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Pancreatic Neoplasms: HELP
Articles by Claudio Luchini
Based on 21 articles published since 2010
(Why 21 articles?)
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Between 2010 and 2020, Claudio Luchini wrote the following 21 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review From Genetic Alterations to Tumor Microenvironment: The Ariadne's String in Pancreatic Cancer. 2020

Bazzichetto, Chiara / Conciatori, Fabiana / Luchini, Claudio / Simionato, Francesca / Santoro, Raffaela / Vaccaro, Vanja / Corbo, Vincenzo / Falcone, Italia / Ferretti, Gianluigi / Cognetti, Francesco / Melisi, Davide / Scarpa, Aldo / Ciuffreda, Ludovica / Milella, Michele. ·Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy. · Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy. · Division of Oncology, University of Verona, 37126 Verona, Italy. · Medicine-Digestive Molecular Clinical Oncology Research Unit, University of Verona, 37126 Verona, Italy. · ARC-Net Research Centre, University and Hospital Trust of Verona, 37126 Verona, Italy. · SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy. ·Cells · Pubmed #32012917.

ABSTRACT: The threatening notoriety of pancreatic cancer mainly arises from its negligible early diagnosis, highly aggressive progression, failure of conventional therapeutic options and consequent very poor prognosis. The most important driver genes of pancreatic cancer are the oncogene

2 Review Liquid Biopsy as Surrogate for Tissue for Molecular Profiling in Pancreatic Cancer: A Meta-Analysis Towards Precision Medicine. 2019

Luchini, Claudio / Veronese, Nicola / Nottegar, Alessia / Cappelletti, Vera / Daidone, Maria G / Smith, Lee / Parris, Christopher / Brosens, Lodewijk A A / Caruso, Maria G / Cheng, Liang / Wolfgang, Christopher L / Wood, Laura D / Milella, Michele / Salvia, Roberto / Scarpa, Aldo. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis", Castellana Grotte, 70013 Bari, Italy. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. · Applied Research and Technological Development Department, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, 20133 Milano, Italy. · Faculty of Science and Engineering, Anglia Ruskin University, Cambridge CB1 1PT, UK. · Department of Pathology, University Medical Center Utrecht, Utrecht University, 3584CX Utrecht, The Netherlands. · Department of Pathology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6526GA Nijmegen, The Netherlands. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Medicine, Section of Medical Oncology, University and Hospital Trust of Verona, 37134 Verona, Italy. · Department of General and Visceral Surgery, The Pancreas Institute, University and Hospital Trust of Verona, 37134 Verona, Italy. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · ARC-Net Research Center, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. ·Cancers (Basel) · Pubmed #31405192.

ABSTRACT: Liquid biopsy (LB) is a non-invasive approach representing a promising tool for new precision medicine strategies for cancer treatment. However, a comprehensive analysis of its reliability for pancreatic cancer (PC) is lacking. To this aim, we performed the first meta-analysis on this topic. We calculated the pooled sensitivity, specificity, positive (LR+) and negative (LR-) likelihood ratio, and diagnostic odds ratio (DOR). A summary receiver operating characteristic curve (SROC) and area under curve (AUC) were used to evaluate the overall accuracy. We finally assessed the concordance rate of all mutations detected by multi-genes panels. Fourteen eligible studies involving 369 patients were included. The overall pooled sensitivity and specificity were 0.70 and 0.86, respectively. The LR+ was 3.85, the LR- was 0.34 and DOR was 15.84. The SROC curve with an AUC of 0.88 indicated a relatively high accuracy of LB for molecular characterization of PC. The concordance rate of all mutations detected by multi-genes panels was 31.9%. LB can serve as surrogate for tissue in the molecular profiling of PC, because of its relatively high sensitivity, specificity and accuracy. It represents a unique opportunity to be further explored towards its introduction in clinical practice and for developing new precision medicine approaches against PC.

3 Review Molecular and clinical patterns of local progression in the pancreatic remnant following resection of pancreatic intraductal papillary mucinous neoplasm (IPMN). 2019

Sereni, Elisabetta / Luchini, Claudio / Salvia, Roberto / Pea, Antonio. ·Unit of General and Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy. · Department of Pathology, University of Verona Hospital Trust, Verona, Italy. · Unit of General and Pancreatic Surgery, University of Verona Hospital Trust, Verona, Italy. antonio.pea@univr.it. ·Chin Clin Oncol · Pubmed #31070041.

ABSTRACT: Intraductal papillary mucinous neoplasms (IPMN) are pancreatic cystic lesions that can progress to invasive carcinoma. Consensus guidelines indicate surgery for IPMN at high risk of malignant progression, as assessed by specific radiological and clinical criteria, whereas an active radiological surveillance is recommended for IPMN at low risk of malignancy. The management of IPMN is further complicated by the risk of developing a distinct new cyst or a ductal adenocarcinoma in the remnant pancreas, either synchronously or metachronously. Several studies therefore investigated local progression in the remnant pancreas following partial pancreatic resection for IPMN and whether an unstable epithelium at risk for malignant degeneration may exist. Understanding the biological mechanisms behind progression of IPMN will help in identifying patients that would benefit from the resection of the entire pancreas.

