (descriptive analysis).AUTHORS' CONCLUSIONS:We were unable to achieve all of the objectives specified for the review. This review shows that the overall effect of CFX (administered as intensive schedule) in the treatment of progressive MS does not support its use in clinical practice.

2007 - RISK FOR CARDIOVASCULAR EVENTS IN A LOCAL POPULATION OF DIABETIC PATIENTS [Abstract in Rivista]
Elisa, Pellegrini; Iolanda M., Giannico; Mauro, Maurantonio; D'Amico, Roberto; Dorval, Ganazzi; Augusto, Baldini; Carulli, Lucia; Bertolotti, Marco; Loria, Paola; Carulli, Nicola
abstract

AbstractBackground and aim. The aim of this study is to analyze the risk of cardiovascular events in a local cohort of patients with type 2 diabetes, and to evaluate the prognostic accuracy of four algorithms used to estimate cardiovascular risk: Framingham study, UKPDS study, Riskard study and Progetto Cuore. Method and results. We analyzed clinical charts of the Diabetes Clinics of Modena during the period 1991-1995. Patients aged 35-65 with type 2 diabetes and no previous cardiovascular disease were eligible. The incidence of new cardiovascular disease was compared with estimated rates deriving from the different functions. A stratification was obtained in subgroups at different cardiovascular risk, allowing comparison between the algorithms. 1532 patients were eligible; women presented a worse cardiovascular risk profile. An absolute 10-yr rate of cardiovascular events of 14.9% was observed. Comparing patients with events with event-free subjects we found significant differences in systolic blood pressure, age at visit, smoke, HDL-cholesterol, duration of diabetes, HbA1c and comorbidities. Comparing the estimated risk rate according to the different functions, Italian algorithms were more consistent with observed data; however, Progetto Cuore shows underestimation of events, particularly when applied to females.Conclusions. Estimation of cardiovascular risk is dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population, including risk peculiar for diabetes should be adopted to increase the performance of such functions which is presently clearly unsatisfactory.

2007 - RISK FOR CARDIOVASCULAR EVENTS IN AN ITALIAN POPULATION OF PATIENTS WITH TYPE 2 DIABETES [Abstract in Rivista]
Elisa, Pellegrini; Mauro, Maurantonio; Iolanda M., Giannico; M., Sole Simonini; Dorval, Ganazzi; Carulli, Lucia; D'Amico, Roberto; Augusto, Baldini; Loria, Paola; Bertolotti, Marco; Carulli, Nicola
abstract

Background and aim. The aim of this study is to analyze the risk of cardiovascular events in a local cohort of patients with type 2 diabetes, and to evaluate the prognostic accuracy of four algorithms used to estimate cardiovascular risk: Framingham study, UKPDS study, Riskard study and Progetto Cuore. Method and results. We analyzed clinical charts of the Diabetes Clinics of Modena during the period 1991-1995. Patients aged 35-65 with type 2 diabetes and no previous cardiovascular disease were eligible. The incidence of new cardiovascular disease was compared with estimated rates deriving from the different functions. A stratification was obtained in subgroups at different cardiovascular risk, allowing comparison between the algorithms. 1532 patients were eligible; women presented a worse cardiovascular risk profile. An absolute 10-yr rate of cardiovascular events of 14.9% was observed. Comparing patients with events with event-free subjects we found significant differences in systolic blood pressure, age at visit, smoke, HDL-cholesterol, duration of diabetes, HbA1c and comorbidities. Comparing the estimated risk rate according to the different functions, Italian algorithms were more consistent with observed data; however, Progetto Cuore shows underestimation of events, particularly when applied to females.Conclusions. Estimation of cardiovascular risk is dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population, including risk peculiar for diabetes should be adopted to increase the performance of such functions which is presently clearly unsatisfactory.

2006 - Antibiotic prophylaxis to prevent nosocomial infections in patients in intensive care units: evidence that struggle to convince practising clinicians [Articolo su rivista]
Liberati, Alessandro; D'Amico, Roberto; S., Pifferi; V., Torri; L., Brazzi; Gensini, G. F.; R., Gusinu
abstract

BACKGROUND:Pneumonia is an important cause of mortality in intensive care units. The incidence of pneumonia in such patients ranges between 7 and 40%, and the crude mortality from ventilator associated pneumonia may exceed 50%. Although not all deaths in patients with this form of pneumonia are directly attributable to pneumonia, it has been shown to contribute to mortality in intensive care units independently of other factors that are also strongly associated with such deaths.OBJECTIVES:The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care. Search strategy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2003), which contains the Acute Respiratory Infections (ARI) Group specialised trials register; MEDLINE (January 1966 to September 2003); EMBASE (January 1990 to September 2003); proceedings of scientific meetings and reference lists of articles from January 1984 to December 2002. We also contacted investigators in the field. Selection criteria. Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients. Data collection and analysis. At least two reviewers independently extracted data and assessed trial quality.RESULTS:Overall 36 trials involving 6922 people were included. There was variation in the antibiotics used, patient characteristics and risk of respiratory tract infections and mortality in the control groups. In 17 trials (involving 4295 patients) that tested a combination of topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 29% respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.35, 95% confidence interval [CI] 0.29-0.41) and total mortality (odds ratio 0.78, 95% CI 0.68-0.89) in the treated group. On average 5 patients needed to be treated to prevent one infection and 21 patients to prevent one death. In 17 trials (involving 2664 patients) that tested topical antimicrobials alone (or comparing topical plus systemic versus systemic alone) the rates of respiratory tract infections and deaths in the control groups were 30 and 26% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.52, 95% CI 0.43-0.63), but not in total mortality (odds ratio 0.97, 95% CI 0.81-1.16) in the treated group.CONCLUSIONS:A combination of topical and systemic prophylactic antibiotics reduces respiratory tract infections and overall mortality in adult patients receiving intensive care. A treatment based on the use of topical prophylaxis alone reduces respiratory infections, but not mortality. The risk of occurrence of resistance as a negative consequence of antibiotic use was appropriately explored only in the most recent trial by de Jonge, which did not show any such effect.

2006 - Prenatal education for congenital toxoplasmosis [Articolo su rivista]
Di Mario, S.; Basevi, V.; Gagliotti, C.; Spettoli, D.; Gori, G.; D'Amico, R.; Magrini, N.
abstract

This is the protocol for a review and there is no abstract. The objectives are as follows: The primary objectives of this review are to assess the efcacy of prenatal education to reduce the rate of: (1) new cases of congenital toxoplasmosis; (2) toxoplasmosis seroconversion during pregnancy. Secondary objectives are to assess the efficacy of prenatal education to increase the rate of: (1) pregnant women's knowledge on risk factors for acquiring toxoplasmosis infection; (2) pregnant women's awareness of the importance to avoid toxoplasmosis infection during pregnancy; (3) pregnant women's behavior with respect to avoidance of risk factors for toxoplasmosis infection during pregnancy. Copyright © 2006 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

2006 - Prognostic value of Dworak grade of regression (GR) in patients with rectal carcinoma treated with preoperative radiochemotherapy [Articolo su rivista]
Losi, Lorena; G., Luppi; M., Gavioli; Iachetta, Francesco; Bertolini, Federica; D'Amico, Roberto; Jovic, Gordana; F., Bertoni; Falchi, Anna Maria; Conte, Pierfranco
abstract

Preoperative radiochemotherapy improves local control in locally advanced rectal cancer; however, its role in prolonging survival is still controversial. In order to better define the subset in patients who might benefit from this multimodal treatment, we have evaluated the correlation between grade of regression (GR) to preoperative treatment and disease-free survival (DFS). METHODS: We reviewed retrospectively the surgical specimens of 106 patients with locally advanced T3/T4 N0/ M0 rectal cancer. All patients were treated preoperatively with radiotherapy and 5-fluorouracil-based regimen chemotherapy. We evaluated ypTNM stage, and tumor regression was graded using the Dworak system that varies from GR 0 (absence of regression) to GR 4 (complete regression). RESULTS: GR was as follows: GR 4, 16 patients (15%); GR 3, 25 patients (23.6%), GR 2, 30 patients (28.4%), GR 1, 32 patients (30.2%) and GR 0, 3 patients (2.8%). A significant correlation was found between GR and DFS. Three-year DFS was 100, 85, 82, 66 and 33% in GR 4, 3, 2, 1 and 0, respectively (p=0.01). DFS was significantly lower in patients with advanced stages at diagnosis and in patients without down-staging. Moreover, in postoperative stage II and III cases, GR 3 correlated with a better DFS than GR 2-0 (p=0.2 and p=0.4, respectively). CONCLUSIONS: The GR was a significant prognostic factor in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy. The pathological stage and down-staging also have prognostic value. The use of a standardized system to evaluate GR in rectal cancer can allow for comparisons between different institutions and can identify patients at worse prognosis to be treated with adjuvant therapy

