{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:43:45Z","timestamp":1760060625100,"version":"build-2065373602"},"reference-count":52,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T00:00:00Z","timestamp":1757289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015763","name":"University of Szeged","doi-asserted-by":"publisher","award":["7272"],"award-info":[{"award-number":["7272"]}],"id":[{"id":"10.13039\/501100015763","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Neuroendocrine neoplasms (NENs) are a diverse group of malignancies in which somatostatin receptor expression can be crucial in guiding therapy. We aimed to evaluate the effectiveness of [99mTc]Tc-EDDA\/HYNIC-TOC SPECT\/CT in differentiating neuroendocrine tumor histology, selecting candidates for radioligand therapy, and identifying correlations between somatostatin receptor expression and non-imaging parameters in metastatic NENs. Methods: This retrospective study included 65 patients (29 women, 36 men, mean age 61) with metastatic neuroendocrine neoplasms confirmed by histology, follow-up, or imaging, comprising 14 poorly differentiated carcinomas and 51 well-differentiated tumors. Somatostatin receptor SPECT\/CT results were assessed visually and semiquantitatively, with mathematical models incorporating histological, oncological, immunohistochemical, and laboratory parameters, followed by biostatistical analysis. Results: Of 392 lesions evaluated, the majority were metastases in the liver, lymph nodes, and bones. Mathematical models estimated somatostatin receptor expression accurately (70\u201383%) based on clinical parameters alone. Key factors included tumor origin, oncological treatments, and the immunohistochemical marker CK7. Associations were found between age, grade, disease extent, and markers (CEA, CA19-9, AFP). Conclusions: Our findings suggest that [99mTc]Tc-EDDA\/HYNIC-TOC SPECT\/CT effectively evaluates somatostatin receptor expression in NENs. Certain immunohistochemical and laboratory parameters, beyond recognized factors, show potential prognostic value, supporting individualized treatment strategies.<\/jats:p>","DOI":"10.3390\/cancers17172935","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T10:29:07Z","timestamp":1757327347000},"page":"2935","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Machine Learning Uncovers Novel Predictors of Peptide Receptor Radionuclide Therapy Eligibility in Neuroendocrine Neoplasms"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1259-0576","authenticated-orcid":false,"given":"G\u00e1bor","family":"Sipka","sequence":"first","affiliation":[{"name":"Department of Nuclear Medicine, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Istv\u00e1n","family":"Farkas","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annam\u00e1ria","family":"Bakos","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anik\u00f3","family":"Mar\u00e1z","sequence":"additional","affiliation":[{"name":"Department of Oncotherapy, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zs\u00f3fia S\u00e1ra","family":"Mik\u00f3","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tam\u00e1s","family":"Cz\u00e9kus","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M\u00e1ty\u00e1s","family":"Bukva","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Science and Informatics, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Szabolcs","family":"Urb\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L\u00e1szl\u00f3","family":"P\u00e1vics","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9115-9620","authenticated-orcid":false,"given":"Zsuzsanna","family":"Besenyi","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, University of Szeged, 6720 Szeged, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,8]]},"reference":[{"key":"ref_1","first-page":"3","article-title":"Incidence of neuroendocrine tumors in the United States from 2001\u20132015: A United States cancer statistics analysis of 50 states","volume":"11","author":"Patel","year":"2019","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1001\/jamaoncol.2017.0589","article-title":"Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States","volume":"3","author":"Dasari","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/s12022-022-09708-2","article-title":"Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms","volume":"33","author":"Rindi","year":"2022","journal-title":"Endocr. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.neo.2017.09.002","article-title":"Nothing But NET: A Review of Neuroendocrine Tumors and Carcinomas","volume":"19","author":"Oronsky","year":"2017","journal-title":"Neoplasia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1097\/MPA.0000000000000700","article-title":"Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors","volume":"45","author":"Qian","year":"2016","journal-title":"Pancreas"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Rogoza, O., Megnis, K., Kudrjavceva, M., Gerina-Berzina, A., and Rovite, V. (2022). Role of Somatostatin Signalling in Neuroendocrine Tumours. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031447"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1159\/000471879","article-title":"ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine & Hybrid Imaging","volume":"105","author":"Sundin","year":"2017","journal-title":"Neuroendocrinology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1097\/RLU.0000000000001877","article-title":"Optimizing Somatostatin Receptor Imaging in Patients With Neuroendocrine Tumors: The Impact of 99mTc-HYNICTOC SPECT\/SPECT\/CT Versus 68Ga-DOTATATE PET\/CT Upon Clinical Management","volume":"42","author":"Kunikowska","year":"2017","journal-title":"Clin. Nucl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1159\/000475526","article-title":"ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues","volume":"105","author":"Hicks","year":"2017","journal-title":"Neuroendocrinology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"937","DOI":"10.2967\/jnumed.118.230607","article-title":"NANETS\/SNMMI Procedure Standard for Somatostatin Receptor\u2013Based Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE","volume":"60","author":"Hope","year":"2019","journal-title":"J. Nucl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1088\/1742-6596\/1497\/1\/012025","article-title":"Quantitative imaging with commercial SPECT","volume":"1497","author":"Said","year":"2020","journal-title":"J. Phys. Conf. Ser."