{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:10:45Z","timestamp":1789038645062,"version":"build-2803163510"},"reference-count":121,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015550","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["PNRR-TR1-2023-12377062"],"award-info":[{"award-number":["PNRR-TR1-2023-12377062"]}],"id":[{"id":"10.13039\/501100015550","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PNRR-TR1-2023-12377062"],"award-info":[{"award-number":["PNRR-TR1-2023-12377062"]}],"id":[{"id":"https:\/\/ror.org\/00789fa95","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) comprise a biologically and clinically heterogeneous spectrum of tumors with substantial inter- and intratumoral variability. Despite advances in molecular classification, imaging, and treatment, accurate diagnosis, prognostication, and disease monitoring remain challenging. Established biomarkers, including chromogranin A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA), provide limited and context-dependent information, highlighting the need for more biologically informative approaches. Recent advances in liquid biopsy, transcriptomic and genomic profiling, spatial technologies, molecular imaging, radiomics, and artificial intelligence are expanding the ability to characterize tumor biology and evolution. However, biological association and analytical validity do not necessarily translate into clinical utility. This narrative review critically evaluates established and emerging biomarkers according to the biological information they provide, with particular emphasis on molecular heterogeneity, tumor evolution, and the distinction between validated and investigational applications. We further discuss how complementary molecular, circulating, spatial, imaging, and clinical information may be integrated through multimodal and artificial intelligence-based approaches to advance tumor characterization and support precision oncology in GEP-NENs.<\/jats:p>","DOI":"10.3390\/cancers18182935","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T10:27:21Z","timestamp":1789036041000},"page":"2935","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biomarkers and Emerging Approaches in Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NEN): Current Evidence and Future Directions"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6876-9105","authenticated-orcid":false,"given":"Gabriella","family":"D\u2019Orazi","sequence":"first","affiliation":[{"name":"Departmental Faculty of Medicine, UniCamillus-Saint Camillus International University of Health Sciences, 00131 Rome, Italy"},{"name":"Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Monteonofrio","sequence":"additional","affiliation":[{"name":"Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9972-9237","authenticated-orcid":false,"given":"Alessandra","family":"Verdina","sequence":"additional","affiliation":[{"name":"Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9354-993X","authenticated-orcid":false,"given":"Alessia","family":"Garufi","sequence":"additional","affiliation":[{"name":"Unit of Cellular Networks and Molecular Therapeutic Targets, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","first-page":"471","article-title":"Gastroenteropancreatic Neuroendocrine Tumors","volume":"68","author":"Cives","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"E398","DOI":"10.1503\/cmaj.160771","article-title":"Principles of diagnosis and management of neuroendocrine tumours","volume":"189","author":"Raphael","year":"2017","journal-title":"CMAJ"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.dld.2020.08.031","article-title":"Update on gastroenteropancreatic neuroendocrine tumors","volume":"53","author":"Andreasi","year":"2021","journal-title":"Dig. Liver Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO Classification of Neuroendocrine","volume":"33","author":"Rindi","year":"2022","journal-title":"Neoplasms Endocr. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e13000","DOI":"10.1111\/jne.13000","article-title":"Prognostic features of gastro-entero-pancreatic neuroendocrine neoplasms in primary and metastatic sites: Grade, mesenteric tumour deposits and emerging novelties","volume":"33","author":"Kankava","year":"2021","journal-title":"J. Neuroendocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Reccia, I., Pai, M., Kumar, J., Spalding, D., and Frillin, G.A. (2023). Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms. Cancers, 15.","DOI":"10.3390\/cancers15061861"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17588359231179310","DOI":"10.1177\/17588359231179310","article-title":"Spatial and temporal heterogeneity of digestive neuroendocrine neoplasms","volume":"15","author":"Bourdeleau","year":"2023","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Mukherjee, S.B., Shanker, R.M., Madigan, J.P., and Sadowski, S.M. (2025). The Evolving Landscape of GEP-NENs in the Era of Precision Oncology: Molecular Insights into Tumor Heterogeneity. Cancers, 17.","DOI":"10.3390\/cancers17132080"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.beem.2016.01.002","article-title":"Neuroendocrine tumor biomarkers: From monoanalytes to transcripts and algorithms","volume":"30","author":"Modlin","year":"2016","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e435","DOI":"10.1016\/S1470-2045(15)00186-2","article-title":"Consensus on biomarkers for neuroendocrine tumour disease","volume":"16","author":"Modlin","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1707","DOI":"10.1001\/jamaoncol.2024.4330","article-title":"Biomarkers to Inform Prognosis and Treatment for Unresectable or Metastatic GEP-NENs","volume":"10","author":"Loree","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/GIM.0b013e318184137c","article-title":"EGAPP Working Group. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: Methods of the EGAPP Working Group","volume":"11","author":"Teutsch","year":"2009","journal-title":"Genet. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1159\/000494258","article-title":"Unmet Needs in Functional and Nonfunctional Pancreatic Neuroendocrine Neoplasms","volume":"108","author":"Jensen","year":"2019","journal-title":"Neuroendocrinology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s12020-023-03418-3","article-title":"Utility of histopathological revision in the management of gastro-entero-pancreatic neuroendocrine neoplasia","volume":"82","author":"Marasco","year":"2023","journal-title":"Endocrine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.gie.2022.07.014","article-title":"Reliability of grading preoperative pancreatic neuroendocrine tumors on EUS specimens: A systematic review with meta-analysis of aggregate and individual data","volume":"96","author":"Tacelli","year":"2022","journal-title":"Gastrointest. Endosc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1159\/000530968","article-title":"Molecular and Functional Heterogeneity of Primary Pancreatic Neuroendocrine Tumors and Metastases","volume":"113","author":"Guo","year":"2023","journal-title":"Neuroendocrinology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s12022-020-09660-z","article-title":"Genomics of High-Grade Neuroendocrine Neoplasms: Well-Differentiated Neuroendocrine Tumor with High-Grade Features (G3 NET) and Neuroendocrine Carcinomas (NEC) of Various Anatomic Sites","volume":"32","author":"Uccella","year":"2021","journal-title":"Endocr. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1126\/science.1200609","article-title":"DAXX\/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors","volume":"331","author":"Jiao","year":"2011","journal-title":"Science"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1053\/j.gastro.2013.10.020","article-title":"Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors","volume":"146","author":"Marinoni","year":"2014","journal-title":"Gastroenterology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1158\/1078-0432.CCR-16-1113","article-title":"Alternative lengthening of telomere and loss of DAXX\/ATRX expression predicts metastatic disease and poor survival in patients with pancreatic neuroendocrine tumors","volume":"23","author":"Singhi","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s11912-021-01096-w","article-title":"Alternative Lengthening of Telomeres (ALT) in Pancreatic Neuroendocrine Tumors: Ready for Prime-Time in Clinical Practice?","volume":"23","author":"Luchini","year":"2021","journal-title":"Curr. Oncol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bevere, M., Masetto, F., Carazzolo, M.E., Bettega, A., Gkountakos, A., Scarpa, A., and Simbolo, M. (2023). An Overview of Circulating Biomarkers in Neuroendocrine Neoplasms: A Clinical Guide. Diagnostics, 13.","DOI":"10.3390\/diagnostics13172820"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.3892\/etm.2021.10914","article-title":"Perspectives on the diagnostic, predictive and prognostic markers of neuroendocrine