2006 - Risk for cardiovascular events in a local population of diabetic patients [Abstract in Rivista]
E., Pellegrini; M., Maurantonio; D'Amico, Roberto; B., Madeo*; I. M., Giannico; D., Ganazzi; A., Baldini*; Carulli, Lucia; Loria, Paola; Bertolotti, Marco; Carulli, Nicola
abstract

Diabetes mellitus (DM) is a major risk factor for cardiovascular (CV) events. Many algorithms have been devised to assess CV risk, some of which specific for diabetics. Most of them, however, are based on data which can hardly be extrapolated to Mediterranean countries. AIM of the present study was to analyze CV risk and the incidence of CV events in a local cohort of patients with type 2 DM. METHODS. Clinical charts of two Diabetes Clinics of Modena in the period 1991-1994 were analyzed. Patients aged 35-65 with type 2 DM and no history of CV disease were eligible. Global CV risk was computed according to Framingham, RISCARD, Progetto Cuore and UKPDS algorithms and compared with the actual rate of CV events over the following 10 years. RESULTS. 774 patients were screened; 473 of them (61.1%) were eligible on the basis of predefined criteria and completeness of data. In such population an absolute 10-yr risk rate of 10.8% was observed. When comparing the estimated risk rate according to the different functions, a high degree of variability was present; Italian algorithms were more consistent with the observed data even if only 31% of patients with CV events had a risk > 20% at initial observation. CONCLUSIONS. Estimation of CV risk is largely dependent on the algorithm adopted and on the baseline risk of the reference cohort. Functions designed for a specific population should be adopted. The overall performance of such functions is however low. The algorithm derived from the present study will be utilized for a prospective evaluation of CV risk in our local cohort.

2006 - The pacifier debate [Articolo su rivista]
R., Buzzetti; D'Amico, Roberto
abstract

no abstract

2006 - Use in routine clinical practice of two commercial blood tests for diagnosis of infection with Mycobacterium tuberculosis: a prospective study [Articolo su rivista]
G., Ferrara; Losi, Monica; D'Amico, Roberto; P., Roversi; R., Piro; M., Meacci; B., Meccugni; Im, Dori; A., Andreani; Bergamini, Barbara Maria; Mussini, Cristina; F., Rumpianesi; Fabbri, Leonardo; Richeldi, Luca
abstract

BACKGROUND: Two commercial blood assays for the diagnosis of latent tuberculosis infection--T-SPOT.TB and QuantiFERON-TB Gold--have been separately compared with the tuberculin skin test. Our aim was to compare the efficacy of all three tests in the same population sample. METHODS: We did a prospective study in 393 consecutively enrolled patients who were tested simultaneously with T-SPOT.TB and QuantiFERON-TB Gold because of suspected latent or active tuberculosis. 318 patients also had results available for a tuberculin skin test. FINDINGS: Overall agreement with the skin test was similar (T-SPOT.TB kappa=0.508, QuantiFERON-TB Gold kappa=0.460), but fewer BCG-vaccinated individuals were identified as positive by the two blood assays than by the tuberculin skin test (p=0.003 for T-SPOT.TB and p<0.0001 for QuantiFERON-TB Gold). Indeterminate results were significantly more frequent with QuantiFERON-TB Gold (11%, 43 of 383) than with T-SPOT.TB (3%, 12 of 383; p<0.0001) and were associated with immunosuppressive treatments for both tests. Age younger than 5 years was significantly associated with indeterminate results with QuantiFERON-TB Gold (p=0.003), but not with T-SPOT.TB. Overall, T-SPOT.TB produced significantly more positive results (38%, n=144, vs 26%, n=100, with QuantiFERON-TB Gold; p<0.0001), and close contacts of patients with active tuberculosis were more likely to be positive with T-SPOT.TB than with QuantiFERON-TB Gold (p=0.0010). INTERPRETATION: T-SPOT.TB and QuantiFERON-TB Gold have higher specificity than the tuberculin skin test. Rates of indeterminate and positive results, however, differ between the blood tests, suggesting that they might provide different results in routine clinical practice.

2005 - Assessment of methodological quality of primary studies by systematic reviews: results of the metaquality cross sectional study. [Articolo su rivista]
MOJA, L. P.; R., TELARO; D'AMICO, Roberto; I., MOSCHETTI; L., COE; A., LIBERATI
abstract

OBJECTIVES:To describe how the methodological quality of primary studies is assessed in systematic reviews and whether the quality assessment is taken into account in the interpretation of results.DATA SOURCES:Cochrane systematic reviews and systematic reviews in paper based journals.STUDY SELECTION:965 systematic reviews (809 Cochrane reviews and 156 paper based reviews) published between 1995 and 2002.DATA SYNTHESIS:The methodological quality of primary studies was assessed in 854 of the 965 systematic reviews (88.5%). This occurred more often in Cochrane reviews than in paper based reviews (93.9% v 60.3%, P < 0.0001). Overall, only 496 (51.4%) used the quality assessment in the analysis and interpretation of the results or in their discussion, with no significant differences between Cochrane reviews and paper based reviews (52% v 49%, P = 0.58). The tools and methods used for quality assessment varied widely.CONCLUSIONS:Cochrane reviews fared better than systematic reviews published in paper based journals in terms of assessment of methodological quality of primary studies, although they both largely failed to take it into account in the interpretation of results. Methods for assessment of methodological quality by systematic reviews are still in their infancy and there is substantial room for improvement.

2005 - Early aggressive versus conservative managment on one year outcome in octogenarians patients with unstable angina and non-st-elevation myocardial infarction [Abstract in Atti di Convegno]
Sgura, Fa; Guerri, E; D'Amico, R; Chiurlia, E; Rossi, R; Leuzzi, C; Modena, Mg
abstract

Early aggressive versus conservative managment on one year outcome in octogenarians patients with unstable angina and non-st-elevation myocardial infarction

2005 - Gallstone disease in non-alcoholic fatty liver: Prevalence and associated factors [Articolo su rivista]
P., Loria; A., Lonardo; S., Lombardini; Carulli, Lucia; A., Verrone; D., Ganazzi; A., Rudilosso; D'Amico, Roberto; Bertolotti, Marco; N., Carulli
abstract

Background: Insulin resistance is a risk factors for non-alcoholic fatty liver disease (NAFLD) and for gallstone disease (GD). Aims of the present study were to assess the prevalence of and factors associated with GD in unselected patients with NAFLD. Methods: A total of 161 consecutive patients with NAFLD diagnosed through compatible ultrasonography in the absence of known etiologies of liver disease (in all patients) and/or confirmed histologically (in 61 patients), was studied. Gallstone disease was diagnosed through ultrasound scanning or on the basis of previous cholecystectomy. Anthropometric and biochemical variables and concurrent diseases were compared in 32 NAFLD-GD patients and in 129 NAFLD patients without GD (controls) according to gender. Results: The overall prevalence of GD was 19.88%, higher in female patients (P< 0.05), who were older (P < 001). The overall percentage of GD increased with age (P < 0.05). The GD patients had higher uric acid (men), total cholesterol and apolipoprotein B (apo-B) serum concentrations (women, P < 0.05); women also had a higher prevalence of hypertriglyceridemia (P < 0.05). The age-corrected odds ratio of having GD by tertiles increased significantly with increasing uric acid (men) and with increasing total cholesterol, triglycerides and apo-B (women). At univariate continuous analysis GD was associated with insulin 120 min and uric acid in male patients; and with body mass index, insulin 120 min, apo-B, total cholesterol and triglycerides in female patients. On multivariate analysis it was found that among these factors only uric acid in men and apo-B in women were independently associated with GD in NAFLD. Conclusions: The prevalence of GD in NAFLD is more elevated than reported in the general population. The factors independently associated with GD in NAFLD are different from those reported in the general population and vary according to the gender.

