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Pancreatic Neoplasms: HELP
Articles by Aldo Scarpa
Based on 138 articles published since 2010
(Why 138 articles?)
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Between 2010 and 2020, A. Scarpa wrote the following 138 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 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.

2 Review Preclinical Modelling of PDA: Is Organoid the New Black? 2019

D'Agosto, Sabrina / Andreani, Silvia / Scarpa, Aldo / Corbo, Vincenzo. ·ARC-Net Research Centre, University of Verona, 37134 Verona, Italy. sabrinaluigia.dagosto@univr.it. · ARC-Net Research Centre, University of Verona, 37134 Verona, Italy. silvia.andreani@univr.it. · ARC-Net Research Centre, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · ARC-Net Research Centre, University of Verona, 37134 Verona, Italy. vincenzo.corbo@univr.it. · Department of Diagnostics and Public Health, University of Verona, 37134 Verona, Italy. vincenzo.corbo@univr.it. ·Int J Mol Sci · Pubmed #31195689.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is a malignancy of the exocrine pancreas with the worst prognosis among all solid tumours, and soon to become the second leading cause of cancer-related deaths. A more comprehensive understanding of the molecular mechanisms underlying this disease is crucial to the development of diagnostic tools as well as to the identification of more effective therapies. High-frequency mutations in PDA occur in "undruggable" genes, and molecular subtyping based on bulk transcriptome analysis does not yet nominate valid therapeutic intervention strategies. Genome-wide sequencing studies have also demonstrated a considerable intra- and inter-patient's genetic heterogeneity, which further complicate this dire scenario. More than in other malignancies, functionalization of the PDA genome and preclinical modelling at the individual patient level appear necessary to substantially improve survival rates for pancreatic cancer patients. Traditional human PDA models, including monolayer cell cultures and patient-derived xenografts, have certainly led to valuable biological insights in the past years. However, those model systems suffer from several limitations that have contributed to the lack of concordance between preclinical and clinical studies for PDA. Pancreatic ductal organoids have recently emerged as a reliable culture system to establish models from both normal and neoplastic pancreatic tissues. Pancreatic organoid cultures can be efficiently generated from small tissue biopsies, which opens up the possibility of longitudinal studies in individual patients. A proof-of-concept study has demonstrated that patient-derived PDA organoids are able to predict responses to conventional chemotherapy. The use of this three-dimensional culture system has already improved our understanding of PDA biology and promises to implement precision oncology by enabling the alignment of preclinical and clinical platforms to guide therapeutic intervention in PDA.

3 Review The landscape of molecular alterations in pancreatic and small intestinal neuroendocrine tumours. 2019

Scarpa, Aldo. ·RC-Net Centre for applied research on cancer, University and Hospital Trust of Verona, 37134 Verona, Italy; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy. Electronic address: aldo.scarpa@univr.it. ·Ann Endocrinol (Paris) · Pubmed #31072588.

ABSTRACT: Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) arise throughout the gut and feature varying biological behaviour and malignant potential. GEP-NENs include two genetically different entities, well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinomas (NEC). NECs are characterized by a dismal prognosis and by distinctive TP53 and RB1 inactivation which sets them apart from NETs. The latter, conversely, have a wide spectrum of aggressiveness and molecular alterations. Knowledge on their biology has recently expanded thanks to high-throughput studies focused on two important groups of well-differentiated neuroendocrine neoplasms: pancreatic (PanNETs) and small intestinal (SiNETs) tumours. PanNETs have been among the most studied also due to genetic syndromes featuring their onset. Research stemming from this observation has uncovered the inactivation of MEN1, VHL, TSC1/2, and the hyperactivation of the PI3K/mTOR pathway as distinctive biological features of these neoplasms. Next-Generation Sequencing added information on the role of telomere lengthening via ATRX/DAXX inactivation in a fraction of PanNETs, while other display shortened telomeres and recurrent chromosomal alterations. The data so far disclosed a heterogeneous combination of driver events, yet converging into four pathways including DNA damage repair, cell cycle regulation, PI3K/mTOR signalling and telomere maintenance. SiNETs showed a lesser relationship with mutational driver events, even in the case of familial cases. High throughput studies identified putative driver mutations in CDKN1 and APC which, however, were reported in a minor fraction (∼10%) of cases. Tumorigenesis of SiNETs seems to depend more on chromosomal alterations (loss of chromosome 8, gains at 4, 5 and 20) and epigenetic events, which converge to hyperactivate the PI3K/mTOR, MAPK and Wnt pathways. While calling for further integrative studies, these data lay previous and recent findings in a more defined frame and provide clinical research with several candidate markers for patient stratification and companion diagnostics.

