{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:07Z","timestamp":1792789087039,"version":"4.5.0"},"reference-count":21,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"crossref","award":["PJT-180251"],"award-info":[{"award-number":["PJT-180251"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"award":["PJT-180251"],"award-info":[{"award-number":["PJT-180251"]}],"id":[{"id":"https:\/\/ror.org\/01gavpb45","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Mitacs Elevate"},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"crossref","award":["DH-2025-00119"],"award-info":[{"award-number":["DH-2025-00119"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]},{"award":["DH-2025-00119"],"award-info":[{"award-number":["DH-2025-00119"]}],"id":[{"id":"https:\/\/ror.org\/01h531d29","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Introduction: Prostate cancer (PCa) is the most commonly diagnosed malignancy among men and remains a major cause of cancer-related mortality worldwide. We aimed to evaluate whether radiomic features extracted from normal endocrine organs, combined with clinical variables, could predict clinical progression in patients with PSMA-negative prostate cancer. Materials and Methods: In this retrospective study, 101 men with biochemically recurrent prostate cancer and negative [18F]DCFPyL PET\/CT scans were included. Radiomic features were extracted from the adrenal glands, thyroid, the hypothalamus\u2013pituitary complex, and testes. Post-imaging variables were excluded to prevent temporal data leakage. Models were developed using a stratified train\/test split framework with preprocessing and feature selection performed exclusively within the training subset prior to evaluation on the held-out test set. Performance was evaluated using AUC, accuracy, sensitivity, specificity, and Brier score, while bootstrap confidence intervals and DeLong analysis were used for statistical assessment. Results: Multimodal fusion models integrating CT radiomics, PET radiomics, and clinical variables demonstrated the strongest predictive performance. The highest-performing model combined TESTIS_CT and TESTIS_PET radiomics with clinical variables, achieving an AUC of 0.758 (95% CI: 0.653\u20130.849). Clinical-only models remained highly competitive, with the best configuration achieving an AUC of 0.727 (95% CI: 0.618\u20130.833). PET + clinical and CT + clinical models achieved AUC values of up to 0.733 and 0.729, respectively, while imaging-only models demonstrated substantially lower discrimination. Although endocrine organ radiomics numerically improved predictive performance and specificity, DeLong analysis demonstrated no statistically significant improvement beyond clinical variables alone. Discussion: These findings suggest that endocrine organ radiomics may provide complementary system-level imaging biomarkers reflecting tumor\u2013host interactions in PSMA-negative prostate cancer. However, their incremental clinical value remains modest. Conclusions: Endocrine organ radiomics combined with clinical variables demonstrated promising predictive performance in PSMA-negative prostate cancer, particularly in multimodal fusion models. Nevertheless, the added value beyond clinical variables alone was not statistically significant and requires validation in larger independent cohorts.<\/jats:p>","DOI":"10.3390\/cancers18111767","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T12:09:07Z","timestamp":1779970147000},"page":"1767","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Microenvironment at a Distance: Multi-Endocrine-Organ Radiomics to Identify Systemic Signatures in PSMA-Negative Prostate Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0761-1309","authenticated-orcid":false,"given":"Hamid","family":"Abdollahi","sequence":"first","affiliation":[{"name":"Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Basic and Translational Research, BC Cancer Research Institute, 675 West 10th Ave., Vancouver, BC V5Z 1L3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Harsini","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Research, BC Cancer Research Institute, 675 West 10th Ave., Vancouver, BC V5Z 1L3, Canada"},{"name":"Department of Medical Imaging, University of Toronto, Toronto, ON M5T 1W7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fereshteh","family":"Yousefirizi","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Basic and Translational Research, BC Cancer Research Institute, 675 West 10th Ave., Vancouver, BC V5Z 1L3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahareh","family":"Hatami","sequence":"additional","affiliation":[{"name":"Department of Radiology, Tehran University of Medical Sciences (TUMS), Tehran 1416753955, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"B\u00e9nard","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Basic and Translational Research, BC Cancer Research Institute, 675 West 10th Ave., Vancouver, BC V5Z 1L3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2397-6914","authenticated-orcid":false,"given":"Ahmad","family":"Shariftabrizi","sequence":"additional","affiliation":[{"name":"Division of Nuclear Medicine, Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Alberts","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Basic and Translational Research, BC Cancer Research Institute, 675 West 10th Ave., Vancouver, BC V5Z 1L3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9980-2403","authenticated-orcid":false,"given":"Arman","family":"Rahmim","sequence":"additional","affiliation":[{"name":"Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada"},{"name":"Department of Basic and Translational Research, BC Cancer Research Institute, 675 West 10th Ave., Vancouver, BC V5Z 1L3, Canada"},{"name":"Research Center for Molecular and Cellular Imaging (RCMCI), Advanced Medical Technologies and Equipment Institute (AMTEI), Tehran University of Medical Sciences (TUMS), Tehran 1416753955, Iran"},{"name":"Departments of Physics & Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 1Z1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5123","DOI":"10.1038\/s41598-025-88392-8","article-title":"Global burden and risk factors of male cancers from 1990 to 2021, with forecasts to 2040","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/s41585-024-00875-x","article-title":"From biology to the clinic\u2014Exploring liver metastasis in prostate cancer","volume":"21","author":"Ni","year":"2024","journal-title":"Nat. Rev. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.7150\/thno.92612","article-title":"PSMA-targeted radiotheranostics in modern nuclear medicine: Then, now, and what of the future?","volume":"14","author":"Sallam","year":"2024","journal-title":"Theranostics"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"von Stauffenberg, F., Poyet, C., Beintner-Skawran, S., Maurer, A., and Schmid, F.A. (2024). Current clinical applications of PSMA-PET for prostate cancer diagnosis, staging, and treatment. Cancers, 16.","DOI":"10.3390\/cancers16244263"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s40644-024-00752-1","article-title":"Prognostic significance of a negative PSMA PET\/CT in biochemical recurrence of prostate cancer","volume":"24","author":"Harsini","year":"2024","journal-title":"Cancer Imaging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"881","DOI":"10.20892\/j.issn.2095-3941.2025.0149","article-title":"The immune landscape of systemic inflammation in prostate cancer","volume":"22","author":"Zhang","year":"2025","journal-title":"Cancer Biol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/nrurol.2010.231","article-title":"Blockade of testicular and adrenal androgens in prostate cancer treatment","volume":"8","author":"Labrie","year":"2011","journal-title":"Nat. Rev. Urol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bossio, S., Urlandini, L., Perri, A., Conforti, F., Aversa, A., Di Agostino, S., and Rago, V. (2024). Prostate cancer: Emerging modifiable risk factors and therapeutic strategies in the management of advanced cancer. Life, 14.","DOI":"10.3390\/life14091094"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/nrc4016","article-title":"Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer","volume":"15","author":"Watson","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"115234","DOI":"10.1016\/j.celrep.2025.115234","article-title":"Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions","volume":"44","author":"Cote","year":"2025","journal-title":"Cell Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12TR02","DOI":"10.1088\/1361-6560\/ac6fab","article-title":"Radiomics-guided radiation therapy: Opportunities and challenges","volume":"67","author":"Abdollahi","year":"2022","journal-title":"Phys. Med. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jafari, E., Zarei, A., Dadgar, H., Keshavarz, A., Abdollahi, H., Samimi, R., Manafi-Farid, R., Divband, G., Nikkholgh, B., and Fallahi, B. (2025). Efficacy of PSMA PET\/CT radiomics analysis for risk stratification in newly diagnosed prostate cancer: A multicenter study. BMC Med. Imaging, 25.","DOI":"10.1186\/s12880-025-01914-8"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S99","DOI":"10.1016\/j.ijrobp.2025.06.1141","article-title":"Prediction of metastasis-free survival in patients with prostate adenocarcinoma using primary tumor and lymph node radiomics from pre-treatment PSMA PET\/CT scans","volume":"123","author":"Singh","year":"2025","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1097\/RLU.0000000000005400","article-title":"Organomics: A concept reflecting the importance of PET\/CT healthy organ radiomics in non-small cell lung cancer prognosis prediction using machine learning: A concept reflecting the importance of PET\/CT healthy organ radiomics in Non-small cell lung cancer prognosis prediction using machine learning","volume":"49","author":"Salimi","year":"2024","journal-title":"Clin. Nucl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.2967\/jnumed.121.262618","article-title":"Improved prognosis of treatment failure in cervical cancer with nontumor PET\/CT radiomics","volume":"63","author":"Yusufaly","year":"2022","journal-title":"J. Nucl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e104","DOI":"10.1158\/0008-5472.CAN-17-0339","article-title":"Computational radiomics system to decode the radiographic phenotype","volume":"77","author":"Fedorov","year":"2017","journal-title":"Cancer Res."},{"key":"ref_17","unstructured":"Yousefirizi, F., Harsini, S., Mohebi, M., Alberts, I., Yusufaly, T., Luo, M., Abdollahi, H., Yazdani, E., Mirabedin, S., and Sabouri, M. (2026). Beyond the tumor: Recurrence-prone radiomics for prognostication in negative PSMA PET\/CT scans of prostate cancer. arXiv."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1158\/1078-0432.CCR-18-1431","article-title":"Contribution of adrenal glands to intratumor androgens and growth of castration-resistant prostate cancer","volume":"25","author":"Mostaghel","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1158\/0008-5472.CAN-08-0249","article-title":"Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth","volume":"68","author":"Montgomery","year":"2008","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1038\/bjc.2014.268","article-title":"Androgen metabolism in prostate cancer: From molecular mechanisms to clinical consequences","volume":"111","author":"Chang","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e220228","DOI":"10.1530\/ETJ-22-0228","article-title":"The androgen-thyroid hormone crosstalk in prostate cancer and the clinical implications","volume":"12","author":"Torabinejad","year":"2023","journal-title":"Eur. Thyroid. J."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1767\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T04:29:59Z","timestamp":1780115399000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1767"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":21,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18111767"],"URL":"https:\/\/doi.org\/10.3390\/cancers18111767","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]}}}