2005 - Headache is a risk factor for the onset of hypertension in pregnancy [Abstract in Rivista]
Facchinetti, Fabio; Nappi, Re; Marozio, L; D'Amico, Roberto; Bertozzi, L; Enrietti, M; Ornati, A; Allais, G; Benedetto, C.
abstract

2005 - Incidence and clinical impact of sterilized disease and minimal residual disease after preoperative radiochemotherapy for rectal cancer [Articolo su rivista]
Gavioli, M; Luppi, G; Losi, Lorena; Bertolini, Federica; Santantonio, M; Falchi, Anna Maria; D'Amico, Roberto; Conte, Pierfranco; Natalini, G.
abstract

In advanced rectal cancer, chemoradiation can induce downstaging until complete disappearance of the tumor or its persistence in minimal form. The complete sterilized and the minimal residual disease often are considered similar. We evaluated the specific incidence of these two conditions and analyzed their impact in terms of local recurrence, distant metastasis, and survival. METHODS: We studied 139 uT3/T4 N0/N+ rectal cancers, treated with preoperative chemoradiation and curative surgery after six to eight weeks. We evaluated ypTNM stage and tumoral regression, according to the five degrees proposed by Dworak, with special attention to 4 and 3 (sterilized and minimal residual disease). RESULTS: Tumor downstaging occurred in 65 patients (46.7 percent), including 25 sterilized lesions (17.9 percent) and 24 minimal residual disease (17.2 percent). In median follow-up of 30 months, none of the patients with sterilized disease developed local or distant recurrence. Among patients with minimal residual disease, none developed local recurrence, whereas two (8.3 percent) developed distant metastasis, and one died from disease. In patients with gross residual disease (Grade 2, 1, 0) the percentage of local recurrence was 8.8 percent, distant recurrence 26.6 percent, and 13.3 percent died from disease. The difference between three groups is statistically significant as regards local and distant recurrence. CONCLUSIONS: After preoperative therapy, the sterilized disease shows an excellent prognosis. The minimal residual disease has an important numeric incidence. Its outcome is different, with a not-negligible risk of distant recurrence. The minimal residual disease has a much better prognosis in comparison with the gross residual disease

2005 - Indirect comparisons of competing interventions [Capitolo/Saggio]
Glenny, A. M.; Altman, D. G.; F., Song; C., Sakarovitch; Deeks, J. J.; D'Amico, Roberto; M., Bradburn; Eastwood, A. J.; INTERNATIONAL STROKE TRIAL COLLABORATIVE, Group
abstract

AbstractOBJECTIVES:To survey the frequency of use of indirect comparisons in systematic reviews and evaluate the methods used in their analysis and interpretation. Also to identify alternative statistical approaches for the analysis of indirect comparisons, to assess the properties of different statistical methods used for performing indirect comparisons and to compare direct and indirect estimates of the same effects within reviews.DATA SOURCES:Electronic databases.REVIEW METHODS:The Database of Abstracts of Reviews of Effects (DARE) was searched for systematic reviews involving meta-analysis of randomised controlled trials (RCTs) that reported both direct and indirect comparisons, or indirect comparisons alone. A systematic review of MEDLINE and other databases was carried out to identify published methods for analysing indirect comparisons. Study designs were created using data from the International Stroke Trial. Random samples of patients receiving aspirin, heparin or placebo in 16 centres were used to create meta-analyses, with half of the trials comparing aspirin and placebo and half heparin and placebo. Methods for indirect comparisons were used to estimate the contrast between aspirin and heparin. The whole process was repeated 1000 times and the results were compared with direct comparisons and also theoretical results. Further detailed case studies comparing the results from both direct and indirect comparisons of the same effects were undertaken.RESULTS:Of the reviews identified through DARE, 31/327 (9.5%) included indirect comparisons. A further five reviews including indirect comparisons were identified through electronic searching. Few reviews carried out a formal analysis and some based analysis on the naive addition of data from the treatment arms of interest. Few methodological papers were identified. Some valid approaches for aggregate data that could be applied using standard software were found: the adjusted indirect comparison, meta-regression and, for binary data only, multiple logistic regression (fixed effect models only). Simulation studies showed that the naive method is liable to bias and also produces over-precise answers. Several methods provide correct answers if strong but unverifiable assumptions are fulfilled. Four times as many similarly sized trials are needed for the indirect approach to have the same power as directly randomised comparisons. Detailed case studies comparing direct and indirect comparisons of the same effect show considerable statistical discrepancies, but the direction of such discrepancy is unpredictable.CONCLUSIONS:Direct evidence from good-quality RCTs should be used wherever possible. Without this evidence, it may be necessary to look for indirect comparisons from RCTs. However, the results may be susceptible to bias. When making indirect comparisons within a systematic review, an adjusted indirect comparison method should ideally be used employing the random effects model. If both direct and indirect comparisons are possible within a review, it is recommended that these be done separately before considering whether to pool data. There is a need to evaluate methods for the analysis of indirect comparisons for continuous data and for empirical research into how different methods of indirect comparison perform in cases where there is a large treatment effect. Further study is needed into when it is appropriate to look at indirect comparisons and when to combine both direct and indirect comparisons. Research into how evidence from indirect comparisons compares to that from non-randomised studies may also be warranted. Investigations using individual patient data from a meta-analysis of several RCTs using different protocols and an evaluation of the impact of choosing different binary effect measures for the inverse variance method would also be useful.

2005 - Outcome reporting bias in government-funded RCT's [Articolo su rivista]
P. L., Moja; I., Moschetti; D'Amico, Roberto
abstract

no abstract

2005 - Renal safety and efficacy of intravenous bisphosphonates in patients with skeletal metastases treated for up to ten years [Articolo su rivista]
Guarneri, Valentina; S., Donati; M., Nicolini; S., Giovannelli; D'Amico, Roberto; Conte, Pierfranco
abstract

Introduction. Bisphosphonates (BPs) delay the onset or reduce the incidence of skeletal complications in patients with bone metastases. However, there are few data on the renal safety and activity of i.v. BPs beyond 2 years of administration. Materials and Methods. We retrospectively analyzed serum creatinine (SCr) levels and skeletal-related events (SREs) in cancer patients receiving i.v. BPs for >= 24 months. All patients received 90 mg pamidronate every 3-4 weeks. Pre- and post-treatment SCr levels and the peak levels attained were recorded. A notable SCr increase was defined as: an increase > 0.5 mg/dl for patients with baseline SCr < 1.4 mg/dl; an increase > 1 mg/dl for patients with baseline SCr > 1.4 mg/dl; or doubling over baseline. The following parameters were also analyzed: the proportion of patients with at least one SRE, the distribution of each type of SRE, the time to first SRE, and the skeletal morbidity rate (SMR). Results. Fifty-seven patients with bone metastases resulting from breast cancer (BC) (n = 48), multiple myeloma (n = 7), renal cell carcinoma (n = 1), and prostate cancer (n = 1) were evaluated. The median age at the start of treatment was 57 years (range, 27-81); 25% of the patients were > 70 years old. Forty-three patients received pamidronate then switched to zoledronic acid. The median overall duration of BP administration was 34 months (range, 24+ to 131+), with a median duration of zoledronic acid therapy of 25 months (range, 2-40). Twenty-seven of 48 BC patients received different chemotherapy regimens (median number of lines, 2; range, 1-6). The median SCr levels were: baseline, 0.82 mg/dl (range, 0.4-1.4); time of analysis, 0.89 mg/dl (0.4-2); highest level, 1.0 mg/dl (0.5-2). A notable SCr increase was observed in seven patients (12.2%; all grade 1). Twenty-six patients (45.6%) experienced SREs after starting BP treatment. The median time to first SRE was 911 days (95% confidence interval, 731; 1,023). The SMR was 0.20 events per year. Ten patients ceased treatment because of: an SCr level of 2 mg/dl (n = 1) physician decision (n = 6) and jaw osteonecrosis (n = 3). Ten patients died of progressive disease. Conclusion. i.v. BPs are safe and active during prolonged treatment administration, and renal function is maintained in patients receiving multiple cytotoxic therapies. Jaw osteonecrosis occurred in 5% of the study population, and its causal relationship with BP treatment requires further observation and study.