neoplasms","volume":"22","author":"Ciobanu","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"R11","DOI":"10.1530\/ERC-17-0269","article-title":"Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: More flaws than fame","volume":"25","author":"Marotta","year":"2018","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.ejca.2011.08.012","article-title":"Choice of Tumour Markers in Patients with Neuroendocrine Tumours Is Dependent on the Histological Grade. A Marker Study of Chromogranin A, Neuron Specific Enolase, Progastrin-Releasing Peptide and Cytokeratin Fragments","volume":"48","author":"Korse","year":"2012","journal-title":"Eur. J. Cancer"},{"key":"ref_26","first-page":"6745","article-title":"Larger Tumor Size and Elevated Serum Chromogranin A Levels Predict Metastatic Disease on DOTATATE Imaging in Patients with Gastroenteropancreatic Neuroendocrine Tumors","volume":"31","author":"Strosberg","year":"2024","journal-title":"Ann. Surg. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1093\/annonc\/mdx193","article-title":"Efficacy of Everolimus Plus Octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: Final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study","volume":"28","author":"Pavel","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3906","DOI":"10.1200\/JCO.2016.68.0702","article-title":"Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers from the Randomized, Phase III RADIANT-3 Study","volume":"34","author":"Yao","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1007\/s00259-015-3250-z","article-title":"Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors","volume":"43","author":"Bodei","year":"2016","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_30","first-page":"684","article-title":"Chromogranin A (CgA)\u2014The influence of various factors in vivo and in vitro, and existing disorders on its concentration in blood","volume":"61","author":"Glinicki","year":"2010","journal-title":"Endokrynol. Pol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1159\/000321535","article-title":"Effect of proton-pump inhibitor therapy on serum chromogranin A level","volume":"84","author":"Pregun","year":"2011","journal-title":"Digestion"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Yu, H., Wang, H., Su, X., Cao, A., Yao, X., Wang, Y., Zhu, B., Wang, H., and Fang, J. (2022). Serum chromogranin A correlated with albuminuria in diabetic kidney disease. BMC Nephrol., 23.","DOI":"10.1186\/s12882-022-02667-0"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"57","DOI":"10.21037\/tgh-24-113","article-title":"Rethinking chromogranin A: Unveiling gastrointestinal factors beyond neuroendocrine neoplasms-a narrative review","volume":"10","author":"Romano","year":"2025","journal-title":"Transl. Gastroenterol. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Baekdal, J., Krogh, J., Klose, M., Holmager, P., Langer, S.W., Oturai, P., Kjaer, A., Federspiel, B., Hilsted, L., and Rehfeld, J.F. (2020). Limited Diagnostic Utility of Chromogranin a Measurements in Workup of Neuroendocrine Tumors. Diagnostics, 10.","DOI":"10.3390\/diagnostics10110881"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e13423","DOI":"10.1111\/jne.13423","article-title":"European Neuroendocrine Tumor Society (ENETS) 2024 guidance paper for the management of well-differentiated small intestine neuroendocrine tumours","volume":"36","author":"Lamarca","year":"2024","journal-title":"J. Neuroendocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e13343","DOI":"10.1111\/jne.13343","article-title":"European Neuroendocrine Tumour Society (ENETS) 2023 guidance paper for nonfunctioning pancreatic neuroendocrine tumours","volume":"35","author":"Denecke","year":"2023","journal-title":"J. Neuroendocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9","DOI":"10.5662\/wjm.v7.i1.9","article-title":"Chromogranin A as a valid marker in oncology: Clinical application or false hopes?","volume":"7","author":"Gkolfinopoulos","year":"2017","journal-title":"World J. Methodol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Rossi, R.E., Lavezzi, E., Jaafar, S., Cristofolini, G., Laffi, A., Nappo, G., Carrara, S., Bertuzzi, A.F., Uccella, S., and Repici, A. (2023). Urinary 5-Hydroxyindolacetic Acid Measurements in Patients with Neuroendocrine Tumor-Related Carcinoid Syndrome: State of the Art. Cancers, 15.","DOI":"10.3390\/cancers15164065"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"710","DOI":"10.4158\/EP-2018-0022","article-title":"Prognostic Utility of 24-Hour Urinary 5-HIAA Doubling Time in Patients with Neuroendocrine Tumors","volume":"24","author":"Tirosh","year":"2018","journal-title":"Endocr. Pract."