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Nicola Fazio Division of gastrointestinal medical oncology and neuroendocrine tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Lorenzo Gervaso Division of gastrointestinal medical oncology and neuroendocrine tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy
Molecular Medicine Program, University of Pavia, Pavia, Italy

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Thorvardur R Halfdanarson Division of Medical Oncology Mayo Clinic, Rochester, Minnesota, USA

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Mohamad Sonbol Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona, USA

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Rachel A Eiring Division of Medical Oncology Mayo Clinic, Rochester, Minnesota, USA

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Sara Pusceddu Division of Medical Oncology, National Cancer Institute, Milan, Italy

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Natalie Prinzi Division of Medical Oncology, National Cancer Institute, Milan, Italy

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Benedetta Lombardi Stocchetti Division of Medical Oncology, National Cancer Institute, Milan, Italy

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Simona Grozinsky-Glasberg Neuroendocrine Tumor Unit, ENETS Center of Excellence, Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, The Hebrew University, Jerusalem, Israel

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David J Gross Neuroendocrine Tumor Unit, ENETS Center of Excellence, Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, The Hebrew University, Jerusalem, Israel

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Thomas Walter Medical Oncology Department, Hopital Edourad Herriot, Hospices civils de Lyon, Lyon, France

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Patrick Robelin Medical Oncology Department, Hopital Edourad Herriot, Hospices civils de Lyon, Lyon, France

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Catherine Lombard-Bohas Medical Oncology Department, Hopital Edourad Herriot, Hospices civils de Lyon, Lyon, France

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Samuele Frassoni Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy

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Vincenzo Bagnardi Department of Statistics and Quantitative Methods, University of Milan-Bicocca, Milan, Italy

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Lorenzo Antonuzzo Clinical Oncology Unit, Careggi University Hospital, Florence, Italy
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

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Clotilde Sparano Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences ’Mario Serio’, University of Florence, Florence, Italy

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Sara Massironi Division of Gastroenterology, and Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, University of Milano-Bicocca School of Medicine, Monza, Italy

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Fabio Gelsomino Division of Oncology. Department of Hematology and Oncology, University Hospital of Modena, Modena, Italy

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Alberto Bongiovanni Oncologia medica, IRCCS Istituto Romagnolo per lo Studio dei Tumori ’Dino Amadori’, IRST S.r.l., Meldola, Italy

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Nicoletta Ranallo Oncologia medica, IRCCS Istituto Romagnolo per lo Studio dei Tumori ’Dino Amadori’, IRST S.r.l., Meldola, Italy

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Salvatore Tafuto Oncologia Sarcomi e Tumori rari, I.R.C.C.S. Ist. Naz. Tumori di Napoli ’G. Pascale’, Napoli, Italy

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Maura Rossi Oncology Unit and Centro Documentazione Osteonecrosi, Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

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Mauro Cives Department of Interdisciplinary Medicine, University of Bari ’Aldo Moro’, Bari, Italy

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Ibrahim Rasul Kakil National Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar

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Hytam Hamid Department of Surgery, Al-Moalem Medical City, Khartoum, Sudan

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Alessandra Chirco UO Oncologia Medica ASST Papa Giovanni XXIII, Bergamo, Italy

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Michela Squadroni Oncologia medica, Humanitas Gavazzeni Bergamo, Bergamo, Italy

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Anna La Salvia Medical Oncology Department, Hospital Universitario Doce de Octubre, Imas12, UCM, Madrid, Spain

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Jorge Hernando Vall Hebron University Hospital and Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain

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Johannes Hofland Department of Internal Medicine, Sector Endocrinology, Rotterdam, the Netherlands

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Anna Koumarianou Hematology-Oncology Unit, Fourth Department of Internal Medicine, Attikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Sabrina Boselli Data Management-Clinical Trial Office. Scientific Direction. European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Darina Tamayo Data Management-Clinical Trial Office. Scientific Direction. European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Cristina Mazzon Data Management-Clinical Trial Office. Scientific Direction. European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Manila Rubino Division of gastrointestinal medical oncology and neuroendocrine tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy

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Francesca Spada Division of gastrointestinal medical oncology and neuroendocrine tumors, European Institute of Oncology (IEO) IRCCS, Milan, Italy

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We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

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Sara Pusceddu Department of Medical Oncology ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

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Francesco Barretta Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy

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Annalisa Trama Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Evaluative Epidemiology Unit, ENETS Center of Excellence, Milan, Italy

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Laura Botta Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Evaluative Epidemiology Unit, ENETS Center of Excellence, Milan, Italy

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Massimo Milione Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ENETS Center of Excellence, Milan, Italy

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Roberto Buzzoni Department of Medical Oncology ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

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Filippo De Braud Department of Medical Oncology ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
University of Milan, Milan, Italy

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Vincenzo Mazzaferro University of Milan, Milan, Italy
Liver Surgery, Transplantation and Gastroenterology, University of Milan and Istituto Nazionale Tumori Fondazione IRCCS, ENETS Center of Excellence, Milano, Milan, Italy

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Ugo Pastorino Department of Thoracic Surgical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ENETS Center of Excellence, Milan, Italy

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Ettore Seregni Department of Nuclear Medicine ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Milan, Italy

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Luigi Mariani Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy

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Gemma Gatta Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Evaluative Epidemiology Unit, ENETS Center of Excellence, Milan, Italy

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Maria Di Bartolomeo Department of Medical Oncology ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

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Daniela Femia Department of Medical Oncology ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

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Natalie Prinzi Department of Medical Oncology ENETS Center of Excellence, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

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Jorgelina Coppa Liver Surgery, Transplantation and Gastroenterology, University of Milan and Istituto Nazionale Tumori Fondazione IRCCS, ENETS Center of Excellence, Milano, Milan, Italy

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Francesco Panzuto Department of Medical Gastroenterology, Azienda Ospedaliera Sant’Andrea, Roma ENETS Center of Excellence, Rome, Italy

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Lorenzo Antonuzzo Department of Medical Oncology, Azienda Ospedaliera Universitaria Careggi, Firenze, Italy

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Emilio Bajetta Department of Medical Oncology, Policlinico di Monza, Monza, Italy

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Maria Pia Brizzi Department of Medical Oncology, Azienda Ospedaliera Universitaria San Luigi Gonzaga, Orbassano, Italy

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Davide Campana Department of Medical Oncology, Policlinico Sant’Orsola Malpighi, Bologna, Italy

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Laura Catena Department of Medical Oncology, Policlinico di Monza, Monza, Italy

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Harry Comber Ireland National Cancer Registry, Cork, Ireland

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Fiona Dwane Ireland National Cancer Registry, Cork, Ireland

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Nicola Fazio Department of Medical Oncology, IEO – Istituto Europeo di Oncologia, Milano, ENETS Center of Excellence, Milan, Italy

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Antongiulio Faggiano Department of Thyroid and Parathyroid Surgery Unit, Azienda Ospedaliera Universitaria Federico II, ENETS Center of Excellence, Naples, Italy

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Dario Giuffrida Department of Medical Oncology, IOM – Istituto Oncologico del Mediterraneo, Catania, Italy

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Kris Henau Belgian Cancer Registry, Brussels, Belgium

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Toni Ibrahim Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST, IRCCS, Meldola, Italy

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Riccardo Marconcini Department of Medical Oncology, Ospedale Santa Chiara, Pisa, Italy

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Sara Massironi Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ospedale Maggiore Policlinico, Milan, Italy

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Maja Primic Žakelj Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Ljubljana, Slovenia

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Francesca Spada Department of Medical Oncology, IEO – Istituto Europeo di Oncologia, Milano, ENETS Center of Excellence, Milan, Italy

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Salvatore Tafuto Department of Medical Oncology, Fondazione IRCCS Pascale, ENETS Center of Excellence, Naples, Italy

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Elizabeth Van Eycken Belgian Cancer Registry, Brussels, Belgium

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Jan Maaten Van der Zwan Department of Research, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands

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Tina Žagar Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Ljubljana, Slovenia

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Luca Giacomelli Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy

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Rosalba Miceli Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ENETS Center of Excellence, Milan, Italy

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NEPscore Working Group
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No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS ≥70%; (II) intermediate risk group: 30% ≤ 10-year OS < 70%; (III) poor risk group: 10-year OS <30%. The Harrell C statistic was 0.661 in the training set, and 0.626 and 0.601 in the RARECAREnet and Italian multicentric validation sets, respectively. In conclusion, based on the analysis of three ‘field-practice’ cohorts collected in different settings, we defined and validated a prognostic score to classify patients into three groups with different long-term prognoses.

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