2005 - Routine hospital use of a new commercial whole blood interferon-gamma assay for the diagnosis of tuberculosis infection [Articolo su rivista]
Ferrara, G; Losi, M; Meacci, M; Meccugni, B; Piro, R; Roversi, P; Bergamini, Barbara Maria; D'Amico, Roberto; Marchegiano, P; Rumpianesi, F; Fabbri, Lm; Richeldi, Luca
abstract

Rationale: Interferon (IFN)-gamma blood tests may improve the current level of diagnostic accuracy for tuberculosis infection. The Quanti-FERON-TB Gold (QFT-Gold) has been used in selected populations and shows higher specificity than the tuberculin skin test (TST). Objective: To evaluate the QFT-Gold test in unselected patients and assess the level of agreement with the TST. Methods: The test has been routinely performed on whole blood samples in our microbiology laboratory for 8 months. Demographic, clinical, and microbiological data have been collected and correlated to the QFT-Gold results. Measurements and Main Results: Of 318 patients tested, 68 (21.4%) gave an indeterminate (low positive mitogen control) QFT-Gold result. Indeterminate results were significantly overrepresented in patients with a negative TST (28.9% vs. 6.6% in TST-positive patients; p < 0.0001, chi(2) test) and were more frequent in patients receiving immunosuppressive therapies than in those who were not receiving such treatments (odds ratio, 3.35; 95% confidence interval, 1.84-6.08; p < 0.0001). After excluding indeterminate results, the concordance between QFT-Gold and TST was significantly lower in Bacille Calmette-Guerin-vaccinated individuals (41.5%) than in nonvaccinated individuals (80.3%) (p < 0.0001). In 11 patients with active tuberculosis (5 culture-confirmed), QFT-Gold provided more positive results than the TST (66.7% vs. 33.3%; p = 0.165). Conclusions: The QFT-Gold test is feasible in routine hospital use for the diagnosis of tuberculosis infection. As with the TST, immunosuppression may negatively affect the test's performance, with a significant rate of indeterminate results in the most vulnerable population.

2005 - Subclinical coronary artery atherosclerosis in patients with erectile dysfunction [Articolo su rivista]
E., Chiurlia; D'Amico, Roberto; C., Ratti; Ar, Granata; Romagnoli, Renato; Modena, Maria Grazia
abstract

OBJECTIVES The purpose of our study was to assess the prevalence and extent of coronary artery atherosclerosis in asymptomatic patients with vascular erectile dysfunction (ED). BACKGROUND An association between ED and ischemic heart disease has been suggested, but it is unknown if it represents a marker of subclinical coronary atherosclerosis. METHODS We studied 70 consecutive patients with vascular ED, evaluated by penile Doppler, and 73 control subjects with no history of coronary artery disease. We measured traditional coronary risk factors, circulating levels of C-reactive protein (CRP), endothelial function by ultrasound of brachial artery, and coronary artery calcification by multi-slice computed tomography. RESULTS The patients and the control group were similar for age, race, and coronary risk score. Patients with ED had significantly higher high-sensitivity C-reactive protein levels (2.62 vs. 1.03 mg/l, p < 0.001). Flow-mediated dilation of the brachial artery was more impaired in patients with ED than in controls (2.36 vs. 3.92, p < 0.001). Coronary artery calcification was more frequent in individuals with ED than in control subjects (p = 0.01). Multiple logistic regression analysis showed that patients with ED had an overall odds ratio of 3.68 for having calcium score above the 75th percentile, compared to the controls. CONCLUSIONS Coronary atherosclerosis is more severe in patients with vascular ED; ED predicts the presence and extent of subclinical atherosclerosis independent of traditional risk factors for cardiovascular disease. Thus, ED may be considered an additional, early warning sign of coronary atherosclerosis.

2005 - The relationship between headache and preeclampsia: a case-control study [Articolo su rivista]
Facchinetti, Fabio; G., Allais; D'Amico, Roberto; C., Benedetto; Volpe, Annibale
abstract

OBJECTIVES: Pregnancy-induced hypertension with proteinuria (preeclampsia-PE) is linked to increased vascular reactivity, increased vasoconstrictors, endothelial damage and platelet hyperaggregation, which are also typical features of migraine patients. Thus, we investigated the association between headache and PE. METHODS: In a case-control study, we evaluated the occurrence of primary headache forms in 75 women with a recent history of PE. Seventy-five controls were selected from women having uneventful pregnancy at term. Both groups were matched for age and parity. Subjects' headache history was evaluated by using an ad hoc structured questionnaire. The International Headache Society criteria for primary headaches were applied to diagnose the specific form of headache. RESULTS: In PE cases, gestational age at parturition was 34.2+/-3.8 weeks and birthweight was 1820+/-746 g, whereas in controls they were 39.3+/-1.5 weeks and 3365+/-437 g, respectively (P < 0.01). Sixty-six (44%) subjects suffered from headache. Headache was significantly more frequent in PE (47/75) than in controls (19/75), OR 4.95 (95% CI, 2.47-9.92). Migraine without aura was more frequently present in cases than in controls while episodic tension-type headache was equally distributed among groups. Fifty-two patients met the criteria of severe PE. The number of patients suffering from headache was significantly higher in severe patients (39 cases, 75%) than in those with moderate PE (8 cases, 34.8%), OR = 5.63 (95% CI, 1.97-16.03). With respect to controls, PE patients reported a more frequent onset at menarche, more menstrually related attacks and an increased rate of improvement during pregnancy. CONCLUSION: This study shows that there is a strong association between migraine history and PE development, namely with the severe form of PE.

2004 - Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care [Articolo su rivista]
Liberati, Alessandro; D'Amico, Roberto; Pifferi, V; Torri, V; Brazzi, L.
abstract

BACKGROUND:Pneumonia is an important cause of mortality in intensive care units. The incidence of pneumonia in such patients ranges between 7% and 40%, and the crude mortality from ventilator associated pneumonia may exceed 50%. Although not all deaths in patients with this form of pneumonia are directly attributable to pneumonia, it has been shown to contribute to mortality in intensive care units independently of other factors that are also strongly associated with such deaths.OBJECTIVES:The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care.SEARCH STRATEGY:We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (issue 3, 2003), which contains the Acute Respiratory Infections (ARI) Group specialised trials register; MEDLINE (January 1966 to September 2003); EMBASE (January 1990 to September 2003); proceedings of scientific meetings and reference lists of articles from January 1984 to December 2002. We also contacted investigators in the field.SELECTION CRITERIA:Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients.DATA COLLECTION AND ANALYSIS:At least two reviewers independently extracted data and assessed trial quality.MAIN RESULTS:Overall 36 trials involving 6922 people were included. There was variation in the antibiotics used, patient characteristics and risk of respiratory tract infections and mortality in the control groups. In 17 trials (involving 4295 patients) that tested a combination of topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 29% respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.35, 95% confidence interval 0.29 to 0.41) and total mortality (odds ratio 0.78, 95% confidence interval 0.68 to 0.89) in the treated group. On average 5 patients needed to be treated to prevent one infection and 21 patients to prevent one death. In 17 trials (involving 2664 patients) that tested topical antimicrobials alone (or comparing topical plus systemic versus systemic alone) the rates of respiratory tract infections and deaths in the control groups were 30% and 26% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.52, 95% confidence interval 0.43 to 0.63) but not in total mortality (odds ratio 0.97, 95% confidence interval 0.81 to 1.16) in the treated group.REVIEWER'S CONCLUSIONS:A combination of topical and systemic prophylactic antibiotics reduces respiratory tract infections and overall mortality in adult patients receiving intensive care. A treatment based on the use of topical prophylaxis alone reduces respiratory infections but not mortality. The risk of occurrence of resistance as a negative consequence of antibiotic use was appropriately explored only in the most recent trial by de Jonge which did not show any such effect.

2004 - Comparing warfarin with asprin after biological aortic valve replacement: a prospective study [Articolo su rivista]
T., Gherli; A., Colli; C., Fragnito; F., Nicolini; B., Borello; S., Saccani; D'Amico, Roberto; C., Beghi
abstract

BACKGROUND: Patients with prosthetic heart valves have a higher risk of developing valve thrombosis and arterial thromboembolism. Antithrombotic therapy in the early postoperative period after biological aortic valve replacement (BAVR) is controversial. The American College of Cardiology/American Heart Association and European Society of Cardiology guidelines recommend the use of warfarin for the first 3 months after BAVR, although the American College Chest Physician guidelines suggest that the recommendations are very weak and that the risk/benefit is unclear. This prospective study investigated the efficacy of postoperative warfarin compared with aspirin in patients after aortic valve replacement. METHODS AND RESULTS: Patients undergoing BAVR between 2001 and 2002 received 2 antithrombotic therapies: 141 patients received warfarin for the first 3 months, and 108 patients received only aspirin. The major end points evaluated were the rate of cerebral ischemic events, bleeding, and survival. There were 3 and 5 postoperative cerebral ischemic events between 24 hours and 3 months for patients treated with aspirin and warfarin, respectively. After 3 months, the incidence of cerebral ischemic events did not differ between the 2 groups. The rate of major bleeding events, the stroke-free survival, and the overall survival rates were not statistically significant between the warfarin and aspirin groups. CONCLUSIONS: There seem to be no advantages in performing early anticoagulation therapy compared with a low-antiplatelet regimen with regard to early cerebral ischemic events, bleeding, and survival. Currently there is no evidence to support the fact that warfarin is more effective than aspirin.