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1530\/EJE-16-0392","article-title":"Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours","volume":"175","author":"Zandee","year":"2016","journal-title":"Eur. J. Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Babkina, A.S., Lyubomudrov, M.A., Golubev, M.A., Pisarev, M.V., and Golubev, A.M. (2024). Neuron-Specific Enolase-What Are We Measuring?. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25095040"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.21873\/invivo.12574","article-title":"Pretreatment Levels of Chromogranin A and Neuron-specific Enolase in Patients with Gastroenteropancreatic Neuroendocrine Neoplasia","volume":"35","author":"Palaj","year":"2021","journal-title":"In Vivo"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1159\/000519948","article-title":"Serum Biomarker Status with a Distinctive Pattern in Prognosis of Gastroenteropancreatic Neuroendocrine Carcinoma","volume":"112","author":"Zhang","year":"2022","journal-title":"Neuroendocrinology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e13249","DOI":"10.1111\/jne.13249","article-title":"European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma","volume":"35","author":"Sorbye","year":"2023","journal-title":"J. Neuroendocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17628","DOI":"10.1038\/s41598-026-48891-8","article-title":"Role of tumor markers before or during chemotherapy for digestive neuroendocrine carcinomas as an exploratory analysis of JCOG1213","volume":"16","author":"Satake","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2971","DOI":"10.1245\/s10434-014-3728-0","article-title":"Pancreastatin predicts survival in neuroendocrine tumors","volume":"21","author":"Sherman","year":"2014","journal-title":"Ann. Surg. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Martins, I., Ribeiro, I.P., Jorge, J., Gon\u00e7alves, A.C., Sarmento-Ribeiro, A.B., Melo, J.B., and Carreira, I.M. (2021). Liquid Biopsies: Applications for Cancer Diagnosis and Monitoring. Genes, 12.","DOI":"10.3390\/genes12030349"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Franchina, M., Cavalcoli, F., Falco, O., La Milia, M., Elvevi, A., and Massironi, S. (2024). Biochemical markers for neuroendocrine tumors: Traditional circulating markers and recent development\u2014A comprehensive review. Diagnostics, 14.","DOI":"10.3390\/diagnostics14121289"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Almeida, C., Gervaso, L., Frig\u00e8, G., Spada, F., Cella, C.A., Mazzarella, L., and Fazio, N. (2024). The Role of Liquid Biopsy in Gastroenteropancreatic Neuroendocrine Neoplasms. Cancers, 3016.","DOI":"10.3390\/cancers16193349"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Linkner, T.R., Nagy, Z.B., Kalm\u00e1r, A., Farkas, E., B\u00e1nyai, F., Szak\u00e1llas, N., Tak\u00e1cs, I., and Moln\u00e1r, B. (2025). Circulating tumor cells: Indicators of cancer progression, plasticity and utility for therapies. Pathol. Oncol. Res., 31.","DOI":"10.3389\/pore.2025.1612181"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"617421","DOI":"10.1155\/2010\/617421","article-title":"Significance of Circulating Tumor Cells Detected by the CellSearch System in Patients with Metastatic Breast, Colorectal and Prostate Cancer","volume":"2010","author":"Miller","year":"2010","journal-title":"J. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"81558","DOI":"10.18632\/oncotarget.18277","article-title":"Epithelial-to-mesenchymal transition, circulating tumor cells and cancer metastasis: Mechanisms and clinical applications","volume":"8","author":"Jie","year":"2017","journal-title":"Oncotarget"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1158\/1078-0432.CCR-10-1776","article-title":"Circulating tumor cells and EpCAM expression in neuroendocrine tumors","volume":"17","author":"Khan","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1093\/annonc\/mdu018","article-title":"Circulating Tumour Cells: The Evolving Concept and the Inadequacy of Their Enrichment by EpCAM-Based Methodology for Basic and Clinical Cancer Research","volume":"25","author":"Grover","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1158\/1078-0432.CCR-15-1008","article-title":"Early Changes in Circulating Tumor Cells Are Associated with Response