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/S0140-6736(89)91258-0","article-title":"Localisation of endocrine-related tumours with radioiodinated analogue of somatostatin","volume":"1","author":"Krenning","year":"1989","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2638","DOI":"10.1007\/s00259-019-04391-8","article-title":"Radiomics in nuclear medicine: Robustness, reproducibility, standardization, and how to avoid data analysis traps and replication crisis","volume":"46","author":"Zwanenburg","year":"2019","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1214\/aos\/1013203451","article-title":"Greedy function approximation: A gradient boosting machine","volume":"29","author":"Friedman","year":"2001","journal-title":"Ann. Stat."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/A:1010933404324","article-title":"Random forests","volume":"45","author":"Breiman","year":"2001","journal-title":"Mach. Learn."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1007\/s00259-022-06001-6","article-title":"Joint EANM\/SNMMI guideline on radiomics in nuclear medicine: Jointly supported by the EANM Physics Committee and the SNMMI Physics, Instrumentation and Data Sciences Council","volume":"50","author":"Hatt","year":"2023","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1613\/jair.953","article-title":"SMOTE: Synthetic minority over-sampling technique","volume":"16","author":"Chawla","year":"2002","journal-title":"J. Artif. Intell. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1145\/1007730.1007735","article-title":"A study of the behaviour of several methods for balancing machine learning training data","volume":"6","author":"Batista","year":"2004","journal-title":"SIGKDD Explor."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11769351231167992","DOI":"10.1177\/11769351231167992","article-title":"Novel Biomarker Prediction for Lung Cancer Using Random Forest Classifiers","volume":"22","author":"Lavanya","year":"2023","journal-title":"Cancer Inform."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1093\/bioinformatics\/btq134","article-title":"Permutation importance: A corrected feature importance measure","volume":"26","author":"Altmann","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"704","DOI":"10.2967\/jnumed.109.069765","article-title":"Functional imaging of neuroendocrine tumors: A head-to-head comparison of somatostatin receptor scintigraphy, 123I-MIBG scintigraphy, and 18F-FDG PET","volume":"51","author":"Binderup","year":"2010","journal-title":"J. Nucl. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1007\/s00259-010-1512-3","article-title":"Procedure guidelines for PET\/CT tumour imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE","volume":"37","author":"Virgolini","year":"2010","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s11912-021-01029-7","article-title":"Epidemiology, Incidence, and Prevalence of Neuroendocrine Neoplasms: Are There Global Differences?","volume":"23","author":"Das","year":"2021","journal-title":"Curr. Oncol. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100510","DOI":"10.1016\/j.lanepe.2022.100510","article-title":"Incidence and survival of neuroendocrine neoplasia in England 1995\u20132018: A retrospective, population-based study","volume":"23","author":"White","year":"2022","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1196\/annals.1294.002","article-title":"The gastroenteropancreatic neuroendocrine cell system and its tumors: The WHO classification","volume":"1014","author":"Perren","year":"2004","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_26","first-page":"235","article-title":"Chapter 14\u2014High grade neuroendocrine carcinoma of the cervix","volume":"Volume 1","author":"Frumovitz","year":"2023","journal-title":"Diagnosis and Treatment of Rare Gynecologic Cancers"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1097\/PAS.0000000000000169","article-title":"Poorly differentiated neuroendocrine carcinomas of the pancreas: A clinicopathologic analysis of 44 cases","volume":"38","author":"Basturk","year":"2014","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1159\/000528186","article-title":"Prognostic Factors across Poorly Differentiated Neuroendocrine Neoplasms: A Pooled Analysis","volume":"113","author":"Centonze","year":"2023","journal-title":"Neuroendocrinology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1097\/MNM.0b013e3282f3a515","article-title":"PET versus SPECT: Strengths, limitations and challenges","volume":"29","author":"Rahmim","year":"2008","journal-title":"Nucl. Med. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1210\/jc.2010-2022","article-title":"Performance of (18)fluorodeoxyglucose-positron emission tomography and somatostatin receptor scintigraphy for high Ki67 (\u226510%) well-differentiated endocrine carcinoma staging","volume":"96","author":"Abgral","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1210\/endrev\/bnz004","article-title":"Advances in the Diagnosis and Management of Well-Differentiated Neuroendocrine Neoplasms","volume":"41","author":"Hofland","year":"2020","journal-title":"Endocr. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1007\/s002590000289","article-title":"99mTc-EDDA\/HYNIC-TOC: A new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours: First clinical results and intra-patient comparison with 111In-labelled octreotide derivatives","volume":"27","author":"Decristoforo","year":"2000","journal-title":"Eur. J. Nucl. Med."