2004 - Impact of preoperative testing on ophthalmologic and systemic outcomes in cataract surgery [Articolo su rivista]
Cavallini, Gian Maria; P., Saccarola; D'Amico, Roberto; A., Gasparin; L., Campi
abstract

PURPOSE. To evaluate the incidence of ophthalmologic and systemic complications in patients who undergo cataract surgery without preoperative tests compared to subjects undergoing cataract surgery preceded by preoperative tests. METHODS. The randomized controlled study included 1276 consecutive patients admitted to the Institute of Ophthalmology of the University of Modena and Reggio Emilia for cataract surgery. The patients were randomly divided into two groups: 638 were assigned not to undergo preoperative evaluation based on routine medical tests and electrocardiograms; the other 638 underwent preoperative evaluation based on said tests. Ophthalmologic and systemic complications were assessed intraoperatively and 1 month after surgery. RESULTS. Eleven intraoperative complications occurred in the group without preoperative tests and eight in the group with preoperative tests; at 1 month six complications were recorded in the group without tests and five in the group with tests. Systemic adverse events occurred intra operatively in four patients, whereas no systemic adverse event was recorded at 1 month in either group. No statistically significant differences were observed between the two groups. CONCLUSIONS. The findings of this study have broad applicability, because the sample is representative of the population existing in numerous social and healthcare settings; they are of value for administrative purposes, because they may be taken as reference in resource allocation plans; and they have medicolegal implications, as the resulting conduct of healthcare providers is supported by a rigorous scientific study.

2004 - Outcome, incidence, and timing of infections in small bowel/multivisceral transplantation [Articolo su rivista]
Guaraldi, Giovanni; S., Cocchi; N., De Ruvo; M., Codeluppi; Masetti, Michele; C., Venturelli; D'Amico, Roberto; M., Pecorari; Esposito, Roberto; A. D., Pinna
abstract

The objective of this study was to assess the timing, incidence, and outcome of infections in patients with small bowel/multivisceral transplants (SB/MV Tx). A 180-day follow-up was obtained on 13 SB/MV patients transplanted from January 2001 to June 2002. Fifty-six documented infections were observed. By Kaplan-Meier analysis for time to infection, most of which were of bacterial origin (more than 86%), revealed most events to have occurred within the first month post-Tx. Viral infections were equally distributed after the 30th postoperative day.

2003 - Amantadine for fatigue in multiple sclerosis. [Articolo su rivista]
C., Taus; G., Giuliani; E., Pucci; D'Amico, Roberto; A., Solari
abstract

BACKGROUND:Fatigue is one of the most common and disabling symptoms of people with Multiple Sclerosis (MS). The effective management of fatigue has an important impact on the patient's functioning, abilities, and quality of life. Although a number of strategies have been devised for reducing fatigue, treatment recommendations are based on a limited amount of scientific evidence. Many textbooks report amantadine as a first-choice drug for MS-related fatigue because of published randomised controlled trials (RCTs) showing some benefit. We performed a systematic review in order to gather existing evidence, and contribute to the topic.OBJECTIVES:To determine the effectiveness and safety of amantadine in reducing fatigue in people with MS.SEARCH STRATEGY:RCTs of amantadine were identified using MEDLINE, EMBASE, bibliographies of relevant articles, personal communications, manual searches of relevant journals, and information from drug companies.SELECTION CRITERIA:Randomised, placebo or other drugs-controlled, double-blind trials of amantadine in MS people with fatigue.DATA COLLECTION AND ANALYSIS:Three reviewers selected studies for inclusion in the review and they extracted the data reported in the original articles. Missing and unclear data were requested by correspondence with the trial's principal investigator. A meta-analysis was not performed due to the inadequacy of available data, heterogeneity of outcome measures.MAIN RESULTS:Out of twelve pertinent publications, four trials met the criteria for inclusion in this review: one study was a parallel arms study, and 3 were crossover trials. The number of randomised participants ranged between 10 and 115, and a total of 236 MS patients had been studied. Overall the quality of the studies considered was poor and all trials were open to bias. All studies reported small and inconstant improvements in fatigue, whereas the clinical relevance of these findings and the impact on patient's functioning and health related quality of life remains undetermined. The number of participants reporting side effects during amantadine therapy ranged from 10% to 57%, without significant differences between treatment and placebo. The side effects reported were generally mild, and discontinuation of the drug due to side effects occurred in less than 10% of the patients.REVIEWER'S CONCLUSIONS:Amantadine treatment is overall well tolerated, however its efficacy in reducing fatigue in people with MS is poorly documented and there is insufficient evidence to make recommendations to guide prescribing. It is advisable to (a) improve knowledge on the underlying mechanisms of MS-related fatigue; (b) achieve an agreement on accurate, reliable and responsive outcome measures of fatigue; (c) perform good quality RCTs.

2003 - Evaluating non-randomised intervention studies [Capitolo/Saggio]
Deeks, Jj; Dinnes, J; D'Amico, Roberto; Sowden, Aj; Sakarovitch, C; Song, F; Petticrew, M; Altman, Dg; INTERNATIONAL STROKE TRIAL COLLABORATIVE, Group; European, Carotid; SURGERY TRIAL COLLABORATIVE, Group
abstract

Objectives: To consider methods and related evidence for evaluating bias in non-randomised intervention studies.DATA SOURCES:Systematic reviews and methodological papers were identified from a search of electronic databases; handsearches of key medical journals and contact with experts working in the field. New empirical studies were conducted using data from two large randomised clinical trials.METHODS:Three systematic reviews and new empirical investigations were conducted. The reviews considered, in regard to non-randomised studies, (1) the existing evidence of bias, (2) the content of quality assessment tools, (3) the ways that study quality has been assessed and addressed. (4) The empirical investigations were conducted generating non-randomised studies from two large, multicentre randomised controlled trials (RCTs) and selectively resampling trial participants according to allocated treatment, centre and period.RESULTS:In the systematic reviews, eight studies compared results of randomised and non-randomised studies across multiple interventions using meta-epidemiological techniques. A total of 194 tools were identified that could be or had been used to assess non-randomised studies. Sixty tools covered at least five of six pre-specified internal validity domains. Fourteen tools covered three of four core items of particular importance for non-randomised studies. Six tools were thought suitable for use in systematic reviews. Of 511 systematic reviews that included non-randomised studies, only 169 (33%) assessed study quality. Sixty-nine reviews investigated the impact of quality on study results in a quantitative manner. The new empirical studies estimated the bias associated with non-random allocation and found that the bias could lead to consistent over- or underestimations of treatment effects, also the bias increased variation in results for both historical and concurrent controls, owing to haphazard differences in case-mix between groups. The biases were large enough to lead studies falsely to conclude significant findings of benefit or harm. Four strategies for case-mix adjustment were evaluated: none adequately adjusted for bias in historically and concurrently controlled studies. Logistic regression on average increased bias. Propensity score methods performed better, but were not satisfactory in most situations. Detailed investigation revealed that adequate adjustment can only be achieved in the unrealistic situation when selection depends on a single factor.CONCLUSIONS:Results of non-randomised studies sometimes, but not always, differ from results of randomised studies of the same intervention. Non-randomised studies may still give seriously misleading results when treated and control groups appear similar in key prognostic factors. Standard methods of case-mix adjustment do not guarantee removal of bias. Residual confounding may be high even when good prognostic data are available, and in some situations adjusted results may appear more biased than unadjusted results. Although many quality assessment tools exist and have been used for appraising non-randomised studies, most omit key quality domains. Healthcare policies based upon non-randomised studies or systematic reviews of non-randomised studies may need re-evaluation if the uncertainty in the true evidence base was not fully appreciated when policies were made. The inability of case-mix adjustment methods to compensate for selection bias and our inability to identify non-randomised studies that are free of selection bias indicate that non-randomised studies should only be undertaken when RCTs are infeasible or unethical. Recommendations for further research include: applying the resampling methodology in other clinical areas to ascertain whether the biases described are typical; developing or refining existing quality assessment tools for non-randomised studies; investigating how quality assessments of non-randomised studies can be incorporated into revi

2003 - Interferons in relapsing remitting multiple sclerosis [1] (multiple letters) [Articolo su rivista]
Goodin, D. S.; Kappos, L.; Kesselring, J.; Paty, D.; Arnason, B.; Li, D.; Traboulsee, A.; Freedman, M.; King, J.; Oger, J.; Sharief, M.; Hartung, H. -P.; Filippini, G.; Munari, L.; Ebers, G. C.; D'Amico, R.; Rice, G. P. A.; Rudick, R. A.; Cookfair, D. L.; Griffin, J.; Hauser, S.; Piantadosi, S.; Kolar, O. J.; Bauerle, J. A.; Lee, H.
abstract