and Survival Following Treatment of Metastatic Neuroendocrine Neoplasms","volume":"22","author":"Khan","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e13096","DOI":"10.1111\/jne.13096","article-title":"Circulating tumour cells and tumour biomarkers in functional midgut neuroendocrine tumours","volume":"34","author":"Meyer","year":"2022","journal-title":"J. Neuroendocrinol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1053\/j.gastro.2010.07.002","article-title":"Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy","volume":"139","author":"Reubi","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.csbj.2018.10.002","article-title":"Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management","volume":"16","author":"Elazezy","year":"2018","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_59","first-page":"12","article-title":"Circulating Tumor DNA Detection and Total Metabolic Tumor Volume in Neuroendocrine Carcinoma of Gastroenteropancreatic or Unknown Origin (CIRCAN-NEC study)","volume":"141","author":"Boons","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_60","first-page":"O7","article-title":"Circulating Tumor DNA Detection Using a Personalized, Tumor-Informed Assay in Metastatic Well-Differentiated GEP-NET Patients","volume":"89","author":"Mandair","year":"2023","journal-title":"Endocr. Abstr."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e2500833","DOI":"10.1200\/PO-25-00833","article-title":"Circulating Tumor DNA Monitoring in Peptide Receptor Radionuclide Therapy-Treated Patients with Gastroenteropancreatic Neuroendocrine Tumors","volume":"10","author":"Bogdani","year":"2026","journal-title":"JCO Precis. Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Rossi, R.E., and La Salvia, A. (2025). NETest and Gastro-Entero-Pancreatic Neuroendocrine Tumors: Still Far from Routine Clinical Application? A Systematic Review. Genes, 16.","DOI":"10.3390\/genes16020161"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.jaci.2017.08.034","article-title":"MicroRNA","volume":"141","author":"Lu","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.semcdb.2017.12.011","article-title":"Secretory microRNAs as biomarkers of cancer","volume":"78","author":"Kai","year":"2018","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1038\/s41574-024-01005-8","article-title":"Circulating non-coding RNA biomarkers of endocrine tumours","volume":"20","author":"Butz","year":"2024","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3600","DOI":"10.1158\/1078-0432.CCR-12-3092","article-title":"MicroRNA array analysis finds elevated serum miR-1290 accurately distinguishes patients with low-stage pancreatic cancer from healthy and disease controls","volume":"19","author":"Li","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1186\/s12967-022-03511-7","article-title":"Identification of functional pathways and molecular signatures in neuroendocrine neoplasms by multi-omics analysis","volume":"20","author":"Melone","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1097\/SLA.0000000000003502","article-title":"Circulating MicroRNAs in Small-bowel Neuroendocrine Tumors: A Potential Tool for Diagnosis and Assessment of Effectiveness of Surgical Resection","volume":"274","author":"Malczewska","year":"2021","journal-title":"Ann. Surg."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Bocchini, M., Tazzari, M., Ravaioli, S., Piccinini, F., Foca, F., Tebaldi, M., Nicolini, F., Grassi, I., Severi, S., and Calogero, R.A. (2023). Circulating hsa-miR-5096 predicts 18F-FDG PET\/CT positivity and modulates somatostatin receptor 2 expression: A novel miR-based assay for pancreatic neuroendocrine tumors. Front. Oncol., 23.","DOI":"10.3389\/fonc.2023.1136331"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1053\/j.semnuclmed.2025.02.003","article-title":"The Role of AI in the Evaluation of Neuroendocrine Tumors: Current State of the Art","volume":"55","author":"Yasrab","year":"2025","journal-title":"Semin. Nucl. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1093\/clinchem\/hvaf043","article-title":"MIQE 2.0: Revision of the Minimum Information for Publication of Quantitative Real-Time PCR Experiments Guidelines","volume":"71","author":"Bustin","year":"2025","journal-title":"Clin. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"eaau6977","DOI":"10.1126\/science.aau6977","article-title":"The biology, function, and biomedical applications of exosomes","volume":"367","author":"Kalluri","year":"2020","journal-title":"Science"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Kong, L., Zhao, G., Wu, X., and Ma, S. (2026). Extracellular Vesicles in Cancer Diagnosis and Therapy: Advances, Challenges, and Prospects for Clinical Translation. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27052280"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.devcel.2019.04.011","article-title":"Exosome-mediated metastasis: Communication from a distance","volume":"49","author":"Wortzel","year":"2019","journal-title":"Dev. Cell."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. Extracell. Vesicles"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"54331","DOI":"10.18632\/oncotarget.16908","article-title":"Profiling of metastatic small intestine neuroendocrine tumors reveals characteristic miRNAs detectable in plasma","volume":"8","author":"Bowden","year":"2017","journal-title":"Oncotarget"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s12943-019-0975-5","article-title":"Exosomes in the tumor microenvironment as mediators of cancer therapy resistance","volume":"18","author":"Li","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Irmer, B., Chandrabalan, S., Maas, L., Bleckmann, A., and Menck, K. (2023). Extracellular Vesicles in Liquid Biopsies as Biomarkers for Solid Tumors. Cancers, 15.","DOI":"10.3390\/cancers15041307"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.ecl.2018.05.002","article-title":"The NETest: The Clinical Utility of Multigene Blood Analysis in the Diagnosis and Management of Neuroendocrine Tumors","volume":"47","author":"Modlin","year":"2018","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e220206","DOI":"10.1530\/ERC-22-0206","article-title":"Expert Consensus Practice Recommendations of the North American Neuroendocrine Tumor Society for the management of high grade gastroenteropancreatic and gynecologic neuroendocrine neoplasms","volume":"30","author":"Eads","year":"2023","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1159\/000509866","article-title":"Sensitivity and Specificity of the NETest: A Validation Study","volume":"111","author":"Cives","year":"2021","journal-title":"Neuroendocrinology"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1530\/EC-20-0417","article-title":"NETest is Superior to Chromogranin A in Neuroendocrine Neoplasia: A Prospective ENETS CoE Analysis","volume":"10","author":"Malczewska","year":"2021","journal-title":"Endocr. Connect."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1530\/ERC-14-0190","article-title":"A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection","volume":"21","author":"Modlin","year":"2014","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_84","first-page":"e220146","article-title":"NETest: Serial liquid biopsies in gastroenteropancreatic NET surveillance","volume":"11","author":"Korse","year":"2022","journal-title":"Endocr. Connect."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"e13428","DOI":"10.1111\/jne.13428","article-title":"NETest in advanced high-grade gastroenteropancreatic neuroendocrine neoplasms","volume":"36","author":"Sorbye","year":"2024","journal-title":"J. Neuroendocrinol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1126\/science.aaf2403","article-title":"Visualization and analysis of gene expression in tissue sections by spatial transcriptomics","volume":"353","author":"Vickovic","year":"2016","journal-title":"Science"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Karam, J., Hoffman, S.E., Garza, A., Gui, D., Hoffman, H.I., Titchen, B.M., Tanaka, Y., Pimenta, E., Pappa, T., and Valderrabano, L. (2025). Conserved Neuronal-like and Secretory Programs Define the Spatial Architecture of Gastroenteropancreatic Neuroendocrine Tumors. bioRxiv, 2025.12.28.696762.","DOI":"10.64898\/2025.12.28.696762"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1158\/1078-0432.CCR-25-2854","article-title":"Spatial Transcriptomics Reveals Location-Specific Tumor Cell Subtypes and Signaling within Multifocal Small Intestinal Neuroendocrine Tumors","volume":"32","author":"Yogo","year":"2026","journal-title":"Clin. Cancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1002\/path.6241","article-title":"Spatial profiling reveals tissue-specific neuro-immune signatures in gastroenteropancreatic neuroendocrine tumors","volume":"262","author":"Duan","year":"2024","journal-title":"J. Pathol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1146\/annurev-pathmechdis-111523-023417","article-title":"Challenges and Opportunities in the Clinical Translation of High-Resolution Spatial Transcriptomics","volume":"20","author":"Pentimalli","year":"2025","journal-title":"Annu. Rev. Pathol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.2967\/jnumed.116.179234","article-title":"Molecular Imaging of Gastroenteropancreatic Neuroendocrine Tumors: Current Status and Future Directions","volume":"57","author":"Deroose","year":"2016","journal-title":"J. Nucl. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"204","DOI":"10.2967\/jnumed.122.264860","article-title":"SNMMI Procedure Standard\/EANM Practice Guideline for SSTR PET: Imaging Neuroendocrine Tumors","volume":"64","author":"Hope","year":"2023","journal-title":"J. Nucl. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1007\/s12149-025-02072-1","article-title":"Comparison of radiolabeled somatostatin analogs (DOTATATE, DOTANOC, and DOTATOC) in somatostatin receptor (SSTR) imaging for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): A narrative literature review","volume":"39","author":"Wijaya","year":"2025","journal-title":"Ann. Nucl. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1053\/j.sult.2026.06.006","article-title":"Update on PET Imaging of Neuroendocrine Neoplasms","volume":"47","author":"Singh","year":"2026","journal-title":"Semin. Ultrasound CT MRI"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4182","DOI":"10.1007\/s00259-022-05848-z","article-title":"Correlation of somatostatin receptor PET\/CT imaging features and immunohistochemistry in neuroendocrine tumors of the lung: A retrospective observational study","volume":"49","author":"Rufini","year":"2022","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"808","DOI":"10.2967\/jnumed.120.244798","article-title":"18F-FDG PET is Superior to WHO Grading as a Prognostic Tool in Neuroendocrine Neoplasms and Useful in Guiding PRRT: A Prospective 10-Year Follow-up Study","volume":"62","author":"Binderup","year":"2021","journal-title":"J. Nucl. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e13359","DOI":"10.1111\/jne.13359","article-title":"Use and perceived utility of [18 F]FDG PET\/CT in neuroendocrine neoplasms: A consensus report from the European Neuroendocrine Tumor Society (ENETS) Advisory Board Meeting 2022","volume":"36","author":"Ambrosini","year":"2024","journal-title":"J. Neuroendocrinol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e13474","DOI":"10.1111\/jne.13474","article-title":"The role of combined FDG and SST PET\/CT in neuroendocrine tumors","volume":"37","author":"Fortunati","year":"2025","journal-title":"J. Neuroendocr."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"185","DOI":"10.2967\/jnumed.123.266346","article-title":"[18F]FDG PET\/CT-Avid Discordant Volume as a Biomarker in Patients with Gastroenteropancreatic Neuroendocrine Neoplasms: A Multicenter Study","volume":"65","author":"Chan","year":"2024","journal-title":"J. Nucl. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.ejca.2011.11.036","article-title":"Radiomics: Extracting more information from medical images using advanced feature analysis","volume":"48","author":"Lambin","year":"2012","journal-title":"Eur. J. Cancer"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1148\/radiol.2015151169","article-title":"Radiomics: Images Are More than Pictures, They Are Data","volume":"278","author":"Gillies","year":"2016","journal-title":"Radiology"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Neha, F., and Shukla, D.K. (2026). Radiomics in Medical Imaging: Methods, Applications, and Challenges. J. Imaging., 12.","DOI":"10.3390\/jimaging12060220"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Balma, M., Laudicella, R., Gallio, E., Gusella, S., Lorenzon, L., Peano, S., Costa, R.P., Rampado, O., Farsad, M., and Evangelista, L. (2023). Applications of Artificial Intelligence and Radiomics in Molecular Hybrid Imaging and Theragnostics for Neuro-Endocrine Neoplasms (NENs). Life, 13.","DOI":"10.3390\/life13081647"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"7278","DOI":"10.1007\/s00330-022-08996-w","article-title":"GEP-NET radiomics: A systematic review and radiomics quality score assessment","volume":"32","author":"Staal","year":"2022","journal-title":"Eur. Radiol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2774","DOI":"10.1007\/s00259-024-06730-w","article-title":"Preoperative assessment of lymph nodal metastases with [68Ga]Ga-DOTATOC PET radiomics for improved surgical planning in well-differentiated pancreatic neuroendocrine tumours","volume":"51","author":"Mapelli","year":"2024","journal-title":"Eur. J. Nucl. Med. Mol. Imaging."