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Massimo Milione 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Patrick Maisonneuve Division of Epidemiology and Biostatistics, European Institute of Oncology (IEO), Milan, Italy

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Alessio Pellegrinelli 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Federica Grillo Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova and Policlinico San Martino, Genova, Italy

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Luca Albarello Pathology Unit, IRCCS San Raffaele Scientifica Institute, Milan, Italy

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Paola Spaggiari Cancer Center Humanitas, Milan, Italy

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Alessandro Vanoli Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy

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Giovanna Tagliabue Lombardy Cancer Registry, Varese Province Cancer Registry Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Eleonora Pisa Division of Pathology, European Institute of Oncology (IEO), Milan, Italy

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Luca Messerini Diagnostic and Molecular Pathology, Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy

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Giovanni Centonze Department of Experimental Oncology and Molecular Medicine, Unit of Tumor Genomics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Clinical Research Lab (CRAB), Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

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Frediano Inzani Anatomic Pathology Unit, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy

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Aldo Scarpa ARC-Net Research Centre and Department of Diagnostics and Public Health-Section of Pathology, University and Hospital Trust of Verona, Verona, Italy

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Mauro Papotti Department of Oncology, University of Turin, Turin, Italy

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Marco Volante Department of Oncology, University of Turin, Turin, Italy

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Fausto Sessa Department of Medicine and Surgery, University of Insubria, Varese, Italy

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Nicola Fazio Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology (IEO), Milan, Italy

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Giancarlo Pruneri 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
University of Milan, School of Medicine, Milan, Italy

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Guido Rindi Institute of Anatomic Pathology, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario A. Gemelli, Rome, Italy

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Enrico Solcia Fondazione IRCCS Policlinico San Matteo and Department of Molecular Medicine, University of Pavia, Pavia, Italy

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Stefano La Rosa Service of Clinical Pathology, Lausanne University Hospital, Institute of Pathology, Lausanne, Switzerland

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Carlo Capella Department of Medicine and Surgery, University of Insubria, Varese, Italy

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digestive system proposed the term ‘mixed adenoneuroendocrine carcinoma’ (MANEC) to define these cancers in which, by definition, each component represents at least 30% of the tumor mass ( Bosman et al . 2010 ). The pathogenesis of MANECs is still unclear

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Nora Sahnane Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Daniela Furlan Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Matilde Monti Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Chiara Romualdi Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Alessandro Vanoli Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Emanuela Vicari Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Enrico Solcia Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Carlo Capella Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Fausto Sessa Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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Stefano La Rosa Section of Anatomic Pathology, CRIBI Biotechnology Center, Department of Molecular Medicine, Department of Pathology, Department of Surgical and Morphological Sciences, University of Insubria, Via O. Rossi, 9, 21100 Varese, Italy

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, representing at least 30% of the neoplastic tissue, tumors are classified as mixed adenoneuroendocrine carcinomas (MANECs; Rindi et al . 2010 ). Both the exocrine and neuroendocrine components can have different morphological features, ranging from adenomas

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Mairéad G McNamara Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
Division of Cancer Sciences, University of Manchester, Manchester, UK

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Jean-Yves Scoazec Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France
Université Paris Sud, Faculté de Médecine de Bicêtre, Le Kremlin-Bicêtre, France

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Thomas Walter Department of Gastroenterology and Medical Oncology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France

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tumours in association with loss of MMR expression. These patients may be amenable to immune checkpoint inhibitor therapy. Sahnane et al. 2015 Not reported 89 (53 patients with NEC and 36 with MANEC) Microsatellite instability (MSI) in 12

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Vivian Rosery Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Henning Reis Institute of Pathology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Konstantinos Savvatakis Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

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Bernd Kowall Center of Clinical Epidemiology, Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, University Duisburg-Essen, Essen, Germany

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Martin Stuschke Department of Radiotherapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany

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Andreas Paul German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Alexander Dechêne Department of Gastroenterology and Hepatology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Department of Internal Medicine 6, Paracelsus Medical University, Nürnberg, Germany

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JiaJin Yang Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

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Ben Zhao Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

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Arianna Borgers Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

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Stefan Kasper Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany

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Martin Schuler Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany

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Phyllis F Cheung Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany

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Jens T Siveke Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK), Partner site University Hospital Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany

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-neuroendocrine carcinoma (MANEC). In MiNEN, the Ki-67 index measurement and further analysis on the TME were solely performed in the neuroendocrine component. Data on clinical parameters were extracted from the pathologists’ original reports and the electronic health

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M Heetfeld
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C N Chougnet Department of Hepatology and Gastroenterology, Department of Nuclear Medicine, Department of Surgical Gastroenterology, Department of Internal Medicine, Department of Gastroenterology, Department of Medical Oncology, Department of Medical Oncology, Department of Clinical Medicine and Gastroenterology, Department of Hepatology and Gastroenterology, Charité University Hospital Berlin, Berlin, Germany

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I H Olsen Department of Hepatology and Gastroenterology, Department of Nuclear Medicine, Department of Surgical Gastroenterology, Department of Internal Medicine, Department of Gastroenterology, Department of Medical Oncology, Department of Medical Oncology, Department of Clinical Medicine and Gastroenterology, Department of Hepatology and Gastroenterology, Charité University Hospital Berlin, Berlin, Germany

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A Rinke Department of Hepatology and Gastroenterology, Department of Nuclear Medicine, Department of Surgical Gastroenterology, Department of Internal Medicine, Department of Gastroenterology, Department of Medical Oncology, Department of Medical Oncology, Department of Clinical Medicine and Gastroenterology, Department of Hepatology and Gastroenterology, Charité University Hospital Berlin, Berlin, Germany

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I Borbath Department of Hepatology and Gastroenterology, Department of Nuclear Medicine, Department of Surgical Gastroenterology, Department of Internal Medicine, Department of Gastroenterology, Department of Medical Oncology, Department of Medical Oncology, Department of Clinical Medicine and Gastroenterology, Department of Hepatology and Gastroenterology, Charité University Hospital Berlin, Berlin, Germany

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G Crespo Department of Hepatology and Gastroenterology, Department of Nuclear Medicine, Department of Surgical Gastroenterology, Department of Internal Medicine, Department of Gastroenterology, Department of Medical Oncology, Department of Medical Oncology, Department of Clinical Medicine and Gastroenterology, Department of Hepatology and Gastroenterology, Charité University Hospital Berlin, Berlin, Germany

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J Barriuso Department of Hepatology and Gastroenterology, Department of Nuclear Medicine, Department of Surgical Gastroenterology, Department of Internal Medicine, Department of Gastroenterology, Department of Medical Oncology, Department of Medical Oncology, Department of Clinical Medicine and Gastroenterology, Department of Hepatology and Gastroenterology, Charité University Hospital Berlin, Berlin, Germany

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M Pavel
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D O'Toole Department of Hepatology and Gastroenterology, Department of Nuclear Medicine, Department of Surgical Gastroenterology, Department of Internal Medicine, Department of Gastroenterology, Department of Medical Oncology, Department of Medical Oncology, Department of Clinical Medicine and Gastroenterology, Department of Hepatology and Gastroenterology, Charité University Hospital Berlin, Berlin, Germany

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T Walter Department of Hepatology and Gastroenterology, Department of Nuclear Medicine, Department of Surgical Gastroenterology, Department of Internal Medicine, Department of Gastroenterology, Department of Medical Oncology, Department of Medical Oncology, Department of Clinical Medicine and Gastroenterology, Department of Hepatology and Gastroenterology, Charité University Hospital Berlin, Berlin, Germany

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other Knowledge Network members
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/or chromogranin A (CgA) positivity, iii) GEP primary or of unknown primary and iv) Ki-67 index >20% or poorly differentiated morphology. Mixed tumors (MANEC) and NEN G3 without morphological differentiation available were excluded. Regarding quality of the

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O Hentic Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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P Hammel Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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A Couvelard Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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V Rebours Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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M Zappa Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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M Palazzo Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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F Maire Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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G Goujon Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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A Gillet Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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P Lévy Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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P Ruszniewski Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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expression were at least required for each case) and classified according to the WHO 2010 classification ( Rindi et al . 2010 ). All patients with equivocal pathological diagnosis, that is, mixed tumors (MANEC according to the WHO 2010 classification