2003 - Interferons in relapsing remitting multiple sclerosis: a systematic review [Articolo su rivista]
Filippini, G; Munari, L; Incorvaia, B; Ebers, Gc; Polman, C; D'Amico, Roberto; Rice, Gp
abstract

BACKGROUND:Recombinant interferons have been approved by many national regulatory agencies for treatment of relapsing remitting multiple sclerosis, but widespread discussion continues about their true effectiveness, benefits, side-effects, and costs.METHODS:With the Cochrane Collaboration methodology, we reviewed all published, randomised, placebo-controlled trials of recombinant interferons undertaken in patients with relapsing remitting multiple sclerosis between 1993 and 2002. Our primary aim was to find out whether recombinant interferons reduced the number of patients who had clinical exacerbations and disease progression, compared with placebo.FINDINGS:The seven trials that met our criteria included 1215 randomised patients: data from 667 (55%) were available for analysis at 1 year's and from 919 (76%) at 2 years' follow-up. Interferon seemed to reduce the number of patients who had exacerbations during the first year of treatment (relative risk 0.73, 95% CI 0.54-0.99), but results at 2 years' follow-up were not robust and were difficult to interpret because of the many dropouts. Although the number of patients who had exacerbations (0.81, 0.74-0.89) or progressed (0.70, 0.55-0.88) during the first 2 years fell significantly in the protocol analysis, results were inconclusive after sensitivity analyses for exacerbations (1.11, 0.73-1.68) and disease progression (1.31, 0.60-2.89). Data were insufficient to establish whether steroid use and admissions to hospital were reduced in the interferon group. Similarly, MRI outcome data could not be analysed quantitatively. Side-effects were common, and acute toxic effects adversely affected quality of life.INTERPRETATION:Recombinant interferons slightly reduce the number of patients who have exacerbations during first year of treatment. Their clinical effect beyond 1 year is uncertain and new trials are needed to assess their long-term effectiveness and side-effects.

2002 - New drug treatment for asthma: clinical versus statistical significance [Articolo su rivista]
R., Buzzetti; D'Amico, Roberto; A., Addis
abstract

no abstract

2002 - Sindromi steatosiche non alcoliche. Stato dell'arte e progressi nella ricerca. [Articolo su rivista]
Loria, P.; Lonardo, A.; Lombardini, S.; Leonardi, F.; Carulli, Lucia; Borsatti, A.; Verrone, A. M.; Canedi, I.; Ricchi, M.; Ganazzi, D.; Bagni, A.; Bertolottti, M.; Rudilosso, A.; D`amico, R.; Neri, P.; Pulvirenti, M.; De Micheli, E.; Carulli, Nicola
abstract

review della letteratura su sindromi steatosiche

2002 - determinants of lt levels and fibrosis in non alcoholic fatty liver disease [Abstract in Rivista]
Loria, P; Lonardo, A; D'Amico, Roberto; Leonardi, F; Borsatii, A; Verrone, A; Carulli, Lucia; Rudilosso, A; Ricchi, M; Bertolotti, Marco; Ganazzi, D. Carulli N.
abstract

The study suggets that as yet incomplety understood factors might account for the progression from steatosis to steatohepatitis and that predictors of fibrosis in our unselected population with non alcoholic fatty liver disease are differet compared to other studies.

2001 - Antibiotics for preventing respiratory tract infections in adults receiving intensive care [Articolo su rivista]
D'Amico, Roberto
abstract

2001 - Effect of arterial revascularis on survival: a systematic review of studies comparing bilateral and single internal mammary arteries [Articolo su rivista]
Dp, Taggart; D'Amico, Roberto; Dg, Altman
abstract

BACKGROUND:Coronary artery bypass grafting (CABG) is the commonest major operation in most developed countries. A single internal mammary artery (IMA) graft has proven survival benefits, but the additional survival advantage of a second graft is unknown. We systematically reviewed published studies of bilateral versus single IMA grafts in CABG to assess any differences in survival.METHODS:We identified from Medline all studies in which single and bilateral IMA grafts were compared. We included studies in which at least 100 patients in each group had been followed up for at least 4 years. We assessed study quality on the basis of patient selection, comparability of intervention groups (especially for age, sex, ventricular function, and diabetes status), outcome assessment, and completeness of follow-up. Our primary outcome was survival. Estimates of treatment effect (single versus bilateral) expressed as hazard ratios were pooled across studies.FINDINGS:None of the studies was a randomised trial, but nine cohort studies met our inclusion criteria. Seven studies yielded survival data for meta-analysis, and included 15962 patients: 11269 single and 4693 bilateral IMA grafts. The bilateral group had significantly better survival than the single group (hazard ratio for death 0.81; 95% CI 0.70-0.94). Exclusion of methodologically weak studies improved survival rates with bilateral IMA grafts.INTERPRETATION:Because no study was a randomised trial, our results are more uncertain than is indicated by the 95% CI. Nevertheless, bilateral IMA grafts seem to give better survival rates than single grafts.

2001 - Effect of arterial revascularisation on survival: A systematic review of studies comparing bilateral and single internal mammary arteries [Articolo su rivista]
Taggart, D. P.; D'Amico, R.; Altman, D. G.
abstract

Background: Coronary artery bypass grafting (CABG) is the commonest major operation in most developed countries. A single internal mammary artery (IMA) graft has proven survival benefits, but the additional survival advantage of a second graft is unknown. We systematically reviewed published studies of bilateral versus single IMA grafts in CABG to assess any differences in survival. Methods: We identified from Medline all studies in which single and bilateral IMA grafts were compared. We included studies in which at least 100 patients in each group had been followed up for at least 4 years. We assessed study quality on the basis of patient selection, comparability of intervention groups (especially for age, sex, ventricular function, and diabetes status), outcome assessment, and completeness of follow-up. Our primary outcome was survival. Estimates of treatment effect (single versus bilateral) expressed as hazard ratios were pooled across studies. Findings: None of the studies was a randomised trial, but nine cohort studies met our inclusion criteria. Seven studies yielded survival data for meta-analysis, and included 15 962 patients: 11 269 single and 4693 bilateral IMA grafts. The bilateral group had significantly better survival than the single group (hazard ratio for death 0.81; 95% CI 0.70-0.94). Exclusion of methodologically weak studies improved survival rates with bilateral IMA grafts. Interpretation: Because no study was a randomised trial, our results are more uncertain than is indicated by the 95% CI. Nevertheless, bilateral IMA grafts seem to give better survival rates than single grafts.

2001 - Influence of methodological quality on study conclusions [3] (multiple letters) [Articolo su rivista]
Liberati, Alessandro; D'Amico, Roberto; Brazzi, L; Pifferi, S.
abstract

no abstract

2001 - Interferon in relapsing -remitting multiple sclerosis [Articolo su rivista]
Gp, Rice; B., Incorvaia; L., Munari; G., Ebers; C., Polman; D'Amico, Roberto; G., Filippini
abstract

BACKGROUND:Recombinant interferons have been shown to suppress both the clinical and magnetic resonance imaging (MRI) measures of disease activity in patients with relapsing remitting multiple sclerosis (RRMS).OBJECTIVES:We performed a Cochrane review of all randomised, placebo-controlled trials of recombinant interferons in RRMS.SEARCH STRATEGY:Of 208 articles identified by a predefined search strategy, seven of these, reporting randomised trials, met all the selection criteria and form the subject of this review.SELECTION CRITERIA:The trials selected were double-blind, placebo-controlled, randomised trials of RRMS patients who were treated with recombinant interferon, given by the subcutaneous or the intramuscular route.DATA COLLECTION AND ANALYSIS:The quality of the trials was variable, with substantial methodological inadequacies in allocation concealment, high proportion and incomplete description of dropouts and failure to adhere to the principles of intention to treat analysis. The baseline characteristics were largely comparable between treatment and placebo groups. Because of prominent treatment-associated side effects, which could be easily identified by patients, these trials could be considered as single blind rather than double-blind.MAIN RESULTS:Although 1215 patients were included in this review, only 919 (76%) contributed to the results concerning exacerbations and progression of the disease at two years. Specifically interferon significantly reduced the occurrence of exacerbations (RR =0.80, 95% CI [0.73,0.88], p<0.001) and progression of the disease (RR =0.69, 95% CI [0.55,0.87], p= 0.002) two years after randomisation. However, the correct assignment of dropouts was essential to the demonstration of efficacy, most conspicuously concerning the effect of the drug on disease progression. If interferon-treated patients who dropped out were deemed to have progressed (worst case scenario) the significance of these effects was lost (RR = 1.31, CI [0.60,2.89], p = 0.5). The evolution in magnetic resonance imaging (MRI) technology in the decade in which these trials were performed and different reporting of data among trials made it impossible to perform a quantitative analysis of the MRI results. Both clinical and laboratory side effects reported in the trials were more frequent in treated patients than in controls. No information was available regarding side effects and adverse events after two years of follow-up. The impact of interferon treatment (and its side effects) on the quality of life of patients was not reported in any trial included in this review.REVIEWER'S CONCLUSIONS:The efficacy of interferon on exacerbations and disease progression in patients with relapsing remitting MS was modest after one and two years of treatment. It was not possible to conduct a quantitative analysis beyond two years. Longer follow-up and more uniform reporting of clinical and MRI outcomes among these trials might have allowed for a more convincing conclusion.