4 Review Prognostic Role of High-Grade Tumor Budding in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis with a Focus on Epithelial to Mesenchymal Transition. 2019

Lawlor, Rita T / Veronese, Nicola / Nottegar, Alessia / Malleo, Giuseppe / Smith, Lee / Demurtas, Jacopo / Cheng, Liang / Wood, Laura D / Silvestris, Nicola / Salvia, Roberto / Scarpa, Aldo / Luchini, Claudio. ·ARC-Net Research Center, University and Hospital Trust of Verona, 37134 Verona, Italy. ritateresa.lawlor@univr.it. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis", 70013 Castellana Grotte, Italy. ilmannato@gmail.com. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. alessia.nottegar@gmail.com. · Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, 37142 Verona, Italy. giuseppe.malleo@univr.it. · Cambridge Centre for Sport and Excercise Sciences, Anglia Ruskin University, Cambridge CB1 1PT, UK. Lee.Smith@anglia.ac.uk. · Primary Care Department, Azienda USL Toscana Sud Est, 58100 Grosseto, Italy. eritrox7@gmail.com. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. liang_cheng@yahoo.com. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ldelong1@jhmi.edu. · Medical Oncology Unit, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, 70124 Bari, Italy. silvestrisnicola@gmail.com. · Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, 37142 Verona, Italy. roberto.salvia@univr.it. · ARC-Net Research Center, University and Hospital Trust of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. claudio.luchini@univr.it. ·Cancers (Basel) · Pubmed #30669452.

ABSTRACT: This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13⁻1.88,

5 Review Histo-molecular oncogenesis of pancreatic cancer: From precancerous lesions to invasive ductal adenocarcinoma. 2018

Riva, Giulio / Pea, Antonio / Pilati, Camilla / Fiadone, Giulia / Lawlor, Rita Teresa / Scarpa, Aldo / Luchini, Claudio. ·Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Surgery, University and Hospital trust of Verona, Verona 37134, Italy. · Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Paris-Descartes University, Paris 75006, France. · ARC-Net Research Center, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona 37134, Italy. claudio.luchini@univr.it. ·World J Gastrointest Oncol · Pubmed #30364837.

ABSTRACT: Pancreatic cancer is a lethal malignancy, whose precursor lesions are pancreatic intraepithelial neoplasm, intraductal papillary mucinous neoplasm, intraductal tubulopapillary neoplasm, and mucinous cystic neoplasm. To better understand the biology of pancreatic cancer, it is fundamental to know its precursors and to study the mechanisms of carcinogenesis. Each of these precursors displays peculiar histological features, as well as specific molecular alterations. Starting from such pre-invasive lesions, this review aims at summarizing the most important aspects of carcinogenesis of pancreatic cancer, with a specific focus on the recent advances and the future perspectives of the research on this lethal tumor type.

6 Review The Roles of Chromatin Remodeling Genes in Pancreatic-Biliary Malignancies. 2017

Luchini, Claudio / Nottegar, Alessia. ·Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37142 Verona, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, 37142 Verona, Italy. · Department of Surgery, San Bortolo Hospital, 36100 Vicenza, Italy. ·Crit Rev Oncog · Pubmed #29604925.

ABSTRACT: Recent studies have definitively established that chromatin remodeling is a crucial epigenetic mechanism not only in physiological conditions but also in influencing cancer biology. It is a dynamic process in which the chromatin, the functional entity of DNA, can undergo specific modifications by obtaining transcriptional activation or transcriptional silencing. One of the most important recent discoveries in cancer genetics and genomics is that the genes involved in the establishment of chromatin structure, the so called chromatin remodelers, are frequently mutated in different types of human cancer. This review aims to summarize the main novelties related to this topic, describing also the contribution of such genes during oncogenesis. Particularly, we focus on the switch/sucrose non-fermentable complexes and on three of the most important chromatin remodeling genes in biliary and pancreatic cancer: ARID1A, PBRM1, and BAP1.

7 Review Pancreatic Ductal Adenocarcinoma and Its Variants. 2016

Luchini, Claudio / Capelli, Paola / Scarpa, Aldo. ·Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy; Surgical Pathology Unit, Santa Chiara Hospital, Largo Medaglie D'oro, Trento 38122, Italy. Electronic address: claudio.luchini@katamail.com. · Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy. · Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy; ARC-Net Research Center, University and Hospital Trust of Verona, Piazzale Scuro, 10, Verona 37134, Italy. ·Surg Pathol Clin · Pubmed #27926359.

ABSTRACT: Pancreatic cancer represents the seventh leading cause of cancer death in the world, responsible for more than 300,000 deaths per year. The most common tumor type among pancreatic cancers is pancreatic ductal adenocarcinoma, an infiltrating neoplasm with glandular differentiation that is derived from pancreatic ductal tree. Here we present and discuss the most important macroscopic, microscopic, and immunohistochemical characteristics of this tumor, highlighting its key diagnostic features. Furthermore, we present the classic features of the most common variants of pancreatic ductal adenocarcinoma. Last, we summarize the prognostic landscape of this highly malignant tumor and its variants.

8 Review Extranodal extension in N1-adenocarcinoma of the pancreas and papilla of Vater: a systematic review and meta-analysis of its prognostic significance. 2016

Luchini, Claudio / Veronese, Nicola / Pea, Antonio / Sergi, Giuseppe / Manzato, Enzo / Nottegar, Alessia / Solmi, Marco / Capelli, Paola / Scarpa, Aldo. ·aDepartment of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona Departments of bMedicine (DIMED) cNeurosciences, University of Padua, Padua, Italy dDepartment of Surgery, Johns Hopkins University, Baltimore, Maryland, USA. ·Eur J Gastroenterol Hepatol · Pubmed #26566063.

