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Vito Amoroso Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology Unit, University of Brescia at ASST Spedali Civili, Brescia, Italy

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Giorgio Maria Agazzi Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Radiology Unit, University of Brescia at ASST Spedali Civili, Brescia, Italy

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Elisa Roca Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology Unit, University of Brescia at ASST Spedali Civili, Brescia, Italy

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

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Alessandra Mosca Medical Oncology Unit, Maggiore della Carità University Hospital, University of Eastern Piedmont, Novara, Italy

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Marco Ravanelli Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Radiology Unit, University of Brescia at ASST Spedali Civili, Brescia, Italy

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Francesca Spada Unit of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, Milan, Italy

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Roberto Maroldi Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Radiology Unit, University of Brescia at ASST Spedali Civili, Brescia, Italy

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Alfredo Berruti Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, Medical Oncology Unit, University of Brescia at ASST Spedali Civili, Brescia, Italy

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Chiara Alessandra Cella Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Milan, Italy
Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy

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Riccardo Cazzoli Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy
Metal Targeted Therapy & Immunology lab, Childrens’ cancer institute, Sydney, NSW, Australia

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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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Giuseppina De Petro Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy

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Germano Gaudenzi Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy

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Silvia Carra Laboratory of Endocrine and Metabolic Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy

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Mauro Romanenghi Department of Experimental Oncology, 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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Ilaria Grossi Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Brescia, Italy

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Isabella Pallavicini Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy

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Saverio Minucci Department of Experimental Oncology, European Institute of Oncology, IEO, IRCCS, Milan, Italy
Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

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Giovanni Vitale Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

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Neuroendocrine tumors (NETs) are highly vascularized malignancies in which angiogenesis may entail cell proliferation and survival. Among the emerging compounds with antivascular properties, cabozantinib (CAB) appeared promising. We analyzed the antitumor activity of CAB against NETs utilizing in vitro and in vivo models. For cell cultures, we used BON-1, NCI-H727 and NCI-H720 cell lines. Cell viability was assessed by manual count coupled with quantification of cell death, performed through fluorescence-activated cell sorting analysis as propidium iodide exclusion assay. In addition, we investigated the modulation of the antiapoptotic myeloid cell leukemia 1 protein under CAB exposure, as a putative adaptive pro-survival mechanism, and compared the responses with sunitinib. The activity of CAB was also tested in mouse and zebrafish xenograft tumor models. Cabozantinib showed a dose-dependent and time-dependent effect on cell viability and proliferation in human NET cultures, besides a halting of cell cycle progression for endoduplication, never reported for other tyrosine kinase inhibitors. In a transplantable zebrafish model, CAB drastically inhibited NET-induced angiogenesis and migration of implanted cells through the embryo body. CAB showed encouraging activity in NETs, both in vitro and in vivo models. On this basis, we envisage future research to further investigate along these promising lines.

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Carmine Valenza Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy

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Francesca Spada Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti, Milan, Italy

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Francesco Multinu Division of Gynecologic Surgery, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy

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Lavinia Benini Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti, Milan, Italy

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Michele Borghesani Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti, Milan, Italy

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Laura Algeri Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti, Milan, Italy

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Manila Rubino Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti, Milan, Italy

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Eleonora Pisa Division of Pathology and Laboratory Medicine, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy

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Lorenzo Gervaso Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti, Milan, Italy

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Chiara Alessandra Cella Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti, Milan, Italy

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Silvestro Carinelli Division of Pathology and Laboratory Medicine, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy

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Simone Bruni Division of Gynecologic Surgery, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy

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Gabriella Schivardi Division of Gynecologic Surgery, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy

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Giuseppe Curigliano Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy

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Vanna Zanagnolo Division of Gynecologic Surgery, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy

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Giovanni Aletti Department of Oncology and Hemato-Oncology (DIPO), University of Milan, Milan, Italy
Division of Gynecologic Surgery, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy

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Nicoletta Colombo Division of Gynecologic Oncology, European Institute of Oncology, IRCCS, Via Ripamonti, Milan, Italy
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy

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Nicola Fazio Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IEO, IRCCS, Via Ripamonti, Milan, Italy