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"e13472","DOI":"10.1111\/jne.13472","article-title":"Radiomics in advanced gastroenteropancreatic neuroendocrine neoplasms: Identifying responders to somatostatin analogs","volume":"37","author":"Polici","year":"2025","journal-title":"J. Neuroendocrinol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Chen, Y., Li, H., Chen, S., Ji, H., Xin, J., and Du, M. Beyond radiogenomics: Advancing imaging integration and multi-omics horizons in cancer precision medicine, J. Genet. Genom. 2026, in press.","DOI":"10.1016\/j.jgg.2026.07.003"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s12943-026-02697-4","article-title":"Multi-omic profiles of neuroendocrine neoplasms of the pancreas: An integrated landscape","volume":"25","author":"Bevere","year":"2026","journal-title":"Mol. Cancer"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"e185","DOI":"10.1002\/mp.13678","article-title":"Machine and deep learning methods for radiomics and radiogenomics in oncology: A review","volume":"47","author":"Avanzo","year":"2020","journal-title":"Med. Phys."},{"key":"ref_110","first-page":"1","article-title":"Integrative Analysis of Multi-Omics Data for Biomarker Discovery","volume":"2025","author":"Varghese","year":"2025","journal-title":"Annu. Int. Conf. IEEE Eng. Med. Biol. Soc."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13073-019-0703-1","article-title":"Molecular profiling for precision cancer therapies","volume":"12","author":"Malone","year":"2020","journal-title":"Genome Med."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"15770","DOI":"10.1038\/s41598-025-00549-7","article-title":"Genomic and transcriptomic landscapes of metastatic neuroendocrine neoplasms from distinct primary sites and their clinical implications","volume":"15","author":"Wee","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41576-018-0071-5","article-title":"Current and Future Perspectives of Liquid Biopsies in Genomics-Driven Oncology","volume":"20","author":"Heitzer","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41591-018-0300-7","article-title":"High-performance medicine: The convergence of human and artificial intelligence","volume":"25","author":"Topol","year":"2019","journal-title":"Nat. Med."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41591-018-0316-z","article-title":"A guide to deep learning in healthcare","volume":"25","author":"Esteva","year":"2019","journal-title":"Nat. Med."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"e70087","DOI":"10.1111\/jne.70087","article-title":"Artificial intelligence in the diagnosis of gastro-entero-pancreatic neuroendocrine neoplasms: Potential benefits and current limitations","volume":"37","author":"Merola","year":"2025","journal-title":"J. Neuroendocrinol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Merola, E., Fanciulli, G., Pes, G.M., and Dore, M.P. (2025). Artificial Intelligence for Prognosis of Gastro-Entero-Pancreatic Neuroendocrine Neoplasms. Cancers, 17.","DOI":"10.3390\/cancers17121981"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"e13462","DOI":"10.1111\/jne.13462","article-title":"Developing a peripheral blood RNA-seq based NETseq ensemble classifier: A potential novel tool for non-invasive detection and treatment response assessment in neuroendocrine tumor patients receiving 177Lu-DOTATATE PRRT","volume":"37","author":"Padwal","year":"2025","journal-title":"J. Neuroendocrinol."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Kelly, C.J., Karthikesalingam, A., Suleyman, M., Greg Corrado, G., and King, D. (2019). Key challenges for delivering clinical impact with artificial intelligence. BMC Med., 17.","DOI":"10.1186\/s12916-019-1426-2"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"e082505","DOI":"10.1136\/bmj-2024-082505","article-title":"PROBAST+AI: An updated quality, risk of bias, and applicability assessment tool for prediction models using regression or artificial intelligence methods","volume":"388","author":"Moons","year":"2025","journal-title":"BMJ"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1093\/bib\/bbx044","article-title":"Deep learning for healthcare: Review, opportunities and challenges","volume":"19","author":"Miotto","year":"2018","journal-title":"Brief. 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