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Pancreatic Neoplasms: HELP
Articles by Maria Rinzivillo
Based on 22 articles published since 2009
(Why 22 articles?)
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Between 2009 and 2019, Maria Rinzivillo wrote the following 22 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Digestive neuroendocrine neoplasms: A 2016 overview. 2016

Merola, Elettra / Rinzivillo, Maria / Cicchese, Noemi / Capurso, Gabriele / Panzuto, Francesco / Delle Fave, Gianfranco. ·Department of Digestive and Liver Disease, S. Andrea Hospital, II Medical School of "Sapienza" University of Rome, Italy. · Department of Digestive and Liver Disease, S. Andrea Hospital, II Medical School of "Sapienza" University of Rome, Italy. Electronic address: gianfranco.dellefave@uniroma1.it. ·Dig Liver Dis · Pubmed #27212431.

ABSTRACT: Digestive neuroendocrine neoplasms (DNENs) have an incidence of 2.39 per 100,000 inhabitants per year, and a prevalence of 35 cases per 100,000; the gap between these rates is to be referred to the relatively long survival that characterizes the majority of these tumors, which can be thus considered as chronic oncological diseases. Up to 80% of patients are stage IV since the first diagnosis, presenting a 5-yr overall survival rate of 35%-55% and a twice higher mortality than limited disease. DNENs express somatostatin receptors in more than 80% of cases, detected through immunohistochemistry or functional imaging tests (FITs). This feature identifies patients who may benefit from "cold" somatostatin analogs (SSAs) or peptide receptors radionuclide therapy, although SSAs are sometimes used also with a negative uptake at FITs. The therapeutic options have been recently increased after the identification of molecular pathways involved in DNENs pathogenesis, and the subsequent use of targeted therapies (i.e., Everolimus and Sunitinib) for these neoplasms. This review offers an overview about pancreatic and small bowel NENs, critically underlining the issues that still need to be clarified and the future perspectives to be investigated.

2 Review Novel molecular targets for the treatment of gastroenteropancreatic endocrine tumors: answers and unsolved problems. 2012

Capurso, Gabriele / Fendrich, Volker / Rinzivillo, Maria / Panzuto, Francesco / Bartsch, Detlef K / Delle Fave, Gianfranco. ·Digestive and Liver Disease Unit, S. Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University of Rome at S. Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy. gianfranco.dellefave@uniroma1.it. ·Int J Mol Sci · Pubmed #23344019.

ABSTRACT: As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the multi-target antiangiogenetic agent Sunitinib, have been shown to be effective and thus have been approved by the FDA for treatment of pancreatic endocrine tumors. However, there is little data on the primary resistance to targeted agents on these tumors. The goals of the present review are to elucidate the possible advantage of combined treatments in overcoming induced resistances, and to identify biomarkers able to predict clinical efficacy. Moreover, the role of interesting targets for which a strong biological rationale exists, and specific inhibitors are available, such as the Src Family Kinases and the Hedgehog Pathway, are discussed. There is now need for more preclinical studies on cell lines and animal models to provide a stronger preclinical background in this field, as well as clinical trials specifically comparing one targeted therapy with another or combining different targeted agents.

3 Review Role of resection of the primary pancreatic neuroendocrine tumour only in patients with unresectable metastatic liver disease: a systematic review. 2011

Capurso, Gabriele / Bettini, Rossella / Rinzivillo, Maria / Boninsegna, Letizia / Delle Fave, Gianfranco / Falconi, Massimo. ·Digestive and Liver Disease Unit, II School of Medicine, 'Sapienza' University of Rome, Rome, Italy. ·Neuroendocrinology · Pubmed #21358176.

ABSTRACT: BACKGROUND: Surgery remains the only curative option for pancreatic neuroendocrine tumours (PNETs), but its indication is limited by metastatic disease in most patients. Indication for removing the primary lesion only in the setting of unresectable liver disease is controversial. The present systematic review aims at determining the potential bene- fits (survival, progression-free survival) or harms (morbidity, mortality) of surgical resection of the primary lesion only in patients with PNETs and unresectable metastases. METHODS: Medline was queried for studies reporting the outcome of PNET patients with unresectable liver metastases whenever there was an explicit comparison between resection of the primary lesion only ('active treatment') and no resection ('non-active treatment'). The primary outcome was survival; possible secondary outcomes were progression-free survival, treatment-related mortality and morbidity, and relief of symptoms. RESULTS: Only 3 cohort studies found were eligible and analysed; no meta-analysis could be performed. The number of patients undergoing 'active treatment' varied from 16 to 20, with a percentage ranging from 17 to 39% of cohorts. Survival was longer in patients who received 'active treatment' in 2 studies, and the 5-year survival rate also seemed higher, without significant complications. DISCUSSION: Available data suggest a possible benefit of resection of the primary lesion only in this setting. However, a bias towards a more aggressive surgical approach in patients with a better performance status or less advanced disease seems likely, and no conclusion can be drawn except for the need of randomised trials. We calculated that such a trial would require at least 118 patients per arm.

4 Clinical Trial Real-world study of everolimus in advanced progressive neuroendocrine tumors. 2014

Panzuto, Francesco / Rinzivillo, Maria / Fazio, Nicola / de Braud, Filippo / Luppi, Gabriele / Zatelli, Maria Chiara / Lugli, Francesca / Tomassetti, Paola / Riccardi, Ferdinando / Nuzzo, Carmen / Brizzi, Maria Pia / Faggiano, Antongiulio / Zaniboni, Alberto / Nobili, Elisabetta / Pastorelli, Davide / Cascinu, Stefano / Merlano, Marco / Chiara, Silvana / Antonuzzo, Lorenzo / Funaioli, Chiara / Spada, Francesca / Pusceddu, Sara / Fontana, Annalisa / Ambrosio, Maria Rosaria / Cassano, Alessandra / Campana, Davide / Cartenì, Giacomo / Appetecchia, Marialuisa / Berruti, Alfredo / Colao, Annamaria / Falconi, Massimo / Delle Fave, Gianfranco. ·Digestive and Liver Disease, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy; Unit of Gastrointestinal and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Oncology and Hematology, Policlinico di Modena, Italy; Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Departments of Endocrinology and Oncologia Medica, Università Cattolica del S. Cuore, Rome, Italy; Departments of Medical and Surgical Sciences and Medical Oncology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; Oncology, Antonio Cardarelli Hospital, Naples, Italy; Division of Medical Oncology and Endocrinology Unit, Regina Elena National Cancer Institute Rome, IRCCS, Rome, Italy; Oncology, San Luigi Gonzaga Hospital, Orbassano, Torino, Italy; Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy; Oncology, Fondazione Poliambulanza, Brescia, Italy; Oncology, Istituto Oncologico Veneto, Padova, Italy; Departments of Medical Oncology and Pancreatic Surgery, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy; Oncology, S. Croce e Carle Hospital, Cuneo, Italy; Department of Medical Oncology A, IRCCS AOU San Martino-IST, Genova, Italy; Oncologia Medica 1, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy; Oncologia, Spedali Civili di Brescia, University of Brescia, Brescia, Italy. · Digestive and Liver Disease, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy; Unit of Gastrointestinal and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy; Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Oncology and Hematology, Policlinico di Modena, Italy; Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; Departments of Endocrinology and Oncologia Medica, Università Cattolica del S. Cuore, Rome, Italy; Departments of Medical and Surgical Sciences and Medical Oncology, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; Oncology, Antonio Cardarelli Hospital, Naples, Italy; Division of Medical Oncology and Endocrinology Unit, Regina Elena National Cancer Institute Rome, IRCCS, Rome, Italy; Oncology, San Luigi Gonzaga Hospital, Orbassano, Torino, Italy; Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy; Oncology, Fondazione Poliambulanza, Brescia, Italy; Oncology, Istituto Oncologico Veneto, Padova, Italy; Departments of Medical Oncology and Pancreatic Surgery, AOU Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy; Oncology, S. Croce e Carle Hospital, Cuneo, Italy; Department of Medical Oncology A, IRCCS AOU San Martino-IST, Genova, Italy; Oncologia Medica 1, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy; Oncology, Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Milan, Italy; Oncologia, Spedali Civili di Brescia, University of Brescia, Brescia, Italy gianfranco.dellefave@uniroma1.it. ·Oncologist · Pubmed #25117065.