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 Unmet Needs in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3). 2019

Sorbye, Halfdan / Baudin, Eric / Borbath, Ivan / Caplin, Martyn / Chen, Jie / Cwikla, Jaroslaw B / Frilling, Andrea / Grossman, Ashley / Kaltsas, Gregory / Scarpa, Aldo / Welin, Staffan / Garcia-Carbonero, Rocio / Anonymous1101017. ·Department of Oncology and Clinical Science, Haukeland University Hospital, Bergen, Norwayhalfdan.sorbye@helse-bergen.no. · Endocrine Oncology, Gustave Roussy, Villejuif, France. · Hepato-Gastroenterology Unit, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium. · Neuroendocrine Tumour Unit, Centre for Gastroenterology, Royal Free Hospital, London, United Kingdom. · Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. · Faculty of Medical Sciences, University of Warmia and Mazury, Olsztyn, Poland. · Department of Surgery and Cancer, Imperial College London, London, United Kingdom. · Neuroendocrine Tumour Unit, Royal Free Hospital, London, United Kingdom. · National and Kapodistrian University of Athens, Athens, Greece. · ARC-Net Centre for Applied Research on Cancer and Section of Pathology of the Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy. · Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden. · Oncology Department, Hospital Universitario 12 de Octubre, CNIO, CIBERONC, Universidad Complutense de Madrid, Madrid, Spain. ·Neuroendocrinology · Pubmed #30153658.

ABSTRACT: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are classified based on morphology and graded based on their proliferation rate as either well-differentiated low-grade (G1 to G2) neuroendocrine tumors (NET) or poorly differentiated high-grade (G3) neuroendocrine carcinomas (NEC). Recently, a new subgroup of well-differentiated high-grade pancreatic tumors (NET G3) has been defined. The GEP NEN G3 group consisting of both NEC and NET G3 has recently been shown to be a quite heterogeneous patient group concerning prognosis and treatment benefit, depending on factors such as the primary tumor site, differentiation, proliferation rate, and molecular alterations. In this review we discuss the existing data on diagnostics, treatment, and biomarkers in this patient group, the unmet needs, and the future perspectives.

6 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.

7 Review Screening/surveillance programs for pancreatic cancer in familial high-risk individuals: A systematic review and proportion meta-analysis of screening results. 2018

Paiella, Salvatore / Salvia, Roberto / De Pastena, Matteo / Pollini, Tommaso / Casetti, Luca / Landoni, Luca / Esposito, Alessandro / Marchegiani, Giovanni / Malleo, Giuseppe / De Marchi, Giulia / Scarpa, Aldo / D'Onofrio, Mirko / De Robertis, Riccardo / Pan, Teresa Lucia / Maggino, Laura / Andrianello, Stefano / Secchettin, Erica / Bonamini, Deborah / Melisi, Davide / Tuveri, Massimiliano / Bassi, Claudio. ·General and Pancreatic Surgery Department, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. Electronic address: salvatore.paiella@univr.it. · General and Pancreatic Surgery Department, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. · Gastroenterology B Unit, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy; ARC-NET Research Center, University and Hospital Trust of Verona, Verona, Italy. · Department of Radiology, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. · Department of Radiology, Casa di Cura Pederzoli Hospital, Peschiera del Garda, Italy. · Oncology Unit, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy. ·Pancreatology · Pubmed #29709409.

ABSTRACT: BACKGROUND/OBJECTIVES: Screening/surveillance programs for pancreatic cancer (PC) in familial high-risk individuals (FPC-HRI) have been widely reported, but their merits remain unclear. The data reported so far are heterogeneous-especially in terms of screening yield. We performed a systematic review and meta-analysis of currently available data coming from screening/surveillance programs to evaluate the proportion of screening goal achievement (SGA), overall surgery and unnecessary surgery. METHODS: We searched MEDLINE, Embase, PubMed and the Cochrane Library database from January 2000 to December 2016to identify studies reporting results of screening/surveillance programs including cohorts of FPC-HRI. The main outcome measures were weighted proportion of SGA, overall surgery, and unnecessary surgery among the FPC-HRI cohort, using a random effects model. SGA was defined as any diagnosis of resectable PC, PanIN3, or high-grade dysplasia intraductal papillary mucinous neoplasm (HGD-IPMN). Unnecessary surgery was defined as any other final pathology. RESULTS: In a meta-analysis of 16 studies reporting on 1551 FPC-HRI cases, 30 subjects (1.82%), received a diagnosis of PC, PanIN3 or HGD-IPMNs. The pooled proportion of SGA was 1.4%(95% CI 0.8-2, p < 0.001, I CONCLUSIONS: The weighted proportion of SGA of screening/surveillance programs published thus far is excellent. However, the probability of receiving surgery during the screening/surveillance program is non-negligible, and unnecessary surgery is a potential negative outcome.

8 Review Systematic review, meta-analysis, and a high-volume center experience supporting the new role of mural nodules proposed by the updated 2017 international guidelines on IPMN of the pancreas. 2018

Marchegiani, Giovanni / Andrianello, Stefano / Borin, Alex / Dal Borgo, Chiara / Perri, Giampaolo / Pollini, Tommaso / Romanò, Giorgia / D'Onofrio, Mirko / Gabbrielli, Armando / Scarpa, Aldo / Malleo, Giuseppe / Bassi, Claudio / Salvia, Roberto. ·General and Pancreatic Surgery, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy. · Radiology, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy. · Gastroenterology and Digestive Endoscopy, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy. · Pathology, ARCNet Research Center, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy. · General and Pancreatic Surgery, Pancreas Institute, University of Verona Hospital Trust, Verona, Italy. Electronic address: roberto.salvia@univr.it. ·Surgery · Pubmed #29454468.