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Non-metastatic neuroendocrine carcinoma of the cervix (NECC) is a rare and aggressive disease. Lacking prospective studies, the optimal multimodal treatment approach has not yet been clearly defined. This study aims to assess the clinical outcomes of patients with non-metastatic NECC treated with surgery and (neo)adjuvant chemotherapy, according to pathologic prognostic factors and multimodal treatments received. We retrospectively examined data from patients with non-metastatic NECC candidate to receive surgery and (neo)adjuvant chemotherapy and discussed at the European Institute of Oncology’s Multidisciplinary Neuroendocrine Tumor Board, between January 2003 and December 2021. Primary endpoints were event-free survival and overall survival. A total of 27 consecutive patients were evaluated, 15 with early stage NECC and 12 with a locally advanced NECC. Eight patients received neoadjuvant and 19 adjuvant platinum-based chemotherapy; 14 received adjuvant pelvic radiotherapy, half with external-beam radiation therapy alone, and half combined with brachytherapy. No patients progressed or relapsed during (neo)adjuvant chemotherapy. The median event-free survival was 21.1 months and the median overall survival was 33.0 months. Pathological FIGO stage ≥ IIB, adjuvant external-beam radiation therapy with or without brachytherapy emerged as significant and independent prognostic factors for event-free survival. Brachytherapy was also prognostic for overall survival. Non-metastatic NECC requires a multimodal approach, mainly weighted on the FIGO stage. The addition of brachytherapy should be considered, especially in patients with locally advanced disease. Because of the scarcity of robust clinical data, treatment strategy should be discussed in multidisciplinary board, taking into account patient.

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Marie-Lise Jaffrain-Rea Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy
Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Sandra Rotondi Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Annarita Turchi Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Gianluca Occhi Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Anne Barlier Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy
Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Erika Peverelli Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Lilya Rostomyan Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Céline Defilles Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Mariolina Angelini Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Maria-Antonietta Oliva Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Filippo Ceccato Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Orlando Maiorani Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Adrian F Daly Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Vincenzo Esposito Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy
Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Francesca Buttarelli Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Dominique Figarella-Branger Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy
Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Felice Giangaspero Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy
Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Anna Spada Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Carla Scaroni Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Edoardo Alesse Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Albert Beckers Department of Biotechnological and Applied Clinical Sciences, Department of Neurological Sciences, Endocrinology, CNRS, AP‐HM, Endocrinology and Diabetology Unit, Endocrinology, Department of Neurology and Psychiatry, INSERM, AP‐HM, Department of Radiology, University of L'Aquila, Via Vetoio, Coppito 2, 67100 L'Aquila, Italy

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Germline aryl hydrocarbon receptor interacting protein (AIP) gene mutations confer a predisposition to pituitary adenoma (PA), predominantly GH-secreting (GH-PA). As recent data suggest a role for AIP in the pathogenesis of sporadic GH-PA and their response to somatostatin analogues (SSA), the expression of AIP and its partner, aryl hydrocarbon receptor (AHR), was determined by semiquantitative immunohistochemistry scoring in 62 sporadic GH-PA (37 treated with SSA preoperatively). The influence of Gsp status was studied in a subset of tumours (n=39, 14 Gsp +) and six GH-PA were available for primary cultures. AIP and AHR were detected in most cases, with a positive correlation between AIP and cytoplasmic AHR (P=0.012). Low AIP expression was significantly more frequent in untreated vs SSA-treated tumours (44.0 vs 20.5%, P=0.016). AHR expression or localisation did not differ between the two groups. Similarly, in vitro octreotide induced a median twofold increase in AIP expression (range 1.2–13.9, P=0.027) in GH-PA. In SSA-treated tumours, the AIP score was significantly higher in the presence of preoperative IGF1 decrease or tumour shrinkage (P=0.008 and P=0.014 respectively). In untreated tumours, low AIP expression was significantly associated with invasiveness (P=0.028) and suprasellar extension (P=0.019). The only effect of Gsp status was a significantly lower nuclear AHR score in Gsp + vs Gsp tumours (P=0.025), irrespective of SSA. In conclusion, AIP is involved in the aggressiveness of sporadic GH-PA, regardless of Gsp status, and AIP up-regulation in SSA-treated tumours is associated with a better preoperative response, with no clear role for AHR.

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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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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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