ABSTRACT: Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs.

5 Article Biliary Stone Disease in Patients with Neuroendocrine Tumors Treated with Somatostatin Analogs: A Multicenter Study. 2019

Brighi, Nicole / Panzuto, Francesco / Modica, Roberta / Gelsomino, Fabio / Albertelli, Manuela / Pusceddu, Sara / Massironi, Sara / Lamberti, Giuseppe / Rinzivillo, Maria / Faggiano, Antongiulio / Spallanzani, Andrea / Ferone, Diego / Prinzi, Natalie / Rossi, Roberta Elisa / Annibale, Bruno / Colao, Anna Maria / Campana, Davide. ·NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy. · Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Digestive Disease Unit, Sant'Andrea University Hospital, ENETS Center of Excellence, Rome, Italy. · Clinical Medicine and Surgery Department - Federico II University, Naples, Italy. · Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy. · Endocrinology Department (DiMi), San Martino University Hospital, Genova, Italy. · Department of Medical Oncology, Fondazione IRCCS Istituto Tumori Milano, ENETS Center of Excellence, Milan, Italy. · Gastroenterology and Endoscopy Department, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy. · Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Bologna, Italy. · Department of Experimental Medicine, Sapienza University, Rome, Italy. · NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy davide.campana@unibo.it. · Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Bologna, Italy. ·Oncologist · Pubmed #31694893.

ABSTRACT: BACKGROUND: Somatostatin analogs (SSAs) are the mainstay of neuroendocrine tumor (NET) treatment. Biliary stone disease is reported as a common side effect of SSAs, with a frequency ranging from 10% to 63%. Studies on SSA-treated patients for acromegaly report an increased incidence of biliary stone disease compared with the general population, whereas data on patients with NETs are few. Guidelines are based on weak evidence, thus resulting in conflicting recommendations. The aim of the study is to evaluate biliary stone disease incidence, complications, and risk factors in a large population of SSA-treated patients with NETs. MATERIALS AND METHODS: A retrospective analysis of a prospectively collected database was performed. Patients with a diagnosis of NET in seven dedicated centers from 1995 to 2017 were included at the time of SSA start. RESULTS: A total of 754 SSA-treated patients were evaluated. Patients with history of cholecystectomy or with known biliary stone disease were excluded; 478 patients were included. Among them, 118 patients (24.7%) received prophylactic ursodeoxycholic acid (UDCA). During the study period, 129 patients (27.0%) developed biliary stone disease; of them, 36 (27.9%) developed biliary complications. On multivariate analysis, primary gastrointestinal (GI)-NET (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were independent risk factors for biliary stone disease. CONCLUSION: We report a high incidence of biliary stone disease particularly in GI-NET or GI surgery. UDCA prophylaxis does not seem to have a protective role. Our data suggest that all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy; no conclusion could be drawn on the indication of prophylactic cholecystectomy in patients with primary pancreatic or thoracic NET for whom abdominal surgery is not planned. IMPLICATIONS FOR PRACTICE: The results of this study confirm an increased rate of gallstones development and related complications in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointestinal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA-related biliary stone disease.

6 Article Competitive Testing of the WHO 2010 versus the WHO 2017 Grading of Pancreatic Neuroendocrine Neoplasms: Data from a Large International Cohort Study. 2018

Rindi, Guido / Klersy, Catherine / Albarello, Luca / Baudin, Eric / Bianchi, Antonio / Buchler, Markus W / Caplin, Martyn / Couvelard, Anne / Cros, Jérôme / de Herder, Wouter W / Delle Fave, Gianfranco / Doglioni, Claudio / Federspiel, Birgitte / Fischer, Lars / Fusai, Giuseppe / Gavazzi, Francesca / Hansen, Carsten P / Inzani, Frediano / Jann, Henning / Komminoth, Paul / Knigge, Ulrich P / Landoni, Luca / La Rosa, Stefano / Lawlor, Rita T / Luong, Tu V / Marinoni, Ilaria / Panzuto, F / Pape, Ulrich-Frank / Partelli, Stefano / Perren, Aurel / Rinzivillo, Maria / Rubini, Corrado / Ruszniewski, Philippe / Scarpa, Aldo / Schmitt, Anja / Schinzari, Giovanni / Scoazec, Jean-Yves / Sessa, Fausto / Solcia, Enrico / Spaggiari, Paola / Toumpanakis, Christos / Vanoli, Alessandro / Wiedenmann, Bertram / Zamboni, Giuseppe / Zandee, Wouter T / Zerbi, Alessandro / Falconi, Massimo. ·Institute of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italyguido.rindi@unicatt.it. · Service of Biometry and Clinical Epidemiology, Research Department, and IRCCS Fondazione Policlinico San Matteo, Pavia, Italy. · Pathology Unit, San Raffaele Scientific Institute, Milan, Italy. · Department of Oncology, Cancer Campus, Villejuif, France. · Department of Endocrinology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italy. · Department of Surgery, University Hospital Heidelberg, Neu Heidelberg, Germany. · Neuroendocrine Tumour Unit, Centre for Gastroenterology, London, United Kingdom. · Department of Pathology, Hopital Beaujon, Paris ENETS Center of Excellence, Clichy, France. · Section Endocrinology, Department of Internal Medicine, Erasmus University Medical Center and and Erasmus MC Cancer Institute Rotterdam, Rotterdam ENETS Center of Excellence, Rotterdam, The Netherlands. · Digestive and Liver Disease Unit, Sant'Andrea University Hospital, Roma ENETS Center of Excellence, Rome, Italy. · Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen ENETS Center of Excellence, Copenhagen, Denmark. · Department of Surgery, University College, Royal Free Hospital, London ENETS Center of Excellence, London, United Kingdom. · Pancreatic Surgery, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, Milan, Italy. · Department of Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen ENETS Center of Excellence, Copenhagen, Denmark. · Institute of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italy. · Department of Hepatology and Gastroenterology, Charité, Campus Virchow Klinikum and Charite Mitte, University Medicine Berlin, Berlin ENETS Center of Excellence, Berlin, Germany. · Institute of Pathology, Stadtspital Triemli, Zurich, Switzerland. · Department of Surgery and Oncology, General and Pancreatic Surgery, The Pancreas Institute, Verona ENETS Center of Excellence, Verona, Italy. · Department of Pathology, Ospedale di Circolo, Università dell'Insubria, Varese, Italy. · Section of Pathology and ARC-Net Research Centre, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona ENETS Center of Excellence, Verona, Italy. · Department of Pathology, University College, Royal Free Hospital, London ENETS Center of Excellence, London, United Kingdom. · Institute of Pathology, University of Bern, Bern, Switzerland. · Pancreatic Surgery Unit, San Raffaele Scientific Institute, Milan, Italy. · Department of Pathology, Marche Polytechnic University, Ancona, Italy. · Department of Gastroenterology and Pancreatology, Hopital Beaujon, Paris ENETS Center of Excellence, Clichy, France. · Department of Medical Oncology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma-Università Cattolica del Sacro Cuore, Roma ENETS Center of Excellence, Rome, Italy. · Department of Medical Biology and Pathology, Cancer Campus, Villejuif, France. · Department of Molecular Medicine, University of Pavia, Pavia, Italy. · Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, Milan, Italy. · Department of Pathology, Sacro Cuore-Don Calabria Hospital, Negrar, Italy. ·Neuroendocrinology · Pubmed #30300897.