ABSTRACT: BACKGROUND: Mural nodules (MNs) have a predominant role in the 2016 revision of the international guidelines on intraductal papillary mucinous neoplasms (IPMN) of the pancreas. The aim of this study was to evaluate MNs as predictors of invasive cancer (iCa) or high-grade dysplasia (HGD) in IPMNs and to investigate the role of MN size in risk prediction. METHODS: A PRISMA-compliant systematic review of the literature and meta-analysis on selected studies were conducted. The random effect model was adopted, and the pooled SMD (standardized mean difference) obtained. The surgical series of IPMNs at a single high-volume institution was reviewed. RESULTS: This review included 70 studies and 2297 resected IPMNs. MNs have a positive predictive value for malignancy of 62.2%. The meta-analysis suggested that MN size has a considerable effect on predicting IPMNs with both iCa or HGD with a mean SMD of 0.79. All studies included in the meta-analysis used contrast-enhanced endosonography (CE-EUS) to assess MNs. Due to the heterogeneity of the proposed thresholds, no reliable MN size cut-off was identified. Of 317 IPMNs resected at our institution, 102 (32.1%) had a preoperative diagnosis of MN. Multivariate analysis showed that MN is the only independent predictor of iCa and HGD for all types of IPMNs. CONCLUSION: MNs are reliable predictors of iCa and HGD in IPMNs as proposed by the 2016 IAP guidelines. CE-EUS seems to be the best tool for characterizing size and has the best accuracy for predicting malignancy. Further studies should determine potential MN dimensional cut-offs.

9 Review Genomic landscape of pancreatic neuroendocrine tumours: the International Cancer Genome Consortium. 2018

Mafficini, Andrea / Scarpa, Aldo. ·ARC-Net Centre for Applied Research on CancerUniversity and Hospital Trust of Verona, Verona, Italy. · Department of Diagnostics and Public HealthSection of Pathology, University and Hospital Trust of Verona, Verona, Italy. · ARC-Net Centre for Applied Research on CancerUniversity and Hospital Trust of Verona, Verona, Italy aldo.scarpa@univr.it. ·J Endocrinol · Pubmed #29321190.

ABSTRACT: Neuroendocrine tumours (NETs) may arise throughout the body and are a highly heterogeneous, relatively rare class of neoplasms difficult to study also for the lack of disease models. Despite this, knowledge on their molecular alterations has expanded in the latest years, also building from genetic syndromes causing their onset. Pancreatic NETs (PanNETs) have been among the most studied, and research so far has outlined a series of recurring features, as inactivation of

10 Review Multimodal treatment of resectable pancreatic ductal adenocarcinoma. 2017

Silvestris, Nicola / Brunetti, Oronzo / Vasile, Enrico / Cellini, Francesco / Cataldo, Ivana / Pusceddu, Valeria / Cattaneo, Monica / Partelli, Stefano / Scartozzi, Mario / Aprile, Giuseppe / Casadei Gardini, Andrea / Morganti, Alessio Giuseppe / Valentini, Vincenzo / Scarpa, Aldo / Falconi, Massimo / Calabrese, Angela / Lorusso, Vito / Reni, Michele / Cascinu, Stefano. ·Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: n.silvestris@oncologico.bari.it. · Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: dr.oronzo.brunetti@tiscali.it. · Department of Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. Electronic address: e.vasile@ao.pisa.toscana.it. · Radiation Oncology Department, Gemelli ART, Università Cattolica del Sacro Cuore, Roma, Italy. Electronic address: francesco.cellini@uniroma3.it. · ARC-NET Research Centre, University of Verona, Verona, Italy. Electronic address: cataldo.ivana@gmail.com. · Medical Oncology Unit, University of Cagliari, Cagliari, Italy. Electronic address: oncologiamedica2reparto@gmail.com. · Department of Medical Oncology, University and General Hospital, Udine, Italy. Electronic address: aprile83@gmail.com. · Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele Scientific Institute, 'Vita-Salute' University, Milan, Italy. Electronic address: partelli.stefano@hsr.it. · Medical Oncology Unit, University of Cagliari, Cagliari, Italy. Electronic address: marioscartozzi@gmail.com. · Department of Medical Oncology, University and General Hospital, Udine, Italy; Department of Medical Oncology, General Hospital of Vicenza, Vicenza, Italy. Electronic address: aprile.giuseppe@aoud.sanita.fvg.it. · Medical Oncology Unit, IRCCS, Meldola, Italy. Electronic address: casadeigardini@gmail.com. · Radiation Oncology Center, Dept. of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy. Electronic address: alessio.morganti2@unibo.it. · Radiation Oncology Department, Gemelli ART, Università Cattolica del Sacro Cuore, Roma, Italy. Electronic address: vincenzo.valentini@unicatt.it. · ARC-NET Research Centre, University of Verona, Verona, Italy. Electronic address: aldo.scarpa@univr.it. · Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele Scientific Institute, 'Vita-Salute' University, Milan, Italy. Electronic address: falconi.massimo@hsr.it. · Radiology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: acalabrese22@gmail.com. · Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: vito.lorusso@oncologico.bari.it. · Medical Oncology Department, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it. · Modena Cancer Center, Policlinico di Modena Università di Modena e Reggio Emilia, Italy. Electronic address: cascinu@yahoo.com. ·Crit Rev Oncol Hematol · Pubmed #28259290.