ABSTRACT: The aim of the study was to investigate the prognostic role of extranodal extension (ENE) of lymph node metastasis in adenocarcinoma of the pancreas (PDAC) and papilla [cancer of the papilla of Vater (CPV)]. A PubMed and SCOPUS search from database inception until 5 January 2015 without language restrictions was conducted. Eligible were prospective studies reporting data on prognostic parameters in individuals with PDAC and/or CPV, comparing participants with the presence of ENE (ENE+) with those with intranodal extension (ENE-). Data were summarized using risk ratios for number of deaths/recurrences and hazard ratios for time-dependent risk related to ENE+, adjusted for potential confounders. ENE was found to be very common in these tumors (up to about 60% in both N1-PDAC and CPV), leading to a significant increased risk for all-cause mortality [risk ratio=1.20; 95% confidence interval (CI): 1.06-1.35, P=0.003, I(2)=44%; hazard ratio=1.415, 95% CI: 1.215-1.650, P<0.0001, I(2)=0%] and recurrence of disease (risk ratio=1.20, 95% CI: 1.03-1.40, P=0.02, I(2)=0%). On the basis of our results, in PDAC and CPV, ENE should be considered mandatorily from the gross sampling and pathology report to the oncologic staging and therapeutic approach.

9 Article The Italian Rare Pancreatic Exocrine Cancer Initiative. 2019

Brunetti, Oronzo / Luchini, Claudio / Argentiero, Antonella / Tommasi, Stefania / Mangia, Anita / Aprile, Giuseppe / Marchetti, Paolo / Vasile, Enrico / Casadei Gardini, Andrea / Scartozzi, Mario / Barni, Sandro / Delfanti, Sara / De Vita, Fernando / Di Costanzo, Francesco / Milella, Michele / Cella, Chiara Alessandra / Berardi, Rossana / Cataldo, Ivana / Santini, Daniele / Doglioni, Claudio / Maiello, Evaristo / Lawlor, Rita T / Mazzaferro, Vincenzo / Lonardi, Sara / Giuliante, Felice / Brandi, Giovanni / Scarpa, Aldo / Cascinu, Stefano / Silvestris, Nicola. ·1 Medical Oncology Unit, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, Bari, Italy. · 2 Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. · 3 Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy. · 4 Functional Biomorphology Laboratory, IRCCS-Istituto Tumori, Bari, Italy. · 5 Medical Oncology Unit, Hospital of Vicenza, Vicenza, Italy. · 6 Medical Oncology Unit, Sant'Andrea Hospital, University of Rome La Sapienza, Rome, Italy. · 7 Medical Oncology Unit, University Hospital of Pisa, Pisa, Italy. · 8 Medical Oncology Unit, Scientific Institute of Romagna for the Study and Treatment of Cancer (IRST), Meldola, Italy. · 9 Medical Oncology Unit, University of Cagliari, Cagliari, Italy. · 10 Medical Oncology Unit, ASST Bergamo Ovest, Treviglio, Italy. · 11 Medical Oncology Unit, IRCCS Foundation Polyclinic San Matteo, Pavia, Italy. · 12 Medical Oncology Unit, II University of Naples, Naples, Italy. · 13 Medical Oncology Unit, Careggi University Hospital, Florence, Italy. · 14 Medical Oncology Unit, "Regina Elena" National Cancer Institute, Rome, Italy. · 15 Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), Milan, Italy. · 16 Medical Oncology Unit, Polytechnic University of the Marche, "Ospedali Riuniti Ancona," Ancona, Italy. · 17 Department of Pathology and Diagnostics, University of Verona Hospital Trust, Policlinico GB Rossi, Verona, Italy. · 18 Medical Oncology Unit, University Campus Biomedico, Rome, Italy. · 19 Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · 20 Medical Oncology Unit, IRCCS "Casa Sollievo della Sofferenza" Foundation, San Giovanni Rotondo, Italy. · 21 Arc-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · 22 Hepato-Biliary-Pancreatic Surgery, University of Milan, Istituto Nazionale Tumori, Fondazione IRCCS, Milan, Italy. · 23 Medical Oncology Unit, IRCCS Veneto Institute of Oncology (IOV), Padua, Italy. · 24 Hepatobiliary Surgery Unit, IRCCS A. Gemelli Polyclinic Foundation, Catholic University of the Sacred Heart, Rome, Italy. · 25 Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. · 26 Medical Oncology Unit, Modena Cancer Center, University Hospital of Modena, Modena, Italy. · 27 Scientific Direction, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, Bari, Italy. ·Tumori · Pubmed #30967031.

ABSTRACT: INTRODUCTION: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available. METHODS: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays. CONCLUSIONS: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices.