ABSTRACT: BACKGROUND: The World Health Organization (WHO) and the American Joint Cancer Committee (AJCC) modified the grading of pancreatic neuroendocrine neoplasms from a three-tier (WHO-AJCC 2010) to a four-tier system by introducing the novel category of NET G3 (WHO-AJCC 2017). OBJECTIVES: This study aims at validating the WHO-AJCC 2017 and identifying the most effective grading system. METHOD: A total of 2,102 patients were enrolled; entry criteria were: (i) patient underwent surgery; (ii) at least 2 years of follow-up; (iii) observation time up to 2015. Data from 34 variables were collected; grading was assessed and compared for efficacy by statistical means including Kaplan-Meier method, Cox regression analysis, Harrell's C statistics, and Royston's explained variation in univariable and multivariable analyses. RESULTS: In descriptive analysis, the two grading systems demonstrated statistically significant differences for the major category sex but not for age groups. In Cox regression analysis, both grading systems showed statistically significant differences between grades for OS and EFS; however, no statistically significant difference was observed between the two G3 classes of WHO-AJCC 2017. In multivariable analysis for the two models fitted to compare efficacy, the two grading systems performed equally well with substantially similar optimal discrimination and well-explained variation for both OS and EFS. The WHO-AJCC 2017 grading system retained statistically significant difference between the two G3 classes for OS but not for EFS. CONCLUSIONS: The WHO-AJCC 2017 grading system is at least equally performing as the WHO-AJCC 2010 but allows the successful identification of the most aggressive PanNET subgroup. Grading is confirmed as probably the most powerful tool for predicting patient survival.

7 Article Heterogeneity of Duodenal Neuroendocrine Tumors: An Italian Multi-center Experience. 2018

Massironi, Sara / Campana, Davide / Partelli, Stefano / Panzuto, Francesco / Rossi, Roberta Elisa / Faggiano, Antongiulio / Brighi, Nicole / Falconi, Massimo / Rinzivillo, Maria / Delle Fave, Gianfranco / Colao, Anna Maria / Conte, Dario. ·Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. sara.massironi@policlinico.mi.it. · Department of Medical and Surgical Sciences, Bologna University St. Orsola-Malpighi Polyclinic Hospital, Bologna, Italy. · Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. · Digestive and Liver Diseases Department, University "La Sapienza" of Rome Sant'Andrea Hospital, Rome, Italy. · Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. · Division of Endocrinology, Department of Clinical Medicine and Surgery, University "Federico II" of Naples, Naples, Italy. ·Ann Surg Oncol · Pubmed #30054824.

ABSTRACT: BACKGROUND: The optimal management of duodenal neuroendocrine neoplasms (dNENs) is unclear, and endoscopic resection is increasingly performed instead of surgery. METHODS: This is a retrospective analysis of patients with histologically confirmed diagnosis of dNENs, managed at five Italian tertiary referral Centers in Italy. RESULTS: From 2000 to 2017, 108 patients (69 males, 39 females, median age 59.5 years) were included in this study. Seventy-one patients had G1, 21 G2, 4 G3 dNENs (12 Ki-67 not available). Fifty-four patients showed metastases at diagnosis, and 20 patients developed metachronous metastases. Thirty patients had a functioning dNEN (14 metastatic). Fifty-seven patients had the dNEN surgically resected, 16 endoscopically, 23 metastatic, received medical therapy + surgery or endoscopy. Seven patients underwent liver-directed therapies, and one patient had PRRT. Median OS was 187 months. During a median follow-up of 76 months, 20 patients died (19 of disease-related causes). At Cox's multivariate proportional hazard regression, grading and age were the only variables independently related to OS. Median PFS was 170 months. Grading and staging at the initial diagnosis were independently related to PFS. No differences in terms of OS and PFS were observed between patients treated surgically or endoscopically. CONCLUSIONS: dNENs prognosis may be highly variable. These tumors can be metastatic in up to 50% of cases at the time of first diagnosis and can develop metastases thereafter. Functioning neoplasms express high metastatic potential. Nuclear imaging should be performed to exclude distant metastases in all dNENs. Endoscopy and surgery play a primary role in the management of the disease. Further prospective studies are needed.

8 Article Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms. 2018

Obazee, Ofure / Capurso, Gabriele / Tavano, Francesca / Archibugi, Livia / De Bonis, Antonio / Greenhalf, William / Key, Tim / Pasquali, Claudio / Milanetto, Anna Caterina / Hackert, Thilo / Fogar, Paola / Lico, Valbona / Dervenis, Christos / Lawlor, Rita T / Landoni, Luca / Gazouli, Maria / Zambon, Carlo Federico / Funel, Niccola / Strobel, Oliver / Jamroziak, Krzysztof / Cantu, Cinzia / Malecka-Panas, Ewa / Landi, Stefano / Neoptolemos, John P / Basso, Daniela / Talar-Wojnarowska, Renata / Rinzivillo, Maria / Andriulli, Angelo / Canzian, Federico / Campa, Daniele. ·Genomic Epidemiology Group, German Cancer Research Centre (DKFZ), Heidelberg, Germany. · Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy. · Division of Gastroenterology and Research Laboratory, San Giovanni Rotondo, Italy. · Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. · Pancreatic and Digestive Endocrine Surgery - Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Padova, Italy. · Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Im Neuenheimer Feld, Heidelberg, Germany. · Department of Laboratory Medicine, University-Hospital of Padova, Padova, Italy. · Department of Surgical Oncology and Hepatobiliary Surgery, Metropolitan General Hospital, Pireas, Greece. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. · Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. · Department of Medicine - DIMED, University of Padova, Padova, Italy. · Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. · Department of Hematology, Medical University of Lodz, Lodz, Poland. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Biology, University of Pisa, Pisa, Italy. ·Carcinogenesis · Pubmed #29868886.

