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P D Leotlela, A Jauch, H Holtgreve-Grez, and R V Thakker

Neuroendocrine tumours (NETs) originate in tissues that contain cells derived from the embryonic neural crest, neuroectoderm and endoderm. Thus, NETs occur at many sites in the body, although the majority occur within the gastro-entero-pancreatic axis and can be subdivided into those of foregut, midgut and hindgut origin. Amongst these, only those of midgut origin are generally argentaffin positive and secrete serotonin, and hence only these should be referred to as carcinoid tumours. NETs may occur as part of complex familial endocrine cancer syndromes, such as multiple endocrine neoplasia type 1 (MEN1), although the majority occur as non-familial (i.e. sporadic) isolated tumours. Molecular genetic studies have revealed that the development of NETs may involve different genes, each of which may be associated with several different abnormalities that include point mutations, gene deletions, DNA methylation, chromosomal losses and chromosomal gains. Indeed, the foregut, midgut and hindgut NETs develop via different molecular pathways. For example, foregut NETs have frequent deletions and mutations of the MEN1 gene, whereas midgut NETs have losses of chromosome 18, 11q and 16q and hindgut NETs express transforming growth factor-alpha and the epidermal growth factor receptor. Furthermore, in lung NETs, a loss of chromosome 3p is the most frequent change and p53 mutations and chromosomal loss of 5q21 are associated with more aggressive tumours and poor survival. In addition, methylation frequencies of retinoic acid receptor-beta, E-cadherin and RAS-associated domain family genes increase with the severity of lung NETs. Thus the development and progression of NETs is associated with specific genetic abnormalities that indicate the likely involvement of different molecular pathways.

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Mairéad G McNamara, Jean-Yves Scoazec, and Thomas Walter

metastatic small cell/neuroendocrine cancers of urothelium or prostate. Different cohorts, with no prior systemic chemotherapy allowed for primary small cell prostate cancer. 30 Different outcome measures including durable response rate, overall response

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Matthew H Kulke

Introduction Neuroendocrine tumors comprise a diverse group of malignancies and, when defined broadly, include not only gastrointestinal neuroendocrine tumors but also pheochromocytoma, thyroid cancer, and even small cell lung

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Ashley K Clift and Andrea Frilling

bypass to efficiently and robustly assess novel molecularly targeted agents. Recent examples include trials for larotrectinib, which targets NTRK -fusion cancers from myriad organs ( Drilon et al. 2018 ). Neuroendocrine neoplasms have only had their

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Aura D Herrera-Martínez, Leo J Hofland, María A Gálvez Moreno, Justo P Castaño, Wouter W de Herder, and Richard A Feelders

Neuroendocrine Tumor Society; ESMO, European Society of Medical Oncology; Gut-NENs include tumors in the jejunum, ileum, appendix, and cecum; NANETS, North American Neuroendocrine Tumor; NCCN, National Comprehensive Cancer Network; NEC, neuroendocrine carcinoma

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Kjell Oberg

Federspiel B Kjaer A 2010 18 F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors . Clinical Cancer Research 16 978 – 985 . doi:10.1158/1078-0432.CCR-09-1759 . Capella C Solcia E Sobin

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Maria Chiara Zatelli, Giuseppe Fanciulli, Pasqualino Malandrino, Valeria Ramundo, Antongiulio Faggiano, Annamaria Colao, and on behalf of NIKE Group

. (2015) identified KRAS mutations in 13 colorectal and two in gastric neuroendocrine carcinomas (NEC) among 53 cases of gastro-entero-pancreatic NEC. KRAS somatic oncogenic mutations characterize cancer patients who do not benefit from everolimus

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Maria Chiara Zatelli, Elia Guadagno, Erika Messina, Fabio Lo Calzo, Antongiulio Faggiano, Annamaria Colao, and NIKE Group

staging for G3 NET? According to the European Neuroendocrine Tumor Society, all NENs are classified in a single system ( Rindi et al. 2006 ). The American Joint Committee on Cancer (AJCC), on the other hand, in the seventh ( Edge et al. 2010 ) and in

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Federica Grillo, Tullio Florio, Francesco Ferraù, Elda Kara, Giuseppe Fanciulli, Antongiulio Faggiano, Annamaria Colao, and NIKE Group

SH Park JO Lim HY Kang WK Lee J , et al . 2013 Phase II study of pazopanib monotherapy in metastatic gastroenteropancreatic neuroendocrine tumours . British Journal of Cancer 109 1414 – 1419 . ( https://doi.org/10.1038/bjc.2013.470 ) 23989950

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Atsuko Kasajima and Günter Klöppel

)]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors . Clinical Cancer Research 23 . ( https://doi.org/10.1158/1078-0432.CCR-16-2743 ) Brambilla E Beasley MB Austin JHM Capelozzi VL Chirieac LR Devesa SS