10 Article Perineural Invasion is a Strong Prognostic Moderator in Ampulla of Vater Carcinoma: A Meta-analysis. 2019

Luchini, Claudio / Veronese, Nicola / Nottegar, Alessia / Riva, Giulio / Pilati, Camilla / Mafficini, Andrea / Stubbs, Brendon / Simbolo, Michele / Mombello, Aldo / Corbo, Vincenzo / Cheng, Liang / Yachida, Shinichi / Wood, Laura D / Lawlor, Rita T / Salvia, Roberto / Scarpa, Aldo. ·National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis," Castellana Grotte, Bari. · Department of Surgery, Section of Pathology, San Bortolo Hospital, Vicenza, Italy. · Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Paris-Descartes University, Paris, France. · ARC-Net Research Center, University of Verona, Verona, Italy. · Health Service and Population Research Department, King's College London, London, United Kingdom. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN. · Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. · Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. ·Pancreas · Pubmed #30451797.

ABSTRACT: OBJECTIVE: Ampulla of Vater carcinoma (AVC) has a broad spectrum of different prognoses. As such, new moderators of survival are urgently needed. We aimed at clarifying the prognostic role of perineural invasion in AVC. METHODS: Using PubMed and SCOPUS databases, we conducted the first systematic review and meta-analysis on this topic. RESULTS: Analyzing 29 articles for a total of 2379 patients, we found that the presence of perineural invasion increased the risk of all-cause mortality more than 2 times (relative risk [RR], 2.07; 95% confidence interval [CI], 1.78-2.42 [P < 0.0001]; hazard ratio [HR], 2.72; 95% CI, 1.86-3.97 [P < 0.0001]), of cancer-specific mortality more than 6 times (RR, 6.12; 95% CI, 3.25-11.54 [P < 0.0001]; HR, 6.59; 95% CI, 2.29-3.49 [P < 0.0001]), and of recurrence more than 2 times (RR, 2.63; 95% CI, 1.89-3.67 [P < 0.0001]; HR, 2.54; 95% CI, 1.24-5.21 [P = 0.01]). CONCLUSIONS: Perineural invasion is strongly associated with a poorer prognosis in AVC, influencing both survival and risk of recurrence. It should be reported in the final pathology report and should be taken into account by future oncologic staging systems, identifying a group of AVC with a more malignant biological behavior.

11 Article CD200 expression is a feature of solid pseudopapillary neoplasms of the pancreas. 2019

Lawlor, Rita T / Daprà, Valentina / Girolami, Ilaria / Pea, Antonio / Pilati, Camilla / Nottegar, Alessia / Piccoli, Paola / Parolini, Claudia / Sperandio, Nicola / Capelli, Paola / Scarpa, Aldo / Luchini, Claudio. ·ARC-Net Research Center, University of Verona, Verona, Italy. · Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Piazzale Scuro, 10, 37134, Verona, Italy. · Department of General and Visceral Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. · Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Paris-Descartes University, Paris, France. · Department of Surgery, Section of Pathology, San Bortolo Hospital, Vicenza, Italy. · ARC-Net Research Center, University of Verona, Verona, Italy. aldo.scarpa@univr.it. · Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Piazzale Scuro, 10, 37134, Verona, Italy. aldo.scarpa@univr.it. ·Virchows Arch · Pubmed #30132130.

ABSTRACT: CD200 has been recently indicated as a robust marker of well-differentiated neuroendocrine neoplasms. Here, we evaluate its role in differential diagnosis of solid pancreatic neoplasms. We immunostained for CD200 22 solid pseudopapillary neoplasms (SPNs), 8 acinar carcinomas (ACs), 2 pancreatoblastomas (PBs), 138 neuroendocrine tumors (PanNETs), and 48 ductal adenocarcinomas. All SPNs showed strong cytoplasmic and membranous staining for CD200, while only one case of AC had focal positivity. The two PBs showed focal CD200 positivity, mainly located in squamoid nests. The vast majority of PanNETs (96%) showed strong cytoplasmic and membranous staining for CD200, whereas all PDACs were negative. As both PanNETs and SPNs express CD200, it has no role in the differential diagnosis between these two entities.

12 Article PD-1, PD-L1, and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications. 2018

Luchini, Claudio / Cros, Jerome / Pea, Antonio / Pilati, Camilla / Veronese, Nicola / Rusev, Borislav / Capelli, Paola / Mafficini, Andrea / Nottegar, Alessia / Brosens, Lodewijk A A / Noë, Michaël / Offerhaus, G Johan A / Chianchiano, Peter / Riva, Giulio / Piccoli, Paola / Parolini, Claudia / Malleo, Giuseppe / Lawlor, Rita T / Corbo, Vincenzo / Sperandio, Nicola / Barbareschi, Mattia / Fassan, Matteo / Cheng, Liang / Wood, Laura D / Scarpa, Aldo. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. · Department of Pathology, Beaujon Hospital, 92110 Clichy, France; Paris-Diderot School of Medicine, Inflammation Research Center, 75013 Paris, France. · Department of Surgery, University and Hospital Trust of Verona, 37134 Verona, Italy. · Personalized Medicine, Pharmacogenomics, Therapeutic Optimization, Paris-Descartes University, 75006 Paris, France. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis," 70013, Castellana Grotte, Bari, Italy. · ARC-Net Research Center, University of Verona, 37134 Verona, Italy. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. · Department of Pathology, University Medical Center Utrecht, 3508 Utrecht, The Netherlands; Department of Pathology, Radboud University Medical Center, 6500, HB, Nijmegen, The Netherlands. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. · Department of Pathology, University Medical Center Utrecht, 3508 Utrecht, The Netherlands. · Surgical Pathology Unit, Santa Chiara Hospital, 38122 Trento, Italy. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA; Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21211, USA. Electronic address: ldwood@jhmi.edu. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy; ARC-Net Research Center, University of Verona, 37134 Verona, Italy. Electronic address: aldo.scarpa@univr.it. ·Hum Pathol · Pubmed #30031096.