ABSTRACT: -- No abstract --

9 Article Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues. 2018

Pusceddu, Sara / Vernieri, Claudio / Di Maio, Massimo / Marconcini, Riccardo / Spada, Francesca / Massironi, Sara / Ibrahim, Toni / Brizzi, Maria Pia / Campana, Davide / Faggiano, Antongiulio / Giuffrida, Dario / Rinzivillo, Maria / Cingarlini, Sara / Aroldi, Francesca / Antonuzzo, Lorenzo / Berardi, Rossana / Catena, Laura / De Divitiis, Chiara / Ermacora, Paola / Perfetti, Vittorio / Fontana, Annalisa / Razzore, Paola / Carnaghi, Carlo / Davì, Maria Vittoria / Cauchi, Carolina / Duro, Marilina / Ricci, Sergio / Fazio, Nicola / Cavalcoli, Federica / Bongiovanni, Alberto / La Salvia, Anna / Brighi, Nicole / Colao, Annamaria / Puliafito, Ivana / Panzuto, Francesco / Ortolani, Silvia / Zaniboni, Alberto / Di Costanzo, Francesco / Torniai, Mariangela / Bajetta, Emilio / Tafuto, Salvatore / Garattini, Silvio Ken / Femia, Daniela / Prinzi, Natalie / Concas, Laura / Lo Russo, Giuseppe / Milione, Massimo / Giacomelli, Luca / Buzzoni, Roberto / Delle Fave, Gianfranco / Mazzaferro, Vincenzo / de Braud, Filippo. ·Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy. Electronic address: sara.pusceddu@istitutotumori.mi.it. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy. · Dipartimento di Oncologia, Università degli Studi di Torino, A. O. Ordine Mauriziano, Turin, Italy. · Dipartimento di Oncologia, Santa Chiara Hospital, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. · IEO - Istituto Europeo di Oncologia, ENETS Center of Excellence, Milan, Italy. · Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy. · Centro di Osteoncologia e Tumori Rari, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Italy. · Policlinico Sant'Orsola Malpighi, Bologna, Italy. · Unità di chirurgia tiroidea e paratiroidea, Istituto Nazionale per lo studio e la cura dei tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy. · IOM- Istituto Oncologico del Mediterraneo, Catania, Italy. · Azienda Ospedaliera Universitaria Sant'Andrea, ENETS Center of Excellence, Rome, Italy. · Azienda Ospedaliera Universitaria, Verona, Italy. · Fondazione Poliambulanza, Brescia, Italy. · A. O. U. Careggi, Firenze, Italy. · Azienda Ospedaliero Universitaria Ospedali Riuniti, Ancona, Italy. · Policlinico di Monza, Monza, Italy. · IRCCS Fondazione Pascale, ENETS Center of Excellence, Naples, Italy. · Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy. · Fondazione IRCCS Policlinico San Matteo, SC oncologia, Pavia, Italy. · Policlinico di Modena, Italy. · Unit of Endocrinology, Ospedale Mauriziano, Torino, Italy. · Istituto Clinico Humanitas, Rozzano, ENETS Center of Excellence, Italy. · Ospedale Policlinico Borgo Roma, Verona, Italy. · Ospedale S Croce e Carle, Cuneo, Italy. · Ospedale Valduce Como, Italy. · Endocrinology Section, Department of Clinical Medicine and Surgery, "Federico II" University of Naples, Italy. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Medical-Surgical Science and Traslational Medicine Departement, Sapienza University, Rome, Italy. · Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Italy. · Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy; Universita' degli Studi di Milano, Milan, Italy. ·Gastroenterology · Pubmed #29655834.

ABSTRACT: BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

10 Article Sunitinib in patients with pre-treated pancreatic neuroendocrine tumors: A real-world study. 2018

Rinzivillo, Maria / Fazio, Nicola / Pusceddu, Sara / Spallanzani, Andrea / Ibrahim, Toni / Campana, Davide / Marconcini, Riccardo / Partelli, Stefano / Badalamenti, Giuseppe / Brizzi, Maria Pia / Catena, Laura / Schinzari, Giovanni / Carnaghi, Carlo / Berardi, Rossana / Faggiano, Antongiulio / Antonuzzo, Lorenzo / Spada, Francesca / Gritti, Sara / Femia, Daniela / Gelsomino, Fabio / Bongiovanni, Alberto / Ricci, Sergio / Brighi, Nicole / Falconi, Massimo / Delle Fave, Gianfranco / Panzuto, Francesco. ·Digestive and Liver Disease, ENETS Center of Excellence Sant'Andrea Hospital - Sapienza University of Rome, Italy. · Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, ENETS Center of Excellence IEO, Milan, Italy. · Department of Medical Oncology, Fondazione IRCCS Istituto Tumori Milano, ENETS Center of Excellence, Milan, Italy. · Division of Oncology, Department of Oncology and Haematology, University Hospital of Modena, Modena, Italy. · Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Department of Medical and Surgical Sciences, S.Orsola-Malpighi University Hospital, Bologna, Italy. · Department of Oncology, Azienda Ospedaliero-Universitaria Pisana and University of Pisa, Istituto Toscano Tumori, Santa Chiara Hospital, Pisa, Italy. · Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita e Salute University, Milan, Italy. · Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy. · Medical Oncology, AOU S. Luigi Gonzaga Regione Gonzole 10, Orbassano, Italy. · Struttura di Oncologia Policlinico di Monza, Monza, MB, Italy. · Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy. · Oncology Unit, Humanitas Clinical and Research Centre, Rozzano, Italy. · Medical Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti Umberto I, Ancona, Italy. · Divisione di Endocrinologia, Dipartimento di Medicina Clinica e Chirurgia, Università di Napoli Federico II, ENETS Center of Excellence Naples, Italy. · S.C di Oncologia Medica, AOU Careggi Florence, Italy. · Department of Experimental, Diagnostic and Specialty Medicine, S.Orsola-Malpighi University Hospital, Bologna, Italy. · Digestive and Liver Disease, ENETS Center of Excellence Sant'Andrea Hospital - Sapienza University of Rome, Italy. Electronic address: fpanzuto@ospedalesantandrea.it. ·Pancreatology · Pubmed #29361429.