2001 - Sudden infant death syndrome and sleeping position [2] [Articolo su rivista]
Buzzetti, R.; D'Amico, R.; Liberati, A.
abstract

2000 - Antibiotic prophylaxis in intensive care units: meta-analyses versus clinical practice [Articolo su rivista]
Liberati, Alessandro; D'Amico, Roberto; S., Pifferi S; E., Telaro
abstract

OBJECTIVE: At least 7 meta-analyses (MA) have been published since 1991 on the effectiveness of antibiotic prophylaxis in Intensive care units (ICU) patients, but controversy still remains about the overall effectiveness and risk-benefits profile of the treatment. This paper aims to summarise available data on effectiveness and discuss reasons why the controversy is still open and possible directions for future research. DESIGN: Review of available published MA on the effectiveness of various regimens of antibiotic prophylaxis with particular emphasis on the results of the individual patient data analysis published in 1998. SETTING: MA or randomised control trials (RCTs), published and unpublished, conducted anywhere in the world. PATIENTS AND PARTICIPANTS: Unselected adult ICU populations included in studies, published and unpublished, comparing different forms of antibiotic prophylaxis. MAIN OUTCOME MEASURE: Respiratory tract infections (RTIs) - however defined in individual studies - and total mortality. DATA SOURCES: General information from the 7 MAs published between 1991 and 1999 and detailed information from the MA published in the British Medical Journal in 1998 that reported data on 5727 patients enrolled in 33 RCTs; access to individual patients data could be obtained from 25 of 33 RCTs and allowed a confirmatory individual patient MA on 4343 patients. RESULTS: Pooled estimates from 16 RCTs (including 3361 patients) testing the effect of the topical and systemic antibiotic combination indicates a significant reduction of both RTIs (OR=0.35, 95% CI=0.29-0.41) and total mortality (OR=0.80, 95% CI=0.69-0.93). Five and 23 patients need to be treated to prevent one infection and one death, respectively, using this treatment. Pooled data from the 17 RCTs (including 2366 patients) testing the effect of a regimen based on topical antimicrobials indicated a statistically significant reduction in RTIs (OR=0.57, 95%CI=0.46-0.69) but not in total mortality (OR=1.01; 95% CI=0.84-1.22). Individual patient data analyses confirmed these results. CONCLUSIONS: After over 30 RCTs and seven MAs, there is strong evidence that antibiotic prophylaxis can reduce both RTIs and total mortality in ICUs patients in a statistically and clinically significant way. Concerns about the possible occurrence of antimicrobial resistance are not supported by available data but cannot, at the same time, be ruled out due to methodologic inadequacies of the studies carried out so far. Whether new trials are needed, and how they should be designed to answer the question of the potential for antibiotic resistance following widespread use of the treatment, are now the main issues to be settled. Convening an international panel of clinical experts and methodologists could be appropriate, in order to explore the best way to resolve the controversy that seems to be preventing the widespread use of a treatment that the best analysis of available data now indicates is effective.

2000 - Antibiotics for preventing respiratory tract infections in adults receiving intensive care [Articolo su rivista]
Liberati, Alessandro; D'Amico, Roberto; S., Pifferi; C., Leonetti; V., Torri; L., Brazzi; A., Tinazzi
abstract

BACKGROUND:Pneumonia is an important cause of mortality in intensive care units. The incidence of pneumonia in such patients ranges between 7% and 40%, and the crude mortality from ventilator associated pneumonia may exceed 50%. Although not all deaths in patients with this form of pneumonia are directly attributable to infections, it has been shown to contribute to mortality in intensive care units independently of other factors that are also strongly associated with such deaths.OBJECTIVES:The objective of this review was to assess the effects of antibiotics for preventing respiratory tract infections and overall mortality in adults receiving intensive care.SEARCH STRATEGY:We searched Medline, the Cochrane Acute Respiratory Infections Group trials register, proceedings of scientific meetings and reference lists of articles from January 1984 to December 1999. We also contacted investigators in the field.SELECTION CRITERIA:Randomised trials of antibiotic prophylaxis for respiratory tract infections and deaths among adult intensive care unit patients.DATA COLLECTION AND ANALYSIS:Investigators were contacted for additional information. At least two reviewers independently extracted data and assessed trial quality.MAIN RESULTS:Overall 33 trials involving 5727 people were included. There was variation in the antibiotics used, patient characteristics and risk of respiratory tract infections and mortality in the control groups. In 16 trials (involving 3361 patients) that tested a combination of topical and systemic antibiotic, the average rates of respiratory tract infections and deaths in the control group were 36% and 30% respectively. There was a significant reduction of both respiratory tract infections (odds ratio 0.35, 95% confidence interval 0.29 to 0.41) and total mortality (odds ratio 0.80, 95% confidence interval 0.69 to 0.93) in the treated group. On average 5 patients needed to be treated to prevent one infection and 23 patients to prevent one death. In 17 trials (involving 2366 patients) that tested topical antimicrobials the rates of respiratory tract infections and deaths in the control groups were 28% and 26% respectively. There was a significant reduction of respiratory tract infections (odds ratio 0.56, 95% confidence interval 0.46 to 0.68) but not in total mortality (odds ratio 1.01, 95% confidence interval 0.84 to 1.22) in the treated group.REVIEWER'S CONCLUSIONS:A combination of topical and systemic prophylactic antibiotics can reduce respiratory tract infections and overall mortality in adult patients receiving intensive care. The design of the trials included in this systematic review does not allow to assess whether or not the treatment leads to antimicrobial resistance. Trials with different design are warranted to reliably address this question.

2000 - Meta-analysis of clinical trials with copolymer 1 in multiple sclerosis [Articolo su rivista]
L., La Mantia; C., Milanese; D'Amico, Roberto
abstract

Glatiramer acetate (copolymer 1) was licensed in the USA in 1996 for the treatment of relapsing-remitting multiple sclerosis. In order to assess its efficacy, a meta-analysis of all randomized controlled trials was performed. Two double-blind studies, accounting for a total number of 299 patients, contribute to this analysis. Patients undergoing the treatment have decreased probability of relapse at 12 months (OR 0.17, 95% CI 0.05-0.51, p = 0.002) and of unsustained progression of disability at 24 and 35 months (OR 0.57, 95% CI 0. 34-0.95, p = 0.031, and OR 0.50, 95% CI 0.28-0.90, p = 0.019). These data suggest that glatiramer acetate represents an alternative to interferon treatment in relapsing-remitting multiple sclerosis. However, further evidence of efficacy is required to justify its use in clinical practice.

2000 - One model, several results: the paradox of the Hosmer-Lemeshow goodness-of-fit test for the logistic regression model [Articolo su rivista]
G., Bertolini; D'Amico, Roberto; D., Nardi; A., Tanazzi; G., Apolone
abstract

BACKGROUND:The Hosmer-Lemeshow test, used extensively to assess the fit of the logistic regression model, is performed by several statistical packages. Recent studies have shown some problems in the use of this test when ties are present. These problems were attributed merely to the test implementation.METHODS:We analysed the order of the observations as an alternative explanation of the problem of ties. Using a data-set of 1393 intensive care unit (ICU) patients we performed the Hosmer-Lemeshow test with all possible subjects dispositions.RESULTS:We obtained about one million different P values, ranging from 0.01 to 0.95.DISCUSSION:It is already known that when the Hosmer-Lemeshow goodness-of-fit test is performed with a number of covariate patterns lower than the number of subjects, its result may be inaccurate. We showed that the extent of this problem could be relevant under particular conditions. We also suggest a strategy for estimating the extent of the problem and subsequent interpretation.

