{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:04:16Z","timestamp":1768568656437,"version":"3.49.0"},"posted":{"date-parts":[[2025,10,22]]},"group-title":"Oncology","reference-count":88,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Thymic involution, characterized by adipose replacement of functional thymic tissue, is a broadly recognized feature of age-related immunosenescence. Currently, no established, non-invasive method measures residual thymus in adults, its relationship with host immunity, or its influence on tumor immunosurveillance, cancer outcomes, and treatment-related toxicities. In a multi-institutional cohort of patients with locally advanced non-small cell lung cancer (NSCLC), we created a new CT-based metric to estimate residual functional thymic tissue and examined its association with toxicities and clinical outcomes. We defined a thymic region atlas and employed a novel segmentation model that integrates Transformer-based attention with convolutional detail preservation to automatically detect and delineate the thymic region on chest CT images. We then computed a new radiographic parameter, capturing the proportion of persistent thymic tissue or \u201cpercent thymic tissue\u201d (pTT), using Gaussian mixture modeling of the components of the delineated primal thymic space. We applied our framework to a publicly available NSCLC radiotherapy dataset (MAASTRO) and an institutional cohort at Memorial Sloan Kettering Cancer Center (MSKCC), assessing associations with age and sex. Kaplan-Meier estimates and Cox proportional hazards modeling were used to evaluate the association between pTT and distant metastasis-free survival (DMFS), locoregional failure (LRF), progression-free survival (PFS), and overall survival (OS). A total of 464 patients with stage III NSCLC, pre-treatment chest CT scans, curated clinical data, and long-term follow-up were analyzed. Of these, 277 were from MAASTRO and 187 from MSKCC. Our pTT method allowed tissue decomposition without manual thresholding or shape priors and was inherently robust to segmentation variability. pTT decreased with age at a rate of 0.36 percentage points per year (p &lt; 0.0001) in the MAASTRO cohort and 0.40 percentage points per year in the MSKCC group. pTT was significantly lower in males (MAASTRO: 9.75% vs. 17.0%, p&lt;0.001; MSKCC: 5.97% vs. 12.3%, p&lt;0.001). On multivariable Cox regression adjusting for age, sex, and histology, pTT was an independent predictor of survival (MAASTRO: aHR = 0.71, 95% CI: 0.50-0.99; p = 0.049; MSKCC: aHR = 0.51, 95% CI: 0.27-0.95; p = 0.058). Notably, pTT was also associated with DMFS (aHR = 0.51, 95% CI: 0.27-0.95; p = 0.03), LRF (aHR, 0.96; 95% CI, 0.93\u20130.99; p = 0.014), and PFS (aHR = 0.57, 95% CI: 0.32-1.01; p = 0.052) in the MSKCC cohort. There was a link between pTT and 12- and 24-month estimates for all end-points. pTT remained a significant predictor of improved DMFS even after adjusting for thymic radiation dose (aHR = 0.97; 95% CI, 0.94\u20130.99; p = 0.037), which itself was independently associated with inferior DMFS (aHR = 2.01; 95% CI, 1.02\u20133.99; p = 0.045). The LRF association also persisted after adjusting for thymus V20 (aHR, 0.96; 95% CI, 0.92\u20130.99; p = 0.008). Severe pneumonitis (grade \u22653) occurred more frequently in patients with low pTT values (13.9% vs. 5.2%; p = 0.04). Patients with both high lung V20 and low pTT represented the subgroup at greatest pneumonitis risk (20.8%, n = 11), whereas those with low lung V20 and high pTT had few observed events (1.9%, n =1). pTT also predicted durvalumab discontinuation due to treatment-related adverse events, particularly among patients with unresectable stage IIIC NSCLC (AUC = 0.8). Thus, the parameter pTT offers a reliable and interpretable non-invasive quantitative measure of residual functional thymus in adults, reflects age-related thymic involution, and independently predicts survival and treatment-related toxicity in stage III NSCLC. These findings support pTT as a structural imaging indicator of thymic function and suggest its potential for studying how cancer therapies impact host immunity, which may, in turn, influence long-term lung cancer treatment outcomes.