ABSTRACT: INTRODUCTION: Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. AIM: To evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. PATIENTS AND METHODS: Retrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th-75th IQR). RESULTS: Eighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3%) had received three or more therapeutic regimens before sunitinib, with 24 patients (30%) having been treated with four previous treatments. Median PFS was 10 months. Similar risk of progression was observed between NET G1 and NET G2 tumors (median PFS 11 months and 8 months, respectively), and between patients who had received ≥ 3 vs ≤ 2 therapeutic approaches before sunitinib (median PFS 9 months and 10 months, respectively). DC rate was 71.3% and SD was the most frequent observed response, occurring in 43 pts (53.8%). Overall, 59 pts (73.8%) experienced AEs, which were grade 1-2 in 43 of them (72.9%), grade 3 in 15 pts (25.4%), and grade 4 in one patient (1.7%). Six pts (7.5%) stopped treatment due to toxicity. CONCLUSIONS: The present real-world experience shows that sunitinib is a safe and effective treatment for panNETs, even in the clinical setting of heavily pre-treated, progressive diseases.

11 Article Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms. 2018

Obazee, Ofure / Capurso, Gabriele / Tavano, Francesca / Archibugi, Livia / De Bonis, Antonio / Greenhalf, William / Key, Tim / Pasquali, Claudio / Milanetto, Anna Caterina / Hackert, Thilo / Fogar, Paola / Liço, Valbona / Dervenis, Christos / Lawlor, Rita T / Landoni, Luca / Gazouli, Maria / Zambon, Carlo Federico / Funel, Niccola / Strobel, Oliver / Jamroziak, Krzysztof / Cantù, Cinzia / Malecka-Panas, Ewa / Landi, Stefano / Neoptolemos, John P / Basso, Daniela / Talar-Wojnarowska, Renata / Rinzivillo, Maria / Andriulli, Angelo / Canzian, Federico / Campa, Daniele. ·Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy. · Division of Gastroenterology and Research Laboratory, San Giovanni Rotondo, Italy. · Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. · Pancreatic and Digestive Endocrine Surgery - Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Padova, Italy. · Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Im Neuenheimer Feld, Heidelberg, Germany. · Department of Laboratory Medicine, University Hospital of Padova, Padova, Italy. · Department of Surgical Oncology and Hepatobiliary Surgery, Metropolitan General Hospital, Pireas, Greece. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. · Department of Basic Medical Sciences, Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece. · Department of Medicine - DIMED, University of Padova, Padova, Italy. · Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. · Department of Hematology, Medical University of Lodz, Lodz, Poland. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Biology, University of Pisa, Pisa, Italy. · Genomic Epidemiology Group, German Cancer Research Centre (DKFZ), Heidelberg, Germany ·Carcinogenesis · Pubmed #29309705.

ABSTRACT: Pancreatic neuroendocrine neoplasms (pNEN) account for less than 5% of all pancreatic neoplasms and genetic association studies on susceptibility to the disease are limited. We sought to identify possible overlap of genetic susceptibility loci between pancreatic ductal adenocarcinoma (PDAC) and pNEN; therefore, PDAC susceptibility variants (n = 23) from Caucasian genome-wide association studies (GWAS) were genotyped in 369 pNEN cases and 3277 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium to evaluate the odds associated with pNEN risk, disease onset and tumor characteristics. Main effect analyses showed four PDAC susceptibility variants-rs9854771, rs1561927, rs9543325 and rs10919791 to be associated with pNEN risk. Subsequently, only associations with rs9543325, rs10919791 and rs1561927 were noteworthy with false positive report probability (FPRP) tests. Stratified analyses considering age at onset (50-year threshold), showed rs2736098, rs16986825 and rs9854771 to be associated with risk of developing pNEN at a younger age. Stratified analyses also showed some single nucleotide polymorphisms to be associated with different degrees of tumor grade, metastatic potential and functionality. Our results identify known GWAS PDAC susceptibility loci, which may also be involved in sporadic pNEN etiology and suggest that some genetic mechanisms governing pathogenesis of these two entities may be similar, with few of these loci being more influential in younger cases or tumor subtypes.

12 Article Clinical Usefulness of 2018

Rinzivillo, Maria / Partelli, Stefano / Prosperi, Daniela / Capurso, Gabriele / Pizzichini, Patrizia / Iannicelli, Elsa / Merola, Elettra / Muffatti, Francesca / Scopinaro, Francesco / Schillaci, Orazio / Salgarello, Matteo / Falconi, Massimo / Delle Fave, Gianfranco / Panzuto, Francesco. ·Digestive and Liver Disease Unit, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy. · Division of Pancreatic Surgery, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute, Vita e Salute University, Milan, Italy. · Department of Nuclear Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy. · Department of Radiology, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy. · Department of Nuclear Medicine, University of Tor Vergata, Rome, Italy. · Department of Nuclear Medicine, Ospedale Sacro Cuore Don Calabria, Negrar, Italy. · Digestive and Liver Disease Unit, ENETS Center of Excellence, Sapienza University of Rome, Rome, Italy fpanzuto@ospedalesantandrea.it. ·Oncologist · Pubmed #29118267.

ABSTRACT: BACKGROUND: The role of RESULTS: A total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small-intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positive IMPLICATIONS FOR PRACTICE: The findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom

13 Article Impact of Ki67 re-assessment at time of disease progression in patients with pancreatic neuroendocrine neoplasms. 2017

Panzuto, Francesco / Cicchese, Noemi / Partelli, Stefano / Rinzivillo, Maria / Capurso, Gabriele / Merola, Elettra / Manzoni, Marco / Pucci, Eugenio / Iannicelli, Elsa / Pilozzi, Emanuela / Rossi, Michele / Doglioni, Claudio / Falconi, Massimo / Delle Fave, Gianfranco. ·Digestive and Liver Disease Unit, Sant'Andrea Hospital Sapienza University of Rome, Roma, Italy. · Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. · Department of Endocrinology and Internal Medicine, San Raffaele Hospital Scientific Institute, Milan, Italy. · Department of Experimental Medicine and Pathology, Sant'Andrea Hospital Sapienza University of Rome, Roma, Italy. · Department of Radiology, Sant'Andrea Hospital Sapienza University of Rome, Roma, Italy. · Department of Pathology, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy. ·PLoS One · Pubmed #28644861.

ABSTRACT: BACKGROUND: Although re-assessment of proliferative activity by K67 evaluation during the course of neuroendocrine neoplasms (NENs) is recommended in selected patients, its impact on patients' management is not clear due to the lack of data supporting this practice. AIM: To investigate Ki67 change at time of progressive disease (PD) in entero-pancreatic NENs (EP-NENs). PATIENTS AND METHODS: Retrospective analysis of sporadic EP-NENs which received histological re-assessment after PD once radiologically documented. RESULTS: Forty-three patients were evaluated, including 24 pancreatic NENs (PNENs), and 19 small intestine NENs (SI-NENs). At time of initial histological evaluation, 19 patients had grade 1 (G1) NETs (44.2%), and 24 grade 2 (G2) NETs (55.8%), overall median Ki67 being 3% (range 1%-20%). At time of PD, 13 patients had G1 NETs (30.2%), 26 G2 NETs (60.5%), and 4 had grade 3 (G3) NECs (9.3%), thus resulting in a significant median Ki67 increase (8%, range 1%-70%; p = 0.0006), and a G upgrading in 12 patients (27.9%). A statistically significant Ki67 increase and G grading change at time of PD was observed in PNENs (p = 0.0005 and p = 0.028, respectively). Conversely, no statistically significant change occurred in non-PNENs. CONCLUSIONS: In PNENs with documented PD, Ki67 increase occurs in a significant proportion of patients, providing useful information necessary to choose appropriate therapeutic options.