ABSTRACT: After a timing preoperative staging, treatment of resectable pancreatic adenocarcinoma (PDAC) includes surgery and adjuvant therapies, the former representing the initial therapeutic option and the latter aiming to reduce the incidence of both distant metastases (chemotherapy) and locoregional failures (chemoradiotherapy). Herein, we provide a critical overview on the role of multimodal treatment in PDAC and on new opportunities related to current more active poli-chemotherapy regimens, targeted therapies, and the more recent immunotherapy approaches. Moreover, an analysis of pathological markers and clinical features able to help clinicians in the selection of the best therapeutic strategy will be discussed. Lastly, the role of neoadjuvant treatment of initially resectable disease will be considered mostly in patients whose malignancy shows morphological but not clinical or biological criteria of resectability. Depending on the results of these investigational studies, today a multidisciplinary approach can offer the best address therapy for these patients.

11 Review Reduced risk of pancreatic cancer associated with asthma and nasal allergies. 2017

Gomez-Rubio, Paulina / Zock, Jan-Paul / Rava, Marta / Marquez, Mirari / Sharp, Linda / Hidalgo, Manuel / Carrato, Alfredo / Ilzarbe, Lucas / Michalski, Christoph / Molero, Xavier / Farré, Antoni / Perea, José / Greenhalf, William / O'Rorke, Michael / Tardón, Adonina / Gress, Thomas / Barberà, Victor / Crnogorac-Jurcevic, Tatjana / Domínguez-Muñoz, Enrique / Muñoz-Bellvís, Luís / Alvarez-Urturi, Cristina / Balcells, Joaquim / Barneo, Luis / Costello, Eithne / Guillén-Ponce, Carmen / Kleeff, Jörg / Kong, Bo / Lawlor, Rita / Löhr, Matthias / Mora, Josefina / Murray, Lim / O'Driscoll, Damian / Peláez, Pablo / Poves, Ignasi / Scarpa, Aldo / Real, Francisco X / Malats, Núria / Anonymous5500850. ·Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain. · Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. · National Cancer Registry Ireland, Cork, Ireland, and Institute of Health & Society, Newcastle University, UK. · Hospital Madrid-Norte-Sanchinarro, Madrid, Spain. · Department of Oncology, Hospital Ramón y Cajal, Madrid, Spain. · Hospital del Mar-Parc de Salut Mar, Barcelona, Spain. · Technical University of Munich, Munich, Germany. · Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain. · Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. · Department of Surgery, 12 de Octubre University Hospital, Madrid, Spain. · The Royal Liverpool University Hospital, Liverpool, UK. · Centre for Public Health, Queen's University Belfast, Belfast, UK. · Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain. · Department of Gastroenterology, University Hospital Giessen and Marburg, Marburg, Germany. · Laboratorio de Genética Molecular, Hospital General Universitario de Elche, Elche, Spain. · Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. · Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain. · Cirugía General y del Aparato Digestivo, Hospital Universitario de Salamanca, Salamanca, Spain. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Gastrocentrum, Karolinska Institutet, Stockholm, Sweden. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. ·Gut · Pubmed #26628509.

ABSTRACT: OBJECTIVE: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk. DESIGN: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model. RESULTS: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk. CONCLUSIONS: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.

12 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.

13 Review International Association of Pancreatology (IAP)/European Pancreatic Club (EPC) consensus review of guidelines for the treatment of pancreatic cancer. 2016

Takaori, Kyoichi / Bassi, Claudio / Biankin, Andrew / Brunner, Thomas B / Cataldo, Ivana / Campbell, Fiona / Cunningham, David / Falconi, Massimo / Frampton, Adam E / Furuse, Junji / Giovannini, Marc / Jackson, Richard / Nakamura, Akira / Nealon, William / Neoptolemos, John P / Real, Francisco X / Scarpa, Aldo / Sclafani, Francesco / Windsor, John A / Yamaguchi, Koji / Wolfgang, Christopher / Johnson, Colin D / Anonymous8350852. ·Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: takaori@kuhp.kyoto-u.ac.jp. · Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy. · Academic Unit of Surgery, University of Glasgow, Glasgow, United Kingdom. · Department of Radiation Oncology, University Hospitals Freiburg, Germany. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. · Pancreatic Surgery Unit, Università Vita e Salute, Milano, Italy. · HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, United Kingdom. · Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan. · Endoscopic Unit, Paoli-Calmettes Institute, Marseille, France. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Radiation Oncology and Image-applied Therapy, Kyoto University Hospital, Kyoto, Japan. · Division of General Surgery, Yale University, New Haven, CT, United States of America. · Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. · Department of Surgery, University of Auckland, HBP/Upper GI Unit, Auckland City Hospital, Auckland, New Zealand. · Department of Advanced Treatment of Pancreatic Disease, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Department of Surgery, The Johns Hopkins University, Baltimore, MD, United States of America. · University Surgical Unit, Southampton General Hospital, Southampton, United Kingdom. ·Pancreatology · Pubmed #26699808.