ABSTRACT: Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has a striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1, and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extrapancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas were immunostained using antibodies against PD-1, PD-L1, and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17 (63%) of 27 cases, more often in cases with an associated PDAC (P = .04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than did patients with PD-L1-negative UCOGCs (hazard ratio, 3.397; 95% confidence interval, 1.023-18.375; P = .034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P = .035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extrapancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. Anaplastic carcinomas have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.

13 Article MiR-21 up-regulation in ampullary adenocarcinoma and its pre-invasive lesions. 2018

Saraggi, Deborah / Galuppini, Francesca / Fanelli, Giuseppe N / Remo, Andrea / Urso, Emanuele D L / Bao, Ricardo Q / Bacchin, Deborah / Guzzardo, Vincenza / Luchini, Claudio / Braconi, Chiara / Farinati, Fabio / Rugge, Massimo / Fassan, Matteo. ·Department of Medicine (DIMED), University of Padua, Padua, PD, Italy. · Department of Pathology, "Mater Salutis" Hospital - ULSS9, 37045, Legnago, VR, Italy. · Department of Surgical Oncology and Gastroenterology (DiSCOG), University of Padua, Padua, PD, Italy. · Department of Diagnostics and Public Health, ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy. · Division of Cancer Therapeutics, Institute of Cancer Research, London, UK. · Department of Medicine (DIMED), University of Padua, Padua, PD, Italy. Electronic address: matteo.fassan@unipd.it. ·Pathol Res Pract · Pubmed #29731265.

ABSTRACT: Poor information is available on the molecular landscape characterizing the carcinogenetic process leading to ampullary carcinoma. MiR-21 is one of the most frequently up-regulated miRNAs in pancreatic adenocarcinoma, a tumor sharing similar molecular features with ampullary adenocarcinomas (AVCs), above all with the pancreatic-biliary type. We profiled, by in situ hybridization (ISH), miR-21 expression in a series of 26 AVCs, 50 ampullary dysplastic lesions (35 low-grade [LG-IEN] and 15 high-grade [HG-IEN]) and 10 normal duodenal mucosa samples. The same series was investigated by immunohistochemistry for β-catenin, p53 and HER2 expression. HER2 gene amplification was evaluated by chromogenic in situ hybridization. To validate miR-21 ISH results we performed miR-21 qRT-PCR analysis in a series of 10 AVCs and their matched normal samples. All the normal control samples showed a negative or faint miR-21 expression, whereas a significant miR-21 up-regulation was observed during the carcinogenetic cascade (p < 0.001), with 21/26 (80.8%) of cancer samples showing a miR-21 overexpression. In comparison to control samples, a significant overexpression was found in samples of LG-IEN (p = .0003), HG-IEN (p = .0001), and AVCs (p < 0.0001). No significant difference in miR-21 overexpression was observed between LG-IEN, HG-IEN and AVCs. By qRT-PCR analysis, AVCs showed a 1.7-fold increase over the controls (p = .003). P53 was frequently dysregulated in both dysplastic and carcinoma samples (44 out of 76; 57.9%). A 20% (10/50) of dysplastic lesions and 11% (3/26) of carcinomas were characterized by a nuclear localization of β-catenin. Only 2 AVCs (7.7%; both intestinal-type) showed a HER2 overexpression (both 2+), which corresponded to a HER2 gene amplification at CISH analysis. This is the first study demonstrating a miRNA dysregulation in the whole spectrum of ampullary carcinogenesis. MiR-21 overexpression is an early molecular event during ampullary carcinogenesis and its levels increase with the neoplastic progression.

14 Article Genetic unrelatedness of co-occurring pancreatic adenocarcinomas and IPMNs challenges current views of clinical management. 2018

Scarpa, Aldo / Real, Francisco X / Luchini, Claudio. ·Department of Diagnostics and Public Health-Section of Pathology, ARC-Net Research Center, University and Hospital Trust of Verona, Verona, Italy. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. ·Gut · Pubmed #29661802.

ABSTRACT: -- No abstract --

15 Article Pancreatic undifferentiated carcinoma with osteoclast-like giant cells is genetically similar to, but clinically distinct from, conventional ductal adenocarcinoma. 2017

Luchini, Claudio / Pea, Antonio / Lionheart, Gemma / Mafficini, Andrea / Nottegar, Alessia / Veronese, Nicola / Chianchiano, Peter / Brosens, Lodewijk Aa / Noë, Michaël / Offerhaus, G Johan A / Yonescu, Raluca / Ning, Yi / Malleo, Giuseppe / Riva, Giulio / Piccoli, Paola / Cataldo, Ivana / Capelli, Paola / Zamboni, Giuseppe / Scarpa, Aldo / Wood, Laura D. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · ARC-Net Research Center, University of Verona, Verona, Italy. · National Research Council, Neuroscience Institute, Aging Branch, Padua, Italy. · Institute for Clinical Research and Education in Medicine (IREM), Padua, Italy. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. · Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #28722124.