14 Article Prognostic impact of the cumulative dose and dose intensity of everolimus in patients with pancreatic neuroendocrine tumors. 2017

Berardi, Rossana / Torniai, Mariangela / Pusceddu, Sara / Spada, Francesca / Ibrahim, Toni / Brizzi, Maria Pia / Antonuzzo, Lorenzo / Ferolla, Piero / Panzuto, Francesco / Silvestris, Nicola / Partelli, Stefano / Ferretti, Benedetta / Freddari, Federica / Gucciardino, Calogero / Testa, Enrica / Concas, Laura / Murgioni, Sabina / Bongiovanni, Alberto / Zichi, Clizia / Riva, Nada / Rinzivillo, Maria / Brunetti, Oronzo / Giustini, Lucio / Di Costanzo, Francesco / Delle Fave, Gianfranco / Fazio, Nicola / De Braud, Filippo / Falconi, Massimo / Cascinu, Stefano. ·Clinica di Oncologia Medica, Università Politecnica delle Marche, AOU Ospedali Riuniti di, Ancona, Italy. · Medicina Oncologica 1, ENETS Center of excellence, Fondazione IRCCS Istituto Tumori, Milano, Italy. · Unità di Oncologia Medica Gastrointestinale e Tumori Neuroendocrini (Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors), IEO Istituto Europeo di Oncologia, Milano, Italy. · Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. · Oncologia Medica, A.O.U. San Luigi, Orbassano (TO), Italy. · SC di Oncologia Medica, Azienda Opedaliero-Universitaria Careggi, Firenze, Italy. · Doctorate Course in Genetics, Oncology and Clinical Medicine, University of Siena, Siena, Italy. · Multidisciplinary NET Group, Umbria Regional Cancer Network, Perugia, Italy. · Digestive and Liver Disease, Sapienza University of Rome, Sant'Andrea Hospital, Rome, Italy. · Medical Oncology Unit, National Cancer Institute Giovanni Paolo II, Bari, Italy. · Chirurgia del Pancreas, Università Politecnica delle Marche, AOU Ospedali Riuniti di, Ancona, Italy. · Chirurgia del Pancreas, Ospedale San Raffaele IRCCS, Università Vita e Salute, Milano, Italy. · Oncologia Medica, Ospedale di San Severino, San Severino Marche (MC), Italy. · Oncologia Medica, Ospedale di Senigallia, Senigallia, Italy. · Oncologia Medica, Ospedale di Fermo, Fermo, Italy. · Oncologia Medica, Ospedale di Urbino, Urbino, Italy. · Oncologia Medica, Università di Modena e Reggio Emilia, Modena, Italy. ·Cancer Med · Pubmed #28547856.

ABSTRACT: The aim of this work is to assess if cumulative dose (CD) and dose intensity (DI) of everolimus may affect survival of advanced pancreatic neuroendocrine tumors (PNETs) patients. One hundred and sixteen patients (62 males and 54 females, median age 55 years) with advanced PNETs were treated with everolimus for ≥3 months. According to a Receiver operating characteristics (ROC) analysis, patients were stratified into two groups, with CD ≤ 3000 mg (Group A; n = 68) and CD > 3000 mg (Group B; n = 48). The response rate and toxicity were comparable in the two groups. However, patients in group A experienced more dose modifications than patients in group B. Median OS was 24 months in Group A while in Group B it was not reached (HR: 26.9; 95% CI: 11.0-76.7; P < 0.0001). Patients who maintained a DI higher than 9 mg/day experienced a significantly longer OS and experienced a trend to higher response rate. Overall, our study results showed that both CD and DI of everolimus play a prognostic role for patients with advanced PNETs treated with everolimus. This should prompt efforts to continue everolimus administration in responsive patients up to at least 3000 mg despite delays or temporary interruptions.

15 Article Stage IV Gastro-Entero-Pancreatic Neuroendocrine Neoplasms: A Risk Score to Predict Clinical Outcome. 2017

Panzuto, Francesco / Merola, Elettra / Pavel, Marianne Ellen / Rinke, Anja / Kump, Patrizia / Partelli, Stefano / Rinzivillo, Maria / Rodriguez-Laval, Victor / Pape, Ulrich Frank / Lipp, Rainer / Gress, Thomas / Wiedenmann, Bertram / Falconi, Massimo / Delle Fave, Gianfranco. ·Department of Digestive and Liver Disease, Sapienza University of Rome - Sant'Andrea Hospital, Rome, Italy. · Department of Hepatology and Gastroenterology, Charité Campus Mitte and Virchow Clinic, Charité University Medicine, Berlin, Germany. · Department of Gastroenterology, Philipps-University of Marburg, Germany. · Clinical Division of Gastroenterology, Medical University Graz, Austria. · Division of Pancreatic Surgery, Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy. · Department of Radiology Charité University, Campus Virchow Klinikum, Berlin, Germany. · Clinical Division of Oncology, Medical University Graz, Austria. · Department of Digestive and Liver Disease, Sapienza University of Rome - Sant'Andrea Hospital, Rome, Italy gianfranco.dellefave@uniroma1.it. ·Oncologist · Pubmed #28232598.

ABSTRACT: BACKGROUND: Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. PATIENTS AND METHODS: A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. RESULTS: Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement <25%) OR (0.405 if liver involvement 25%-50%) OR (0.462 if liver involvement >50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. CONCLUSION: In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs.

16 Article Everolimus in Pancreatic Neuroendocrine Carcinomas G3. 2017

Panzuto, Francesco / Rinzivillo, Maria / Spada, Francesca / Antonuzzo, Lorenzo / Ibrahim, Toni / Campana, Davide / Fazio, Nicola / Delle Fave, Gianfranco. ·From the *Digestive and Liver Diseases, Sant'Andrea Hospital-Sapienza University of Roma, Rome; †Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan; ‡Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, Florence, and Department of Medical Biotechnologies, University of Siena, Siena; §Osteoncology and Rare Tumors Center, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola (FC); and ∥Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. ·Pancreas · Pubmed #28099254.