<\/jats:p>","DOI":"10.1101\/2025.10.20.25338395","type":"posted-content","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T18:15:19Z","timestamp":1761156919000},"source":"Crossref","is-referenced-by-count":1,"title":["Thymus Composition, Disease Control, and Toxicity in Locally Advanced Lung Cancer"],"prefix":"10.64898","author":[{"given":"Tafadzwa L.","family":"Chaunzwa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abraham J.","family":"Book","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biniam","family":"Garomsa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuzhong J.","family":"Meng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaine","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gokul","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Chidi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory J.","family":"Riely","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"II","given":"Charles B.","family":"Simone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Narek","family":"Shaverdian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel R.","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025102407200524000_2025.10.20.25338395v1.1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41392-023-01451-2","article-title":"Immunosenescence: molecular mechanisms and diseases","volume":"8","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"2025102407200524000_2025.10.20.25338395v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-00927-z"},{"key":"2025102407200524000_2025.10.20.25338395v1.3","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s11357-013-9564-5","article-title":"Thymus and aging: morphological, radiological, and functional overview","volume":"36","year":"2014","journal-title":"Age (Dordr"},{"key":"2025102407200524000_2025.10.20.25338395v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.04.003"},{"key":"2025102407200524000_2025.10.20.25338395v1.5","doi-asserted-by":"crossref","unstructured":"Thome, J. J. C. et al. Long-term maintenance of human na\u00efve T cells through in situ homeostasis in lymphoid tissue sites. Sci. Immunol. 1, (2016).","DOI":"10.1126\/sciimmunol.aah6506"},{"key":"2025102407200524000_2025.10.20.25338395v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/25374"},{"key":"2025102407200524000_2025.10.20.25338395v1.7","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1097\/HP.0000000000001352","article-title":"Immune Reconstitution and Thymic Involution in the Acute and Delayed Hematopoietic Radiation Syndromes","volume":"119","year":"2020","journal-title":"Health Phys"},{"key":"2025102407200524000_2025.10.20.25338395v1.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2302892"},{"key":"2025102407200524000_2025.10.20.25338395v1.9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.933547"},{"key":"2025102407200524000_2025.10.20.25338395v1.10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01745"},{"key":"2025102407200524000_2025.10.20.25338395v1.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1709937"},{"key":"2025102407200524000_2025.10.20.25338395v1.12","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.00174"},{"key":"2025102407200524000_2025.10.20.25338395v1.13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1507643"},{"key":"2025102407200524000_2025.10.20.25338395v1.14","doi-asserted-by":"crossref","unstructured":"Zer, A. et al. Early and locally advanced non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 0, (2025).","DOI":"10.1016\/j.annonc.2025.08.003"},{"key":"2025102407200524000_2025.10.20.25338395v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2022.12.013"},{"key":"2025102407200524000_2025.10.20.25338395v1.16","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1809697"},{"key":"2025102407200524000_2025.10.20.25338395v1.17","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.lungcan.2021.01.022","article-title":"Association of severe lymphopenia and disease progression in unresectable locally advanced non-small