},{"key":"ref_33","first-page":"708","article-title":"An Intrapatient Comparison of 99mTc-EDDA\/HYNIC-TOC with 111In-DTPA-Octreotide for Diagnosis of Somatostatin Receptor-Expressing Tumors","volume":"44","author":"Gabriel","year":"2003","journal-title":"J. Nucl. Med."},{"key":"ref_34","first-page":"1114","article-title":"99mTc-HYNIC-[Tyr3]-octreotide for imaging somatostatin-receptor-positive tumors: Preclinical evaluation and comparison with 111In-octreotide","volume":"41","author":"Decristoforo","year":"2000","journal-title":"J. Nucl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"522","DOI":"10.2967\/jnumed.122.264422","article-title":"The Latest Advances in Peptide Receptor Radionuclide Therapy for Gastroenteropancreatic Neuroendocrine Tumors","volume":"64","author":"Baudin","year":"2023","journal-title":"J. Nucl. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Merola, E., and Grana, C.M. (2023). Peptide Receptor Radionuclide Therapy (PRRT): Innovations and Improvements. Cancers, 15.","DOI":"10.3390\/cancers15112975"},{"key":"ref_37","first-page":"13355","article-title":"Peptide receptor chemoradionuclide therapy for neuroendocrine neoplasms: A systematic review","volume":"21","author":"Chan","year":"2023","journal-title":"J. Neuroendocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ampofo, E., Nalbach, L., Menger, M.D., and Laschke, M.W. (2020). Regulatory Mechanisms of Somatostatin Expression. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21114170"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Milewska-Kranc, A., Cwikla, J.B., and Kolasinska-Cwikla, A. (2024). The Role of Receptor\u2013Ligand Interaction in Somatostatin Signaling Pathways: Implications for Neuroendocrine Tumors. Cancers, 16.","DOI":"10.3390\/cancers16010116"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1007\/s12032-009-9332-7","article-title":"Gastroenteropancreatic neuroendocrine tumors: 10-year experience in a single center","volume":"27","author":"Yildiz","year":"2010","journal-title":"Med. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Mai, R., Kaemmerer, D., Tr\u00e4ger, T., Neubauer, E., S\u00e4nger, J., Baum, R.P., Schulz, S., and Lupp, A. (2019). Different somatostatin and CXCR4 chemokine receptor expression in gastroenteropancreatic neuroendocrine neoplasms depending on their origin. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-39607-2"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s00428-007-0445-0","article-title":"Neuro-endocrine tumours of the lung. A review of relevant pathological and molecular data","volume":"451","author":"Righi","year":"2007","journal-title":"Virchows Arch."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1093\/annonc\/mdv041","article-title":"ENETS consensus conference participants. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids","volume":"26","author":"Caplin","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1111\/cen.12775","article-title":"Somatostatin and dopamine receptor expression in neuroendocrine neoplasms: Correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores","volume":"83","author":"Diakatou","year":"2015","journal-title":"Clin. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1097\/MPA.0000000000001181","article-title":"The Levels of Tumor Markers in Pancreatic Neuroendocrine Carcinoma and Their Values in Differentiation Between Pancreatic Neuroendocrine Carcinoma and Pancreatic Ductal Adenocarcinoma","volume":"47","author":"Zhuge","year":"2018","journal-title":"Pancreas"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.pan.2023.01.009","article-title":"Diagnostic role and prognostic value of tumor markers in high-grade gastro-enteropancreatic neuroendocrine neoplasms","volume":"23","author":"Gao","year":"2023","journal-title":"Pancreatology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1007\/s00432-022-03970-x","article-title":"Pulmonary neuroendocrine tumors: Study of 266 cases focusing on clinicopathological characteristics, immunophenotype, and prognosis","volume":"149","author":"Zhang","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"143","DOI":"10.11106\/ijt.2021.14.2.143","article-title":"Serum Carcinoembryonic Antigen as a Biomarker for Medullary Thyroid Cancer","volume":"14","author":"Kim","year":"2021","journal-title":"Int. J. Thyroidol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00428-021-03085-7","article-title":"An algorithmic approach utilizing CK7, TTF1, beta-catenin, CDX2, and SSTR2A can help differentiate between gastrointestinal and pulmonary neuroendocrine carcinomas","volume":"479","author":"Yu","year":"2021","journal-title":"Virchows Arch."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/PAP.0000000000000256","article-title":"An Algorithmic Immunohistochemical Approach to Define Tumor Type and Assign Site of Origin","volume":"27","author":"Bellizzi","year":"2020","journal-title":"Adv. Anat. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1097\/PAP.0b013e3182a2dc67","article-title":"Assigning Site of Origin in Metastatic Neuroendocrine Neoplasms: A Clinically Significant Application of Diagnostic Immunohistochemistry","volume":"20","author":"Bellizzi","year":"2013","journal-title":"Adv. Anat. Pathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1053\/j.semnuclmed.2022.12.007","article-title":"Molecular imaging Theranostics of Neuroendocrine Tumors","volume":"53","author":"Fortunati","year":"2023","journal-title":"Semin. Nucl. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/17\/2935\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:41:49Z","timestamp":1760035309000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/17\/2935"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,8]]},"references-count":52,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cancers17172935"],"URL":"https:\/\/doi.org\/10.3390\/cancers17172935","relation":{},"ISSN":["2072-6694"],"issn-type":[{"type":"electronic","value":"2072-6694"}],"subject":[],"published":{"date-parts":[[2025,9,8]]}}}