ABSTRACT: OBJECTIVE: The aim of this study was to investigate everolimus efficacy in well-moderately differentiated pancreatic NEC (pNEC) G3. METHODS: This was a retrospective analysis of patients with pNEC G3 and Ki67 20% to 55% treated with everolimus. RESULTS: Fifteen patients with median Ki67 30% and Eastern Cooperative Oncology Group performance status 0 to 1 were evaluated. Of these, 4 patients received everolimus as first-line treatment, whereas 11 had been pretreated with chemotherapy or peptide receptor radionuclide therapy. Median progression-free survival was 6 months, and median overall survival was 28 months. Eleven patients achieved disease stabilization (DS) at 3 month follow-up. Six patients (40%) maintained DS for at least 12 months. Three of 4 patients who received everolimus as first-line therapy had sustained DS (progression-free survival, 12, 17, and 22 months). The safety profile was consistent with that previously reported, with adverse events occurring in 9 patients (66.7%). CONCLUSIONS: This study suggests that everolimus is active in pNEC G3 with well-moderately differentiated morphology and Ki67 less than 55%, in which more toxic systemic chemotherapy is, to date, the only available treatment.

17 Article Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors. 2016

Campa, Daniele / Capurso, Gabriele / Pastore, Manuela / Talar-Wojnarowska, Renata / Milanetto, Anna Caterina / Landoni, Luca / Maiello, Evaristo / Lawlor, Rita T / Malecka-Panas, Ewa / Funel, Niccola / Gazouli, Maria / De Bonis, Antonio / Klüter, Harald / Rinzivillo, Maria / Delle Fave, Gianfranco / Hackert, Thilo / Landi, Stefano / Bugert, Peter / Bambi, Franco / Archibugi, Livia / Scarpa, Aldo / Katzke, Verena / Dervenis, Christos / Liço, Valbona / Furlanello, Sara / Strobel, Oliver / Tavano, Francesca / Basso, Daniela / Kaaks, Rudolf / Pasquali, Claudio / Gentiluomo, Manuel / Rizzato, Cosmeri / Canzian, Federico. ·Department of Biology, University of Pisa, Pisa, Italy. · Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Dept of Digestive Tract Diseases, Medical University of Lodz, Poland. · Department of Surgery, Oncology and Gastroenterology (DISCOG), Pancreatic and Digestive Endocrine Surgery, University of Padova, Padova, Italy. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Oncology, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. · Department of Basic Medical Sciences, Laboratory of Biology, Medical School National and Kapodistrian University of Athens, Greece. · Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Mannheim Institute of Transfusion Medicine and Immunology, Heidelberg University, Medical Faculty Mannheim, German Red Cross Blood Service Baden-Württemberg - Hessen, Mannheim, Germany. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Blood Transfusion Service, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Surgery, Konstantopouleion General Hospital Nea Ionia, Greece. · Department of Medicine (DIMED), Laboratory Medicine, University of Padova, Padova, Italy. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. ·Sci Rep · Pubmed #28008994.

ABSTRACT: Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (OR

18 Article A Case of Pancreatic Small Cell Neuroendocrine Carcinoma Associated With SIADH. 2016

Pescatori, Lorenzo Carlo / Festa, Stefano / Panzuto, Francesco / Pilozzi, Emanuela / Prosperi, Daniela / Rinzivillo, Maria / Pizzichini, Patrizia / Iaquinto, Gaetano / Iannicelli, Elsa / Mené, Paolo / Delle Fave, Gianfranco / Capurso, Gabriele. ·Digestive and Liver Disease Unit Sant' Andrea Hospital University Sapienza Rome, Italy Department of Clinical and Molecular Medicine Sant' Andrea Hospital University Sapienza Rome, Italy Nuclear Medicine Unit Sant' Andrea Hospital University Sapienza Rome, Italy Digestive and Liver Disease Unit Sant' Andrea Hospital University Sapienza Rome, Italy Nuclear Medicine Unit Sant' Andrea Hospital University Sapienza Rome, Italy Gastroenterology Unit Moscati Hospital Avellino, Italy Radiology Unit Sant' Andrea Hospital University Sapienza Rome, Italy Nephrology Unit Sant' Andrea Hospital University Sapienza Rome, Italy Digestive and Liver Disease Unit Sant' Andrea Hospital University Sapienza Rome, Italy gabriele.capurso@gmail.com. ·Pancreas · Pubmed #27077720.

ABSTRACT: -- No abstract --

19 Article Risk and Protective Factors for Small Intestine Neuroendocrine Tumors: A Prospective Case-Control Study. 2016

Rinzivillo, Maria / Capurso, Gabriele / Campana, Davide / Fazio, Nicola / Panzuto, Francesco / Spada, Francesca / Cicchese, Noemi / Partelli, Stefano / Tomassetti, Paola / Falconi, Massimo / Delle Fave, Gianfranco. · ·Neuroendocrinology · Pubmed #26356731.

ABSTRACT: BACKGROUND: The incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, but few studies have investigated risk factors for their occurrence, suggesting that family history (FH) of any cancer, smoking and previous cholecystectomy are associated with an increased risk. Such studies investigated small series or examined cancer registries without direct interviews. AIM: We therefore aimed at clarifying risk and protective factors for the occurrence of sporadic SI-NETs. SUBJECTS AND METHODS: We performed a multicenter case-control study. Patients with a histologic diagnosis of SI-NETs were prospectively evaluated, excluding familial syndromes. Controls with non-neoplastic/non-chronic disorders seen at gastrointestinal outpatients clinics were matched for sex and age (4:1). All subjects were directly interviewed by means of a specific questionnaire on potential risk and protective factors. Cases and controls were compared by Fisher's test or Student's t test for categorical or continuous variables. Explanatory variables were analyzed by simple logistic regression analysis. A multiple logistic regression analysis was performed with an Enter model; p < 0.05 was considered significant. RESULTS: 215 SI-NET patients and 860 controls were enrolled. FH of colorectal cancer (CRC) (8.8 vs. 5.0%) and breast cancer (10.2 vs. 4.8%), heavy smoking (24.7 vs. 14.8%) and drinking >21 alcohol units per week (7.4 vs. 3.8%) were all significantly more frequent in SI-NET patients than in controls. Multivariate analysis showed that FH of CRC (OR 2.23, 95% CI 1.29-3.84, p = 0.003), FH of breast cancer (OR 2.05, 95% CI 1.13-3.69, p = 0.01) and smoking (OR 1.47, 95% CI 1.07-2.03, p = 0.01) and in particular heavy smoking (OR 1.94, 95% CI 1.29-3.84, p = 0.0008) were associated with an increased risk for carcinoid occurrence, while use of aspirin can be considered a protective factor (OR 0.20, 95% CI 0.06-0.65, p = 0.008). CONCLUSION: FH of colorectal and breast cancer as well as smoking seem to be risk factors for the development of SI-NETs, while use of aspirin might be a protective factor. These factors partially overlap with those associated with CRC, but are different from those previously associated with pancreatic neuroendocrine tumors. These findings may suggest that the mechanisms of carcinogenesis for endocrine cells in different sites can be specific and similar to those of their exocrine counterparts.