ABSTRACT: BACKGROUND: Pancreatic cancer is one of the most devastating diseases with an extremely high mortality. Medical organizations and scientific societies have published a number of guidelines to address active treatment of pancreatic cancer. The aim of this consensus review was to identify where there is agreement or disagreement among the existing guidelines and to help define the gaps for future studies. METHODS: A panel of expert pancreatologists gathered at the 46th European Pancreatic Club Meeting combined with the 18th International Association of Pancreatology Meeting and collaborated on critical reviews of eight English language guidelines for the clinical management of pancreatic cancer. Clinical questions (CQs) of interest were proposed by specialists in each of nine areas. The recommendations for the CQs in existing guidelines, as well as the evidence on which these were based, were reviewed and compared. The evidence was graded as sufficient, mediocre or poor/absent. RESULTS: Only 4 of the 36 CQs, had sufficient evidence for agreement. There was also agreement in five additional CQs despite the lack of sufficient evidence. In 22 CQs, there was disagreement regardless of the presence or absence of evidence. There were five CQs that were not addressed adequately by existing guidelines. CONCLUSION: The existing guidelines provide both evidence- and consensus-based recommendations. There is also considerable disagreement about the recommendations in part due to the lack of high level evidence. Improving the clinical management of patients with pancreatic cancer, will require continuing efforts to undertake research that will provide sufficient evidence to allow agreement.

14 Review Neoadjuvant multimodal treatment of pancreatic ductal adenocarcinoma. 2016

Silvestris, Nicola / Longo, Vito / Cellini, Francesco / Reni, Michele / Bittoni, Alessandro / Cataldo, Ivana / Partelli, Stefano / Falconi, Massimo / Scarpa, Aldo / Brunetti, Oronzo / Lorusso, Vito / Santini, Daniele / Morganti, Alessio / Valentini, Vincenzo / Cascinu, Stefano. ·Medical Oncology Unit, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy. Electronic address: n.silvestris@oncologico.bari.it. · Medical Oncology Unit, 'Mons R Dimiccoli' Hospital, Barletta, Italy. · Radiation Oncology Department, Policlinico Universitario Campus Bio-Medico, Rome, Italy. · Medical Oncology Department, IRCCS San Raffaele Scientific Institute, Milano, Italy. · Medical Oncology Clinic, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy. · ARC-NET Research Centre, University of Verona, Italy. · Pancreatic Unit, Department of Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Medical Oncology Unit, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy. · Medical Oncology Unit, University Campus Biomedico, Roma, Italy. · Radiation Oncology Center, Dept. of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy. ·Crit Rev Oncol Hematol · Pubmed #26653573.

ABSTRACT: Treatment of pancreatic ductal adenocarcinoma (PDAC) is increasingly multidisciplinary, with neoadjuvant strategies (chemotherapy, radiation, and surgery) administered in patients with resectable, borderline resectable, or locally advanced disease. The rational supporting this management is the achievement of both higher margin-negative resections and conversion rates into potentially resectable disease and in vivo assessment of novel therapeutics. International guidelines suggest an initial staging of the disease followed by a multidisciplinary approach, even considering the lack of a treatment approach to be considered as standard in this setting. This review will focus on both literature data supporting these guidelines and on new opportunities related to current more active chemotherapy regimens. An analysis of the pathological assessment of response to therapy and the potential role of target therapies and translational biomarkers and ongoing clinical trials of significance will be discussed.

15 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.

16 Review Genetics and Epigenetics of Pancreatic Neuroendocrine Tumors and Pulmonary Carcinoids. 2015

Dreijerink, Koen M A / Derks, Jules L / Cataldo, Ivana / Scarpa, Aldo / Valk, Gerlof D / Speel, Ernst-Jan M. ·Department of Endocrine Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands. ·Front Horm Res · Pubmed #26303708.

ABSTRACT: In this chapter, we give an overview of the genetic and epigenetic background of neuroendocrine tumors (NETs), in particular pancreatic and pulmonary NETs. Studying the mechanism of disease of the inherited syndromes that feature NETs has provided valuable insights that have revolutionized the therapeutic options for these tumor types: both inhibition of mTOR (mammalian target of rapamycin) signaling and inhibition of angiogenesis have become standard treatments. Although sporadic NETs harbor relatively few somatic gene mutations, these somatic mutations often affect genes that encode epigenetic regulators. Restoring the aberrant epigenetic characteristics may be an attractive approach for future treatment.