cell lung cancer treated with definitive chemoradiation and immunotherapy","volume":"154","year":"2021","journal-title":"Lung Cancer"},{"key":"2025102407200524000_2025.10.20.25338395v1.18","first-page":"101260","article-title":"Dosimetric Effect of Thymus and Thoracic Duct on Radiation-Induced Lymphopenia in Patients With Primary Lung Cancer Who Received Thoracic Radiation. Adv","volume":"8","author":"Zhang","year":"2023","journal-title":"Radiat. Oncol"},{"key":"2025102407200524000_2025.10.20.25338395v1.19","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1038\/s41571-025-01029-7","article-title":"Rechallenge with immune-checkpoint inhibitors in patients with advanced-stage lung cancer","volume":"22","year":"2025","journal-title":"Nat. Rev. Clin. Oncol"},{"key":"2025102407200524000_2025.10.20.25338395v1.20","doi-asserted-by":"crossref","first-page":"S184","DOI":"10.1016\/j.jacr.2019.02.008","article-title":"ACR appropriateness criteria\u00ae noninvasive clinical staging of primary lung cancer","volume":"16","author":"Expert Panel on Thoracic Imaging:","year":"2019","journal-title":"J. Am. Coll. Radiol."},{"key":"2025102407200524000_2025.10.20.25338395v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejrad.2011.12.015"},{"key":"2025102407200524000_2025.10.20.25338395v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/s00330-015-3796-y"},{"key":"2025102407200524000_2025.10.20.25338395v1.23","doi-asserted-by":"crossref","first-page":"e29950","DOI":"10.1097\/MD.0000000000029950","article-title":"Evaluation of age-related thymic changes using computed tomography images: A retrospective observational study","volume":"101","year":"2022","journal-title":"Medicine (Baltimore)"},{"key":"2025102407200524000_2025.10.20.25338395v1.24","doi-asserted-by":"publisher","DOI":"10.1007\/s10439-025-03805-z"},{"key":"2025102407200524000_2025.10.20.25338395v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmp.2021.05.003"},{"key":"2025102407200524000_2025.10.20.25338395v1.26","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/s42256-024-00807-9","article-title":"Foundation model for cancer imaging biomarkers. Nat","volume":"6","year":"2024","journal-title":"Mach. Intell"},{"key":"2025102407200524000_2025.10.20.25338395v1.27","doi-asserted-by":"crossref","unstructured":"Tak, D. et al. A foundation model for generalized brain MRI analysis. Radiology and Imaging (2024).","DOI":"10.1101\/2024.12.02.24317992"},{"key":"2025102407200524000_2025.10.20.25338395v1.28","doi-asserted-by":"crossref","first-page":"5471","DOI":"10.1038\/s41598-021-84630-x","article-title":"Deep learning classification of lung cancer histology using CT images","volume":"11","year":"2021","journal-title":"Sci. Rep"},{"key":"2025102407200524000_2025.10.20.25338395v1.29","doi-asserted-by":"crossref","first-page":"e2514452","DOI":"10.1001\/jamanetworkopen.2025.14452","article-title":"Multinational Attitudes Toward AI in Health Care and Diagnostics Among Hospital Patients","volume":"8","year":"2025","journal-title":"JAMA Netw Open"},{"key":"2025102407200524000_2025.10.20.25338395v1.30","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1055\/s-0042-1742511","article-title":"Clinical Informatics Approaches to Understand and Address Cancer Disparities","volume":"31","year":"2022","journal-title":"Yearb Med Inform"},{"key":"2025102407200524000_2025.10.20.25338395v1.31","doi-asserted-by":"crossref","first-page":"5935","DOI":"10.1002\/mp.16716","article-title":"Observer preference of artificial intelligence-generated versus clinical prostate contours for ultrasound-based high dose rate brachytherapy","volume":"50","year":"2023","journal-title":"Medical Physics"},{"key":"2025102407200524000_2025.10.20.25338395v1.32","doi-asserted-by":"publisher","DOI":"10.1118\/1.2791035"},{"key":"2025102407200524000_2025.10.20.25338395v1.33","doi-asserted-by":"crossref","unstructured":"Zeng, Q. , Zhou, J. , Ji, Y. & Wang, H . A semiparametric Gaussian mixture model for chest CT-based 3D blood vessel reconstruction. Biostatistics 