1999 - Artificial nutrition in the critical patient: a useful thing? [Articolo su rivista]
G., Bertolini; C., Minelli; S., Pifferi; D'Amico, Roberto
abstract

No abstract available

1999 - Numbers needed to treat derived from meta-analysis [Articolo su rivista]
Charlton, B. G.; Hopayian, K.; Mcgough, J.; D'Amico, R.; Deeks, J. J.; Altman, D. G.; Moore, A.; Mcquay, H.
abstract

1999 - Numbers needed to treat derived from meta-analysis. Length of follow up is poorly reported [Articolo su rivista]
D'Amico, Roberto; Jj, Deeks; Dg, Altman
abstract

No abstract available

1998 - Antibiotic prophylaxis can lead to contamination with Clostridium difficile - Reply [Articolo su rivista]
D'Amico, Roberto; Pifferi, S; Liberati, Alessandro
abstract

Authors' replyEDITOR---Unlike Sanderson, we find it interesting rather than ironic that our review was in the same issue of the House of Lords' report that was aimed at stimulating critical thinking against generalised fears of antimicrobial resistance. Critically ill patients undergoing ventilation are at high risk of pneumonia and death, and the issue whether or not they should be routinely treated with antimicrobials deserves great attention.We accessed data on individual patients, which allowed us to ascertain that most patients in all trials were treated with antimicrobials at some point during their stay in an intensive care unit, regardless of the initial policy of the unit. The question is thus no longer whether, but rather when, they should be treated---immediately, as a policy, or only once their infection becomes clinically evident.

1998 - Antibiotic prophylaxis in intensive therapy. Results of a systematic review of the literature and their implications for clinical practice [Articolo su rivista]
Liberati, Alessandro; D'Amico, Roberto
abstract

no abstract

1998 - Effectiveness of antibiotic prophylaxis in critically ill adult patients: systematic review of randomised controlled trials [Articolo su rivista]
D'Amico, Roberto; S., Pifferi; C., Leonetti; V., Torri; A., Tinazzi A; Liberati, Alessandro
abstract

OBJECTIVE: To determine whether antibiotic prophylaxis reduces respiratory tract infections and overall mortality in unselected critically ill adult patients. DESIGN: Meta-analysis of randomised controlled trials from 1984 and 1996 that compared different forms of antibiotic prophylaxis used to reduce respiratory tract infections and mortality with aggregate data and, in a subset of trials, data from individual patients. SUBJECTS: Unselected critically ill adult patients; 5727 patients for aggregate data meta-analysis, 4343 for confirmatory meta-analysis with data from individual patients. MAIN OUTCOME MEASURES: Respiratory tract infections and total mortality. RESULTS: Two categories of eligible trials were defined: topical plus systemic antibiotics versus no treatment and topical preparation with or without a systemic antibiotic versus a systemic agent or placebo. Estimates from aggregate data meta-analysis of 16 trials (3361 patients) that tested combined treatment indicated a strong significant reduction in infection (odds ratio 0.35; 95% confidence interval 0.29 to 0.41) and total mortality (0.80; 0.69 to 0.93). With this treatment five and 23 patients would need to be treated to prevent one infection and one death, respectively. Similar analysis of 17 trials (2366 patients) that tested only topical antibiotics indicated a clear reduction in infection (0.56; 0.46 to 0.68) without a significant effect on total mortality (1.01; 0.84 to 1.22). Analysis of data from individual patients yielded similar results. No significant differences in treatment effect by major subgroups of patients emerged from the analyses. CONCLUSIONS: This meta-analysis of 15 years of clinical research suggests that antibiotic prophylaxis with a combination of topical and systemic drugs can reduce respiratory tract infections and overall mortality in critically ill patients. This effect is significant and worth while, and it should be considered when practice guidelines are defined.

1998 - Effectiveness of antibiotic prophylaxis in critically ill patients [Articolo su rivista]
Sanderson, P. J.; Allaouchiche, B.; Jaumain, H.; Chassard, D.; Leung, D.; D'Amico, R.; Pifferi, S.; Liberati, A.
abstract

1998 - Effectiveness of antibiotic prophylaxis in critically ill patients (multiple letters) [11] [Articolo su rivista]
Sanderson, P. J.; Allaouchiche, B.; Jaumain, H.; Chassard, D.; Leung, D.; D'Amico, R.; Pifferi, S.; Liberati, A.
abstract

1998 - Predicting outcome in the intensive care unit using scoring systems: is new better? A comparison of SAPS and SAPS II in a cohort of 1,393 patients. GiViTi Investigators (Gruppo Italiano per la Valutazione degli interventi in Terapia Intensiva). Simplified Acute Physiology Score [Articolo su rivista]
G., Bertolini; D'Amico, Roberto; G., Apolone; A., Cattaneo; A., Ravizza; G., Iapichino; Rm, Melotti; L., Brazzi
abstract

OBJECTIVE: This study sought to compare the performance of the old and new versions of the Simplified Acute Physiology Score, SAPS and SAPS II, in classifying patients according to the risk of hospital mortality. METHODS: To compare the performance of the two systems, measures of association between the scores and observed mortality were adopted, together with discrimination (area under the Receiver Operating Characteristics curve) and calibration (goodness-of-fit statistics) estimates. Subjects were 1,393 eligible patients recruited during 1 month in 1994. The outcome measure was vital status at hospital discharge. RESULTS: SAPS II was associated more strongly with hospital mortality than the earlier version. SAPS II also had better discrimination ability than SAPS (area under Receiver Operating Characteristics curve 0.80 versus 0.74) and predicted an overall number of deaths (416.5) closer to the observed figure (475) than SAPS (267.7). Conversely, neither SAPS nor SAPS II fitted our data. Both P values derived from goodness-of-fit statistics were lower than 0.05. CONCLUSIONS: SAPS II offers a real improvement compared with SAPS in its ability to explain hospital mortality, but its standard parameters do not fit our data from Italy. The role and impact of potential determinants of this lack of fit, such as random errors and confounders related to casemix and/or quality of care should be clarified before this scoring system be used outside formal research projects. Special caution is suggested when SAPS II is adopted to predict mortality to compare intensive care unit performance across different countries and systems of care.

1998 - Profilassi antibiotica in terapia intensiva. I risultati delle revisioni sistematiche della letteratura e loro implicazioni per la pratica e la ricerca clinica [Articolo su rivista]
Liberati, A.; D'Amico, R.
abstract

1998 - Review: Prophylactic antibiotics reduce mortality in critically ill adults [Articolo su rivista]
D'Amico, R.; Pifferi, S.; Leonetti, C.; Miller, D. M.; Liberati, A.
abstract

1997 - Meta-analysis of clinical trials with Interferon β and copolymerl in multiple sclerosis [Articolo su rivista]
La Mantia, L.; Eoli, M.; Salmaggi, A.; Torri, V.; D'Amico, R.; Liberati, M. C.
abstract

1996 - The performance of SAPS II in a cohort of patients admitted to 99 Italian ICUs: results from GiViTi. Gruppo Italiano per la Valutazione degli interventi in Terapia Intensiva [Articolo su rivista]
G., Apolone; G., Bertolini; D'Amico, Roberto; G., Iapichino; A., Cattaneo; G., De Salvo; Rm, Melotti
abstract

OBJECTIVE:To assess the validity of SAPS II (new Simplified Acute Physiology Score) in a cohort of patients admitted to a large sample of Italian intensive care units (ICU).DESIGN AND SETTING:The ability of the SAPS II scoring system to predict the probability of hospital mortality was assessed with calibration and discrimination measures obtained using published coefficients. A new logistic regression equation was then developed and further formal calibration and discrimination measures were estimated for the customized model.PATIENTS:From the 2202 consecutive patients recruited during a 1-month period in 99 ICUs, a total of 1393 patients were included in this validation study.RESULTS:When the parameters based on the standard model were applied, the expected probability of mortality did not fit those actually observed in the cohort (p < 0.001), although it showed satisfactory discrimination (area under the receiver operating characteristic curve = 0.80). Such lack of fit yields an overall under prediction of mortality (observed/expected ratio = 1.14) that reflects a uniform pattern across a preselected set of subgroups. Customization allowed new mortality estimates to be calculated, with satisfactory calibration (p = 0.82) and a more uniform pattern across subgroups.CONCLUSIONS:SAPS II maintained its validity in an independent sample of patients recruited in a large network of Italian ICUs only after appropriate adaptation (first-level customization). Whether the determinants of this relatively poor performance are related to differences in unmeasured case-mix, methods of application, or quality of care delivered is a matter for discussion that cannot be solved with the data presently available. However, these findings suggest that caution is warranted before implementing the standard SAPS II scoring system parameters outside formal research projects.

Università degli studi di Modena e Reggio Emilia

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