17 Review MicroRNA in pancreatic adenocarcinoma: predictive/prognostic biomarkers or therapeutic targets? 2015

Brunetti, Oronzo / Russo, Antonio / Scarpa, Aldo / Santini, Daniele / Reni, Michele / Bittoni, Alessandro / Azzariti, Amalia / Aprile, Giuseppe / Delcuratolo, Sabina / Signorile, Michele / Gnoni, Antonio / Palermo, Loredana / Lorusso, Vito / Cascinu, Stefano / Silvestris, Nicola. ·Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy. · Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medical Oncology, University Campus Bio-Medico, Rome, Italy. · Department of Medical Oncology, San Raffaele Scientific Institute, Milan, Italy. · AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy. · Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy. · Department of Medical Oncology, University Hospital of Udine, Udine, Italy. · Department of Medical Oncology, Hospital of Taranto, Taranto, Italy. ·Oncotarget · Pubmed #26259238.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, short overall survival and few chemotherapeutic choices. MicroRNAs (miRNAs) are non-coding, single-stranded RNAs of around 22 nucleotides involved in the pathogenic mechanisms of carcinogenesis and metastasis. They have been studied in many tumors in order to identify potential diagnostic, prognostic or therapeutic targets. In the current literature, many studies have analyzed the role of miRNAs in PDAC. In fact, the absence of appropriate biomarkers, the difficultly of early detection of this tumor, and the lack of effective chemotherapy in patients with unresectable disease have focused attention on miRNAs as new, interesting advance in this malignancy. In this review we analyzed the role of miRNAs in PDAC in order to understand the mechanisms of action and the difference between the onco-miRNA and the tumor suppressor miRNA. We also reviewed all the data related to the use of these molecules as predictive as well as prognostic biomarkers in the course of the disease. Finally, the possible therapeutic use of miRNAs or anti-miRNAs in PDAC is also discussed. In conclusion, although there is still no clinical application for these molecules in PDAC, it is our opinion that the preclinical evidence of the role of specific miRNAs in carcinogenesis, the possibility of using miRNAs as diagnostic or prognostic biomarkers, and their potential therapeutic role, warrant future studies in PDAC.

18 Review Metastatic pancreatic cancer: Is there a light at the end of the tunnel? 2015

Vaccaro, Vanja / Sperduti, Isabella / Vari, Sabrina / Bria, Emilio / Melisi, Davide / Garufi, Carlo / Nuzzo, Carmen / Scarpa, Aldo / Tortora, Giampaolo / Cognetti, Francesco / Reni, Michele / Milella, Michele. ·Vanja Vaccaro, Sabrina Vari, Carlo Garufi, Carmen Nuzzo, Francesco Cognetti, Michele Milella, Medical Oncology A, Regina Elena National Cancer Institute, 00144 Rome, Italy. ·World J Gastroenterol · Pubmed #25944992.

ABSTRACT: Due to extremely poor prognosis, pancreatic cancer (PDAC) represents the fourth leading cause of cancer-related death in Western countries. For more than a decade, gemcitabine (Gem) has been the mainstay of first-line PDAC treatment. Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results. Recently, the field of systemic therapy of advanced PDAC is finally moving forward. Polychemotherapy has shown promise over single-agent Gem: regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control, although sometimes at the cost of poor tolerability. The PRODIGE 4/ACCORD 11 was the first phase III trial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX; however the less favorable safety profile and the characteristics of the enrolled population, restrict the use of FOLFIRINOX to young and fit PDAC patients. The nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells. Regardless of whether or not this is its main mechanisms of action, the combination of nab-Paclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints. Furthermore, recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC, particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control. Here, we provide an overview of recent advances in the systemic treatment of advanced PDAC, mostly focusing on recent findings that have set new standards in metastatic disease. Potential avenues for further development in the metastatic setting and current efforts to integrate new effective chemotherapy regimens in earlier stages of disease (neoadjuvant, adjuvant, and multimodal approaches in both resectable and unresectable patients) are also briefly discussed.

19 Review ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. 2015

Maragliano, Roberta / Vanoli, Alessandro / Albarello, Luca / Milione, Massimo / Basturk, Olca / Klimstra, David S / Wachtel, Antonio / Uccella, Silvia / Vicari, Emanuela / Milesi, Marina / Davì, Maria Vittoria / Scarpa, Aldo / Sessa, Fausto / Capella, Carlo / La Rosa, Stefano. ·*Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy ‡‡Department of Pathology, Ospedale di Circolo, Varese, Italy †Department of Molecular Medicine, University of Pavia, Pavia, Italy ‡Department of Pathology, San Raffaele Hospital, Milan, Italy §Department of Pathology, National Institute of Cancer, Milan, Italy #Department of Pathology, Multimedica, Milan, Italy **Department of Medicine, "G.B. Rossi" University Hospital, Verona, Italy ††ARC-NET Research Center and Department of Pathology and Diagnostics, University of Verona, Verona, Italy ∥Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY ¶Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru. ·Am J Surg Pathol · Pubmed #25353285.

