{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T00:39:36Z","timestamp":1792370376611,"version":"4.4.0"},"reference-count":29,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100004336","name":"Novartis","doi-asserted-by":"publisher","award":["NO1501286042"],"award-info":[{"award-number":["NO1501286042"]}],"id":[{"id":"10.13039\/100004336","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014382","name":"Ipsen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014382","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008730","name":"Kreftforeningen","doi-asserted-by":"publisher","award":["223271"],"award-info":[{"award-number":["223271"]}],"id":[{"id":"10.13039\/100008730","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Neuroendocrinology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Digestive high\u2010grade neuroendocrine neoplasms (HG\u2010NEN) are rare and heterogeneous tumours with an aggressive biology and limited treatment efficacy. Genetic intratumour heterogeneity (ITH) is a mechanism of progression and treatment resistance in other cancers, yet unexplored in digestive HG\u2010NEN. Next\u2010generation sequencing with a 360\u2010cancer gene panel was performed on 51 digestive HG\u2010NEN, suitable for multiregional sampling. The mutational status of each sample within a patient was assessed to calculate an ITH\u2010index, defined as the average number of discordant mutations across all pair\u2010wise comparisons between samples. An ITH\u2010index based on primary tumour samples was calculated for chemotherapy\u2010na\u00efve cases: 28 neuroendocrine carcinomas (NEC), 9 mixed neuroendocrine\u2010non\u2010neuroendocrine neoplasms (MiNEN) and 3 neuroendocrine tumour grade 3 (NET G3). Median ITH\u2010index in NEC\/MiNEN was 5, with a wide range (0\u201398.8). Greater heterogeneity was associated with right\u2010sided colonic primaries (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u2009.005) and higher tumour mutational burden (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.74,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u2009.001). Median overall survival was 7\u2009months longer in NEC\/MiNEN with median ITH\u2010index above compared to below median (22.5 vs. 15.5\u2009months,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u2009.077), driven mostly by patients with locoregional disease. Response to first\u2010line chemotherapy was not influenced by median ITH\u2010index. No heterogeneity was found among driver mutations in\n                    <jats:italic>BRAF<\/jats:italic>\n                    and\n                    <jats:italic>KRAS<\/jats:italic>\n                    . NET G3 displayed low heterogeneity (ITH\u2010index 2\u20133). Higher ITH\u2010index was not associated with shorter survival or treatment response, suggesting that genetic ITH is not the primary resistance mechanism in digestive NEC\/MiNEN. Moving towards targeted treatment strategies, our data indicate that a single biopsy may underestimate ITH.\n                    <jats:italic>BRAF<\/jats:italic>\n                    and\n                    <jats:italic>KRAS<\/jats:italic>\n                    may be favourable targets as they displayed no heterogeneity.\n                  <\/jats:p>","DOI":"10.1111\/jne.70296","type":"journal-article","created":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T23:47:57Z","timestamp":1792367277000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic intratumour heterogeneity in digestive high\u2010grade neuroendocrine neoplasms"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8676-772X","authenticated-orcid":false,"given":"Siren","family":"Morken","sequence":"first","affiliation":[{"name":"Cancer Clinic Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7132-6214","authenticated-orcid":false,"given":"Halfdan","family":"Sorbye","sequence":"additional","affiliation":[{"name":"Cancer Clinic Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7561-9172","authenticated-orcid":false,"given":"Wei","family":"Deng","sequence":"additional","affiliation":[{"name":"Cancer Clinic Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9853-059X","authenticated-orcid":false,"given":"Hatice Toprak","family":"Dogramaci","sequence":"additional","affiliation":[{"name":"Cancer Clinic Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Venizelos","sequence":"additional","affiliation":[{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lene Weber","family":"Vestermark","sequence":"additional","affiliation":[{"name":"Department of Oncology University Hospital of Southern Denmark  Esbjerg Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Pfeiffer","sequence":"additional","affiliation":[{"name":"Department of Oncology Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3454-7461","authenticated-orcid":false,"given":"Geir Olav","family":"Hjortland","sequence":"additional","affiliation":[{"name":"Department of Oncology Oslo University Hospital  Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kersten","sequence":"additional","affiliation":[{"name":"Department of Research Hospital of Southern Norway  Kristiansand Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9856-4880","authenticated-orcid":false,"given":"Eva","family":"Hofsli","sequence":"additional","affiliation":[{"name":"Department of Oncology St. Olavs Hospital  Trondheim Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7458-4836","authenticated-orcid":false,"given":"Hege","family":"Elvebakken","sequence":"additional","affiliation":[{"name":"Department of Oncology \u00c5lesund Hospital, M\u00f8re og Romsdal Hospital Trust  \u00c5lesund 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