ABSTRACT: Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well-defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

16 Article PD-L1 overexpression in ampulla of Vater carcinoma and its pre-invasive lesions. 2017

Saraggi, Deborah / Galuppini, Francesca / Remo, Andrea / Urso, Emanuele D L / Bacchin, Deborah / Salmaso, Roberta / Lanza, Cristiano / Bao, Riccardo Q / Fanelli, Giuseppe N / Guzzardo, Vincenza / Luchini, Claudio / Scarpa, Marco / Farinati, Fabio / Fassan, Matteo / Rugge, Massimo. ·Department of Medicine (DIMED), University of Padua, Padua, PD, Italy. · Department of Pathology, 'Mater Salutis' Hospital, Legnago, Italy. · Department of Surgical Oncology and Gastroenterology (DiSCOG), Clinica Chirurgica I, University of Padua, Padua, Italy. · Surgical Pathology Unit, Santa Chiara Hospital, Trento, Italy. · Istituto Oncologico Veneto, Padua, Italy. · Department of Surgical Oncology and Gastroenterology (DiSCOG), Gastroenterology Unit, University of Padua, Padua, Italy. · Veneto Cancer Registry, Padua, Italy. ·Histopathology · Pubmed #28502094.

ABSTRACT: AIMS: PD-1/PD-L1 checkpoint immunotherapy has been proposed recently as a promising treatment in relapsed/refractory disease, used eventually in combination with traditional chemotherapy in different cancer settings. To date, no data are available concerning PD-L1 expression in ampulla of Vater carcinoma and its pre-invasive lesions. METHODS AND RESULTS: We assessed the immunohistochemical expression of PD-L1 in a series of 26 ampullary adenocarcinomas, 50 ampullary dysplastic lesions and 10 normal duodenal mucosa samples. Moreover, in all cases DNA mismatch repair proteins status was investigated. PD-L1 was expressed in seven of 26 (26.9%) invasive carcinomas and three of 50 (6.0%) dysplastic samples. Most of the PD-L1-positive tumours (seven of 10) were intestinal-type and poorly differentiated (G3). The number of PD-L1-positive stromal lymphoid cells was significantly higher in dysplastic and invasive lesions than in the normal samples (P = 0.011). Nineteen dysplastic lesions and eight invasive carcinomas did not show any evident epithelial or stromal PD-L1 expression. Four of the carcinomas were mismatch repair-deficient and two of these were PD-L1-positive. Furthermore, mismatch repair-deficient lesions showed a significantly higher average of PD-L1-positive stromal lymphoid cells than those of neoplastic PD-L1-negative samples (62.8 versus 21.6; P < 0.001). CONCLUSIONS: The present results suggest a role of the PD-1/PD-L1 axis in ampullary adenocarcinomas, and therefore this may also prompt consideration of checkpoint immunotherapy as a novel promising treatment for these tumours.

17 Article Fhit down-regulation is an early event in pancreatic carcinogenesis. 2017

Fassan, Matteo / Rusev, Borislav / Corbo, Vincenzo / Gasparini, Pierluigi / Luchini, Claudio / Vicentini, Caterina / Mafficini, Andrea / Paiella, Salvatore / Salvia, Roberto / Cataldo, Ivana / Scarpa, Aldo / Huebner, Kay. ·ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy. matteo.fassan@unipd.it. · Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Via Gabelli 61, 35121, Padua, Italy. matteo.fassan@unipd.it. · ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy. · Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA. · Department of Diagnostics and Public Health, Surgical Pathology Unit, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, Santa Chiara Hospital, Trento, Italy. · Department of Surgery, Unit of General Surgery B, University and Hospital Trust of Verona, Verona, Italy. ·Virchows Arch · Pubmed #28289900.

ABSTRACT: Aberrant Fhit expression characterizes a large proportion of primary pancreatic ductal adenocarcinomas (PDACs), but fragmentary information is available on Fhit expression during the phenotypic changes of pancreatic ductal epithelium during multistep transformation. We assessed Fhit expression by immunohistochemistry in two different multistep pancreatic carcinogenic processes: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). We considered 105 surgically treated PDACs/IPMNs and selected 30 samples of non-neoplastic pancreatic parenchyma, 50 PanIN lesions, 30 IPMNs, 15 IPMNs with associated invasive carcinoma, and 60 adenocarcinomas. Normal pancreatic ducts and surrounding acinar cells consistently showed moderate to strong Fhit immunoreactivity. Significant down-regulation of Fhit expression was observed in association with increasing severity of dysplastia/neoplastia in both carcinogenic processes. This was further confirmed by studying multiple lesions obtained from the same surgical specimen. Of 60 PDACs, only 14 showed Fhit expression comparable to normal pancreatic ductal epithelium, while the remainder (77%) showed clearly negative or reduced Fhit expression. This study demonstrates that Fhit down-regulation is an early event in both multistep carcinogenic processes leading to PDAC.