20 Article The role of combined Ga-DOTANOC and (18)FDG PET/CT in the management of patients with pancreatic neuroendocrine tumors. 2014

Partelli, Stefano / Rinzivillo, Maria / Maurizi, Angela / Panzuto, Francesco / Salgarello, Matteo / Polenta, Vanessa / Delle Fave, Gianfranco / Falconi, Massimo. ·Pancreatic Surgery Unit, Clinica Chirurgia del Pancreas, Università Politecnica delle Marche, Ancona, Italy. ·Neuroendocrinology · Pubmed #25301162.

ABSTRACT: PURPOSE: The aim of this study was to evaluate the effect of combined (68)Ga and (18)F-FDG PET/CT on treatment management for patients with pancreatic neuroendocrine tumor (PNET). METHODS: Between January 2012 and April 2014, 49 consecutive patients with a cytologically and/or histologically proven diagnosis of PNET underwent combined (68)Ga and (18)FDG PET/CT on the same day. RESULTS: The study group consisted of 21 males and 28 females with a median age of 59 years. Disease detection was achieved in 48 out of the 49 cases with (68)Ga imaging, and in 36 of the 49 cases with (18)FDG PET/CT. These results corresponded to sensitivities of 98% for (68)Ga versus 73% for (18)FDG PET/CT. Patients with NET-G1/NET-G2 had a positive (68)Ga and negative (18)FDG PET/CT in 13 cases, whereas both (68)Ga and (18)FDG PET/CT were positive in 27 cases. Patients with NEC-G3 were positive by both (68)Ga and (18)FDG PET/CT in 7 cases and positive only by (18)FDG in 1 case. Another NEC-G3 patient was only positive by (68)Ga PET/CT. The median Ki67 was 7% for (68)Ga PET/CT-positive tumors and 10% for tumors with both (68)Ga and (18)FDG PET/CT positivity (p = 0.130). Half of the patients with a prevalent uptake of (18)FDG (n = 7) had an NEC-G3 compared with 12% of patients with a prevalent uptake of (68)Ga (p = 0.012). There were no significant differences between patients with positive (68)Ga and those with positive (18)FDG with regards to treatment choice. CONCLUSIONS: The association of (18)FDG slightly increases sensitivity of (68)Ga PET/CT alone in the diagnosis of PNET. A combined dual tracer PET/CT does not influence the choice of treatment strategy.

21 Article Advanced digestive neuroendocrine tumors: metastatic pattern is an independent factor affecting clinical outcome. 2014

Panzuto, Francesco / Merola, Elettra / Rinzivillo, Maria / Partelli, Stefano / Campana, Davide / Iannicelli, Elsa / Pilozzi, Emanuela / Mercantini, Paolo / Rossi, Michele / Capurso, Gabriele / Scarpa, Aldo / Cascinu, Stefano / Tomassetti, Paola / Falconi, Massimo / Delle Fave, Gianfranco. ·From the *Digestive and Liver Disease, Sapienza University of Rome, Sant'Andrea Hospital, Rome; †Dept of Surgery, Pancreatic Surgery Unit, Università Politecnica delle Marche, Ancona; ‡Ospedale Sacro Cuore Don Calabria, Negrar; §Department of Clinical Medicine, S. Orsola-Malpighi Hospital, University of Bologna, Bologna; ∥Radiology, ¶Pathology Unit, and #Surgery 1, Sapienza University of Rome, Sant'Andrea Hospital, Rome; **ARC-NET Center for Applied Research on Cancer and Department of Pathology and Diagnostics, University of Verona, Verona; and ††Medical Oncology, Università Politecnica delle Marche, Ancona, Italy. ·Pancreas · Pubmed #24518498.

ABSTRACT: OBJECTIVES: The objective of this study was to determine the impact of different metastatic spread patterns on outcome in advanced digestive neuroendocrine tumors (NETs). METHODS: This was a retrospective analysis of patients with stage IV NETs, classified as group 1 (unilobar liver metastases), group 2 (bilobar liver metastases), group 3 (extra-abdominal metastases). End points were overall survival (OS) and progression-free survival (PFS). Risk factor analysis was performed using Cox proportional hazard model. RESULTS: Of the 229 patients, 135 (58.9%) had pancreatic, and 94 (41.1%) small bowel NETs: 32 (13.9%) were included in group 1, 179 (78.2%) in group 2, and 18 (7.9%) in group 3. Median Ki67 was 4.5%. Overall, 5-year OS was 55%. Different OS was observed among the 3 groups: median survival not reached, 81 and 8 months, respectively (P < 0.001). Median PFS was 18 months. Both OS and PFS were significantly affected by Ki67 and metastatic spread pattern. CONCLUSIONS: The stratification of stage IV NET patients based on metastatic patterns, alongside Ki67, predicts the clinical outcome. The extent of metastatic disease is a previously unrecognized variable, which should be considered when evaluating the results of treatments in NET patients with advanced disease.

22 Article Risk factors for sporadic pancreatic endocrine tumors: a case-control study of prospectively evaluated patients. 2009

Capurso, Gabriele / Falconi, Massimo / Panzuto, Francesco / Rinzivillo, Maria / Boninsegna, Letizia / Bettini, Rossella / Corleto, Vito / Borgia, Piero / Pederzoli, Paolo / Scarpa, Aldo / Delle Fave, Gianfranco. ·Digestive and Liver Disease Unit, II Medical School, University La Sapienza, S Andrea Hospital, Rome, Italy. ·Am J Gastroenterol · Pubmed #19690522.

ABSTRACT: OBJECTIVES: Pancreatic endocrine tumors (PETs) are heterogeneous tumors with increasing prevalence. Little is known about the molecular pathogenesis and risk factors for the occurrence of sporadic PETs. The aim of this study was to identify the risk factors associated with the occurrence of sporadic PETs. METHODS: A case-control study comprising 162 sporadic PETs and 648 controls was undertaken. Subjects were interviewed using a specific questionnaire on demographics and potential risk factors, including smoking, alcohol, height, weight, medical history, and family history of cancer. A multiple hierarchical logistic regression analysis was performed with a stepwise variable- selection procedure. RESULTS: A first-degree family history of any cancer was a significant risk factor (odds ratio (OR) 2.2; 95% confidence interval (CI): 1.5-3.2). Among the different cancer sites, first-degree family history of pancreatic adenocarcinoma was more frequent in PETs than in controls (4.3 vs. 1.2%; P=0.01). A high alcohol intake (OR 4.8; 95% CI: 2.4-9.5), history of chronic pancreatitis (CP) (OR 8.6; 95% CI: 1.4-51), and recent-onset diabetes (OR 40.1; 95% CI: 4.8-328.9) were all independent risk factors. The history of diabetes was also associated with metastatic disease at the time of diagnosis. CONCLUSIONS: This case-control study identified family history of any cancer (and to a less extent of pancreatic adenocarcinoma), CP, high alcohol intake, and recent-onset diabetes as risk factors for PET, thus suggesting a possible partial overlap with risk factors for exocrine pancreatic carcinogenesis.