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M C F Mulders Department of Internal Medicine, ENETS Center of Excellence, Section of Endocrinology, Erasmus Medical Center and Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands

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Q G de Lussanet de la Sablonière Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

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M L F van Velthuysen Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

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E M Roes Department of Gynecologic Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands

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J Hofland Department of Internal Medicine, ENETS Center of Excellence, Section of Endocrinology, Erasmus Medical Center and Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands

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W W de Herder Department of Internal Medicine, ENETS Center of Excellence, Section of Endocrinology, Erasmus Medical Center and Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands

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selection. NOM, neuroendocrine ovarian metastases; MANEC, mixed adenoneuroendocrine carcinoma; NEC, neuroendocrine carcinoma; SSTR, somatostatin receptor; PRRT, peptide receptor radionuclide therapy; SSA, somatostatin analog. PFS First, we

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Tim J Takkenkamp Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Mathilde Jalving Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Frederik J H Hoogwater Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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Annemiek M E Walenkamp Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

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adenoneuroendocrine carcinomas (MANECs) included 53 NECs and 36 MANECs patients from several sites of origin. This study demonstrated that 12.4% of patients with either NECs or MANECs were MSI ( Sahnane et al. 2015 ). A study comparing well-differentiated NETs ( n

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Chiara Borga Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy

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Carlo Alberto Dal Pozzo Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy

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Elisabetta Trevellin Department of Medicine (DIMED), Endocrine-Metabolic Laboratory, University of Padua, Padua, Italy

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Francesca Bergamo Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy

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Sabina Murgioni Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy

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Anna Caterina Milanetto Department of Oncology, Surgery and Gastroenterology (DISCOG), Surgery 1, Pancreatic and Endocrine Digestive Surgical Unit, University of Padua, Padua, Italy

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Claudio Pasquali Department of Oncology, Surgery and Gastroenterology (DISCOG), Surgery 1, Pancreatic and Endocrine Digestive Surgical Unit, University of Padua, Padua, Italy

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Umberto Cillo Department of Oncology, Surgery and Gastroenterology (DISCOG), Hepatobiliary Surgery and Liver Transplant Unit, University of Padua, Padua, Italy

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Giada Munari Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy

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Chiara Martini Department of Medicine (DIMED), Endocrine-Metabolic Laboratory, University of Padua, Padua, Italy

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Eugenio De Carlo Department of Medicine (DIMED), Endocrine-Metabolic Laboratory, University of Padua, Padua, Italy

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Vittorina Zagonel Medical Oncology Unit 1, Department of Oncology, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy

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Vincenza Guzzardo Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy

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Gianmaria Pennelli Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy

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Angelo Paolo Dei Tos Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy

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Roberto Vettor Department of Medicine (DIMED), Endocrine-Metabolic Laboratory, University of Padua, Padua, Italy

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Matteo Fassan Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua, Padua, Italy
Veneto Institute of Oncology IOV - IRCCS, Padua, Italy

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.e.exclusion of MANECs and other carcinomas with spots of neuroendocrine differentiation) and having adequate material for the immunohistochemical characterization and the matched loco-regional nodal locations (LNLs; diameter of the metastatic foci larger than 5

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A Karpathakis University College London Cancer Institute, Neuroendocrine Tumour Unit, 72 Huntley Street, London WC1E 6BT, UK
University College London Cancer Institute, Neuroendocrine Tumour Unit, 72 Huntley Street, London WC1E 6BT, UK

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H Dibra University College London Cancer Institute, Neuroendocrine Tumour Unit, 72 Huntley Street, London WC1E 6BT, UK

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C Thirlwell University College London Cancer Institute, Neuroendocrine Tumour Unit, 72 Huntley Street, London WC1E 6BT, UK
University College London Cancer Institute, Neuroendocrine Tumour Unit, 72 Huntley Street, London WC1E 6BT, UK

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methylator phenotype; MANEC, mixed adenoneuroendocrine carcinoma. Chromatin remodellers in pNET In a recent study ( Jiao et al . 2011 ), exome sequencing was performed in ten sporadic pNETs followed by Sanger sequencing validation in a

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