ABSTRACT: Adrenocorticotropic hormone (ACTH)-secreting pancreatic neuroendocrine tumors (PanNETs), although rare, are responsible for about 15% of ectopic Cushing syndrome (CS). They represent a challenging entity because their preoperatory diagnosis is frequently difficult, and clear-cut morphologic criteria useful to differentiate them from other types of PanNETs have not been defined. Ectopic ACTH secretion associated with CS can also be rarely due to pancreatic acinar cell carcinoma (ACC) and pancreatoblastoma, rare tumor types with morphologic features sometimes overlapping those of PanNETs and, for this reason, representing a diagnostic challenge for pathologists. We herein describe the clinicopathologic and immunohistochemical features of 10 PanNETs and 1 ACC secreting ACTH and associated with CS together with an extensive review of the literature to give the reader a comprehensive overview on ACTH-producing pancreatic neoplasms. ACTH-secreting PanNETs are aggressive neoplasms with an immunohistochemical profile that partially overlaps that of pituitary corticotroph adenomas. They are generally large and well-differentiated neoplasms without distinctive histologic features but with signs of aggressiveness including vascular and perineural invasion. They are more frequent in female individuals with a mean age of 42 years. At 5 and 10 years after diagnosis, 35% and 16.2% of patients, respectively, were alive. ACTH-secreting ACCs and pancreatoblastomas are very aggressive pediatric tumors with a poor prognosis. Using an appropriate immunohistochemical panel including ACTH, β-endorphin, trypsin, and BCL10 it is possible to recognize ACTH-secreting PanNETs and to distinguish them from the very aggressive ACTH-secreting ACCs.

20 Review Clinical application of microRNA testing in neuroendocrine tumors of the gastrointestinal tract. 2014

Vicentini, Caterina / Fassan, Matteo / D'Angelo, Edoardo / Corbo, Vincenzo / Silvestris, Nicola / Nuovo, Gerard J / Scarpa, Aldo. ·ARC-Net Research Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · ARC-Net Research Centre, University and Hospital Trust of Verona, Verona 37134, Italy. matteo.fassan@gmail.com. · Medical Oncology Unit, National Cancer Institute "Giovanni Paolo II", Bari 70124, Italy. · Comprehensive Cancer Centre, Ohio State University, Columbus, OH 43210, USA. ·Molecules · Pubmed #24566314.

ABSTRACT: It is well documented that dysregulation of microRNAs is a hallmark of human cancers. Thus, this family of small non-coding regulatory molecules represents an excellent source of sensitive biomarkers. Unique microRNAs expression profiles have been associated with different types and subsets of gastrointestinal tumors including gastroenteropancreatic neuroendocrine tumors (GEP-NETs). GEP-NETs are a heterogeneous group of epithelial neoplasms with neuroendocrine differentiation. At present, early detection and surgical resection of GEP-NETs represent the best chance for a cure. Thus, clinically useful biomarkers for GEP-NETs that strongly correlate with early detection are urgently needed. The purpose of this review is to summarize the role of miRNAs in GEP-NET carcinogenesis and their possible use as novel diagnostic, prognostic and predictive biomarkers.

21 Review Molecular targeted therapy in enteropancreatic neuroendocrine tumors: from biology to clinical practice. 2014

Fazio, N / Scarpa, A / Falconi, M. ·Unit of Gastrointestinal and Neuroendocrine Tumor, European Institute of Oncology, Via Ripamonti 435 20141 Milan, Italy. nicola.fazio@ieo.it. ·Curr Med Chem · Pubmed #23992320.

ABSTRACT: Advanced enteropancreatic (EP) neuroendocrine tumors (NETs) can be treated with several different therapies, including chemotherapy, biotherapy, and locoregional treatments. Over the last few decades, impressive progress has been made in the biotherapy field. Three main druggable molecular targets have been studied and developed in terms of therapy: somatostatin receptor (sstr), mammalian target of rapamycin (mTOR), and angiogenic factors. In particular, research has moved from the old somatostatin analogs (SSAs), such as octreotide (OCT) and lanreotide (LAN), specifically binding to the sstr-2, to the newer pasireotide (PAS), which presents a wider sstr spectrum. Over the last ten years, several molecular targeted agents (MTAs) have been studied in phase II trials, and very few of them have reached phase III. The mTOR inhibitor everolimus and the multitargeted inhibitor sunitinib have been approved for clinical use by the FDA and EMA in advanced well/moderately-differentiated (WD, MD) progressive pancreatic neuroendocrine tumors (PNETs), on the basis of the positive results of two international large randomized phase III trials vs. placebo. Bevacizumab has been studied in a large US phase III trial vs. interferon (IFN)-alfa2b, and results are pending. In this review, the biological and clinical aspects of MTAs introduced into clinical practice or which are currently in an advanced phase of clinical investigation are addressed.

22 Review Carcinogenesis of pancreatic adenocarcinoma: precursor lesions. 2013

Gnoni, Antonio / Licchetta, Antonella / Scarpa, Aldo / Azzariti, Amalia / Brunetti, Anna Elisabetta / Simone, Gianni / Nardulli, Patrizia / Santini, Daniele / Aieta, Michele / Delcuratolo, Sabina / Silvestris, Nicola. ·Medical Oncology Unit, Hospital Vito Fazzi, Lecce 73100, Italy. n.silvestris@oncologico.bari.it. ·Int J Mol Sci · Pubmed #24084722.