18 Article Targeted DNA Sequencing Reveals Patterns of Local Progression in the Pancreatic Remnant Following Resection of Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas. 2017

Pea, Antonio / Yu, Jun / Rezaee, Neda / Luchini, Claudio / He, Jin / Dal Molin, Marco / Griffin, James F / Fedor, Helen / Fesharakizadeh, Shahriar / Salvia, Roberto / Weiss, Matthew J / Bassi, Claudio / Cameron, John L / Zheng, Lei / Scarpa, Aldo / Hruban, Ralph H / Lennon, Anne Marie / Goggins, Michael / Wolfgang, Christopher L / Wood, Laura D. ·*Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland †Department of Surgery, The Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy ‡Departments of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland §Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy ¶Departments of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland ||Departments of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland **ARC-Net applied research on cancer center, University and Hospital Trust of Verona, Verona, Italy. ·Ann Surg · Pubmed #27433916.

ABSTRACT: OBJECTIVE: The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS). BACKGROUND: Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm. METHODS: Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression. RESULTS: We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas. CONCLUSIONS: Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas.

19 Article Solid pseudopapillary tumors of the pancreas: Specific pathological features predict the likelihood of postoperative recurrence. 2016

Marchegiani, Giovanni / Andrianello, Stefano / Massignani, Marta / Malleo, Giuseppe / Maggino, Laura / Paiella, Salvatore / Ferrone, Cristina R / Luchini, Claudio / Scarpa, Aldo / Capelli, Paola / Mino-Kenudson, Mari / Lillemoe, Keith D / Bassi, Claudio / Castillo, Carlos Fernàndez-Del / Salvia, Roberto. ·Department of General and Pancreatic Surgery, The Pancreas Institute-University of Verona Hospital Trust, Verona, Italy. · Department of General Surgery, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts. · Department of Diagnostic and Public Health, ARC-Net Research Centre-University of Verona Hospital Trust, Verona, Italy. · Department of Pathology, Massachusetts General Hospital-Harvard Medical School, Boston, Massachusetts. · Department of General and Pancreatic Surgery, The Pancreas Institute-University of Verona Hospital Trust, Verona, Italy. roberto.salvia@univr.it. ·J Surg Oncol · Pubmed #27471041.

ABSTRACT: BACKGROUND: Since their introduction in the WHO classification, the incidence of solid pseudopapillary tumors (SPTs) of the pancreas has progressively increased, mainly because of the widespread use of cross-sectional imaging. Few recent studies have analyzed the biological behavior of SPTs, but reliable data on long-term follow-up are needed. METHODS: Retrospective analysis of two Institutions with high caseload, The Department of General Surgery-Pancreas Institute, University of Verona Hospital Trust and the Department of General Surgery, Massachusetts General Hospital, Harvard Medical School, was carried out. Data from 131 consecutive resections for SPT performed during the last three decades were collected and analyzed. RESULTS: The majority of patients were female (86.3%) with a median age of 33 (7-68) years. The prevalent location was the pancreatic tail (33.5%). Applying the WHO criteria, 16 (12.2%) SPTs were considered malignant due to the presence of at least pancreatic parenchyma (9.9%), perineural (4.6%), and/or angiovascular invasion (2.3%). After a median of 62 months after surgery, only two patients had a recurrence (1.5%). Both of them fulfilled the WHO criteria for malignant SPT (vs. 10.7% of those who did not recur, P = 0.01), had an infiltrative growth pattern (vs. 10.8%, P = 0.01), pancreatic parenchyma invasion (vs. 9.7%, P = 0.01) and capsular invasion (vs. 4.9%, P = 0.004). CONCLUSION: Overall, SPTs are associated with excellent survival results after surgical resection. Disease recurrence is extremely rare, and might occur if the primary tumor presents with either pancreatic parenchyma or capsule invasion. J. Surg. Oncol. 2016;114:597-601. © 2016 Wiley Periodicals, Inc.

20 Article Genomic Sequencing Identifies ELF3 as a Driver of Ampullary Carcinoma. 2016

Yachida, Shinichi / Wood, Laura D / Suzuki, Masami / Takai, Erina / Totoki, Yasushi / Kato, Mamoru / Luchini, Claudio / Arai, Yasuhito / Nakamura, Hiromi / Hama, Natsuko / Elzawahry, Asmaa / Hosoda, Fumie / Shirota, Tomoki / Morimoto, Nobuhiko / Hori, Kunio / Funazaki, Jun / Tanaka, Hikaru / Morizane, Chigusa / Okusaka, Takuji / Nara, Satoshi / Shimada, Kazuaki / Hiraoka, Nobuyoshi / Taniguchi, Hirokazu / Higuchi, Ryota / Oshima, Minoru / Okano, Keiichi / Hirono, Seiko / Mizuma, Masamichi / Arihiro, Koji / Yamamoto, Masakazu / Unno, Michiaki / Yamaue, Hiroki / Weiss, Matthew J / Wolfgang, Christopher L / Furukawa, Toru / Nakagama, Hitoshi / Vogelstein, Bert / Kiyono, Tohru / Hruban, Ralph H / Shibata, Tatsuhiro. ·Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 1040045, Japan; Division of Cancer Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 1040045, Japan. Electronic address: syachida@ncc.go.jp. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 1040045, Japan. · Department of Bioinformatics, National Cancer Center Research Institute, Tokyo 1040045, Japan. · Division of Medical Elemental Technology Development, Department of Advanced Analysis Technology, R&D Group, Olympus Corporation, Tokyo 1630914, Japan. · Division of Virology, National Cancer Center Research Institute, Tokyo 1040045, Japan. · Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo 1040045, Japan. · Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo 1040045, Japan. · Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo 1040045, Japan. · Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo 1628666, Japan. · Department of Gastroenterological Surgery, Kagawa University, Kagawa 7610793, Japan. · Second Department of Surgery, Wakayama Medical University, Wakayama 6418509, Japan. · Department of Surgery, Tohoku University Graduate School of Medicine, Sendai Miyagi 9808575, Japan. · Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima 7348551, Japan. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Institute for Integrated Medical Science, Tokyo Women's Medical University, Tokyo 1628666, Japan. · Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute, Tokyo 1040045, Japan. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Ludwig Center and The Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21287, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo 1040045, Japan; Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo 1088639, Japan. ·Cancer Cell · Pubmed #26806338.