ABSTRACT: Pancreatic adenocarcinoma displays a variety of molecular changes that evolve exponentially with time and lead cancer cells not only to survive, but also to invade the surrounding tissues and metastasise to distant sites. These changes include: genetic alterations in oncogenes and cancer suppressor genes; changes in the cell cycle and pathways leading to apoptosis; and also changes in epithelial to mesenchymal transition. The most common alterations involve the epidermal growth factor receptor (EGFR) gene, the HER2 gene, and the K-ras gene. In particular, the loss of function of tumor-suppressor genes has been documented in this tumor, especially in CDKN2a, p53, DPC4 and BRCA2 genes. However, other molecular events involved in pancreatic adenocarcinoma pathogenesis contribute to its development and maintenance, specifically epigenetic events. In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs. In this scenario, highlighting these molecular alterations could provide new clinical tools for early diagnosis and new effective therapies for this malignancy.

23 Review Pathology - grading and staging of GEP-NETs. 2012

Capelli, Paola / Fassan, Matteo / Scarpa, Aldo. ·Department of Pathology and Diagnostics & ARC-NET Research Centre, University of Verona, Verona, Italy. paola.capelli@ospedaleuniverona.it ·Best Pract Res Clin Gastroenterol · Pubmed #23582914.

ABSTRACT: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) constitute a heterogeneous group of neoplasms. In the last few decades, due to a substantial rise in incidence and prevalence, GEP-NETs have been included among the most common tumours of the gastrointestinal tract. Diagnosis could be challenging and a significant number of patients present with metastatic or unresectable disease. The development of appropriate tools for standardised prognostic stratification and the introduction of effective target therapies have opened new horizons for planning tailored surgical or medical management and follow-up programs for these complex neoplasms. An overview on the GEP-NETs' diagnostic and prognostic criteria proposed by the recently published WHO classification and ENETS and UICC TNM staging systems is presented, focussing on their impact on the clinical and therapeutical approaches.

24 Review Clinical implications of biological markers in Pancreatic Ductal Adenocarcinoma. 2012

Giovinazzo, Francesco / Turri, Giulia / Zanini, Sara / Butturini, Giovanni / Scarpa, Aldo / Bassi, Claudio. ·Laboratory of Translational Surgery, University Laboratories of Medical Research (LURM), G.B. Rossi Hospital, University of Verona, Piazzale L.A. Scuro 10, Verona 37134, Italy. ·Surg Oncol · Pubmed #22981281.

ABSTRACT: Pancreatic Ductal Adenocarcinoma (PDAC) is a malignant neoplasm and is the fourth leading cause of cancer-related deaths in US with a 5-year survival rate less than 5%. Surgery is the only potentially curative treatment even though the result is a palliation in the majority of cases and the majority of lesions are lately diagnosed. Progression from normal pancreatic epithelium to metastatic disease is now a well-characterized sequence of events. Research has shown that pancreatic cancer is fundamentally a genetic disease with several biological pathway implied in apoptosis, cell proliferation and self-sufficiency in growth signaling, but how those findings could be applied in daily clinical practice remain unknown. Several studies tried to characterize diagnostic and prognostic biomarkers in PDAC to make it possible an earlier diagnosis, guarantee a more effective treatment and reach a better prognosis even though the results remain contrasting. The main limit of the published researches is the small number of patients studied, but even the heterogeneity of the used methods of analysis. Examining critically the research of the last years future trials may be addressed toward a translational models integrating "the bench and the bed" with the clinical experience and drive the basic research toward the clinical applications.

25 Review Molecular pathology of pancreatic cancer: from bench-to-bedside translation. 2012

Corbo, Vincenzo / Tortora, Giampaolo / Scarpa, Aldo. ·ARC-NET Research Centre, University Hospital of Verona, Verona, Italy. ·Curr Drug Targets · Pubmed #22458520.

ABSTRACT: Pancreatic ductal adenocarcinoma (referred here as pancreatic cancer) is a lethal disease with the worst prognosis among all solid tumors. Surgical resection represents the only hope for cure but it is possible only in patients that present with local disease (about 20% of cases). Whether dismal prognosis of pancreatic cancer is a result of late diagnosis or early dissemination to distant organ is still a debate. Moreover, this disease shows an intrinsic chemotherapeutic resistance that has been mainly ascribed to the presence of a dense stromal reaction that significantly impairs drugs delivery. Clinical management of pancreatic cancer patients relies on few molecular markers (e.g., the diagnostic marker CA19-9) that, however, present several limitations to their use. The clinical usefulness of somatic alterations in well-characterized genes (such as KRAS and TP53), whose detection is technically feasible in different biological samples, has been extensively investigated leading to inconsistent results. Furthermore, none of the candidate molecular markers identified in recent years has shown an appropriate clinical performance and therefore none is routinely used. This depicts a scenario where the identification of novel and effective clinical biomarkers is mandatory. Very recent genome-wide comprehensive studies have shed light on the high degree of genetic complexity and heterogeneity of the pancreatic cancers. Although far from being introduced into the clinical settings, results from those studies are expected to change definitively the perspective through which we look at the clinical management of pancreatic cancer patients towards a personalized cancer medicine.

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