ABSTRACT: Ampullary carcinomas are highly malignant neoplasms that can have either intestinal or pancreatobiliary differentiation. To characterize somatic alterations in ampullary carcinomas, we performed whole-exome sequencing and DNA copy-number analysis on 60 ampullary carcinomas resected from clinically well-characterized Japanese and American patients. We next selected 92 genes and performed targeted sequencing to validate significantly mutated genes in an additional 112 cancers. The prevalence of driver gene mutations in carcinomas with the intestinal phenotype is different from those with the pancreatobiliary phenotype. We identified a characteristic significantly mutated driver gene (ELF3) as well as previously known driver genes (TP53, KRAS, APC, and others). Functional studies demonstrated that ELF3 silencing in normal human epithelial cells enhances their motility and invasion.

21 Article RASSF1 tumor suppressor gene in pancreatic ductal adenocarcinoma: correlation of expression, chromosomal status and epigenetic changes. 2016

Amato, Eliana / Barbi, Stefano / Fassan, Matteo / Luchini, Claudio / Vicentini, Caterina / Brunelli, Matteo / Malleo, Giuseppe / Scarpa, Aldo / Malpeli, Giorgio. ·ARC-NET Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, The Hospital and University of Verona, Verona, Italy. eliana.amato@gmail.com. · ARC-NET Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, The Hospital and University of Verona, Verona, Italy. stefano.barbi@univr.it. · ARC-NET Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, The Hospital and University of Verona, Verona, Italy. matteo.fassan@gmail.com. · ARC-NET Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, The Hospital and University of Verona, Verona, Italy. claudio.luchini@univr.it. · Department of Pathology, The Hospital and University of Verona, Verona, Italy. claudio.luchini@univr.it. · ARC-NET Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, The Hospital and University of Verona, Verona, Italy. caterinavicentini@hotmail.it. · ARC-NET Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, The Hospital and University of Verona, Verona, Italy. matteo.brunelli@univr.it. · Department of Surgery and Oncology, The Hospital and University of Verona, Verona, Italy. giuseppe.malleo@ospedaleuniverona.it. · ARC-NET Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, The Hospital and University of Verona, Verona, Italy. aldo.scarpa@univr.it. · Department of Pathology, The Hospital and University of Verona, Verona, Italy. aldo.scarpa@univr.it. · ARC-NET Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, The Hospital and University of Verona, Verona, Italy. giorgio.malpeli@univr.it. · Department of Surgery and Oncology, The Hospital and University of Verona, Verona, Italy. giorgio.malpeli@univr.it. ·BMC Cancer · Pubmed #26754001.

ABSTRACT: BACKGROUND: The Ras Association Domain Family Member 1 (RASSF1) is one of the most frequently reported methylation-inactivated tumor suppressor genes in primary pancreatic ductal adenocarcinomas (PDAC). Limited information is still available about the impact of RASSF1 gene silencing on the expression of its different isoforms in neoplastic cells. METHODS: A series of 96 primary PDAC, with known clinico-pathological parameters, was tested for RASSF1 methylation status by methylation-specific PCR, RASSF1 locus copy number alterations by fluorescence in situ hybridization, and Rassf1a protein expression by immunohistochemistry. A further series of 14 xenografted primary PDAC and 8 PDAC-derived cell lines were tested to obtain a detailed methylation mapping of CpG islands A and C of the RASSF1 locus by pyrosequencing and to evaluate the expression of Rassf1 variants by qRT-PCR. RESULTS: Methylation of CpG island A of the RASSF1 gene was observed in 35% of the tumors and allelic loss of RASSF1 locus was seen in 30 disomic and in 20 polysomic cases (52%). Rassf1a immunohistochemical expression was downregulated in half of primary PDAC, and this downregulation was neither correlated with methylation of RASSF1 promoter nor with RASSF1 copy number alterations. RASSF1 status did not influence patients' prognosis. The expression of the seven RASSF1 isoforms in xenografts and cell lines showed that RASSF1A, RASSF1B, and RASSF1C isoforms were present in all xenografts and cell lines, whereas RASSF1D, RASSF1E, and RASSF1F isoforms were variably expressed among samples. RASSF1G was never expressed in either xenografts or cell lines. The variable expression of RASSF1 isoforms in PDAC xenografts and cell lines was not dependent on RASSF1 methylation status of CpG islands A and C. CONCLUSIONS: RASSF1 alterations occurring in PDAC mainly consist in variations of expression of the different isoforms. Different genetic mechanisms seem to contribute to RASSF1 deregulation in this setting, but RASSF1 methylation does not seem to substantially affect RASSF1 isoforms expression.