26, (2024).","DOI":"10.1093\/biostatistics\/kxae013"},{"key":"2025102407200524000_2025.10.20.25338395v1.34","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1186\/s12880-025-01783-1","article-title":"Development and validation of AI-based automatic segmentation and measurement of thymus on chest CT scans","volume":"25","year":"2025","journal-title":"BMC Medical Imaging"},{"key":"2025102407200524000_2025.10.20.25338395v1.35","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2010.04209.x"},{"key":"2025102407200524000_2025.10.20.25338395v1.36","doi-asserted-by":"publisher","DOI":"10.48550\/arxiv.2211.02701"},{"key":"2025102407200524000_2025.10.20.25338395v1.37","doi-asserted-by":"crossref","first-page":"6193","DOI":"10.3390\/cancers13246193","article-title":"Higher radiation dose to the Immune Cells correlates with worse tumor control and overall survival in patients with stage III NSCLC: A secondary analysis of RTOG0617","volume":"13","year":"2021","journal-title":"Cancers (Basel)"},{"key":"2025102407200524000_2025.10.20.25338395v1.38","doi-asserted-by":"publisher","DOI":"10.1101\/2023.11.13.23298440"},{"key":"2025102407200524000_2025.10.20.25338395v1.39","unstructured":"Bernatz, S , et. al. Thymic health is associated with immunotherapy outcomes in patients with cancer. in ESMO Congress 2025. Abstract 108O."},{"key":"2025102407200524000_2025.10.20.25338395v1.40","doi-asserted-by":"publisher","DOI":"10.7937\/k9\/tcia.2015.pf0m9rei"},{"key":"2025102407200524000_2025.10.20.25338395v1.41","unstructured":"Park, J.-E. et al. A cell atlas of human thymic development defines T cell repertoire formation. Science 367, (2020)."},{"key":"2025102407200524000_2025.10.20.25338395v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21346-6"},{"key":"2025102407200524000_2025.10.20.25338395v1.43","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.3389\/fimmu.2018.01312","article-title":"DN2 thymocytes activate a specific robust DNA damage response to ionizing radiation-induced DNA double-strand breaks","volume":"9","year":"2018","journal-title":"Front. Immunol"},{"key":"2025102407200524000_2025.10.20.25338395v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2015.120"},{"key":"2025102407200524000_2025.10.20.25338395v1.45","doi-asserted-by":"crossref","first-page":"110041","DOI":"10.1016\/j.radonc.2023.110041","article-title":"Modeling frameworks for radiation induced lymphopenia: A critical review","volume":"190","year":"2024","journal-title":"Radiother. Oncol"},{"key":"2025102407200524000_2025.10.20.25338395v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01915-9"},{"key":"2025102407200524000_2025.10.20.25338395v1.47","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/s41577-024-01119-0","article-title":"Endogenous thymic regeneration: restoring T cell production following injury","volume":"25","year":"2025","journal-title":"Nat. Rev. Immunol"},{"key":"2025102407200524000_2025.10.20.25338395v1.48","first-page":"119","article-title":"T lymphocytes and normal tissue responses to radiation","volume":"2","year":"2012","journal-title":"Front. Oncol"},{"key":"2025102407200524000_2025.10.20.25338395v1.49","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1201500"},{"key":"2025102407200524000_2025.10.20.25338395v1.50","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-00457-z"},{"key":"2025102407200524000_2025.10.20.25338395v1.51","doi-asserted-by":"crossref","unstructured":"Keshamouni, V. , Arenberg, D. & Kalemkerian, G . Lung Cancer Metastasis: Novel Biological Mechanisms and Impact on Clinical Practice. (Springer Science & Business Media, 2009).","DOI":"10.1007\/978-1-4419-0772-1"},{"key":"2025102407200524000_2025.10.20.25338395v1.52","doi-asserted-by":"crossref","unstructured":"Chiang, A. C. & Herbst, R. S . Lung Cancer: New Understandings and Therapies. (Springer Nature, 2021).","DOI":"10.1007\/978-3-030-74028-3"},{"key":"2025102407200524000_2025.10.20.25338395v1.53","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.semradonc.2019.12.003","article-title":"Lymphocyte-Sparing Radiotherapy: The rationale for protecting lymphocyte-rich organs when combining radiotherapy with immunotherapy","volume":"30","year":"2020","journal-title":"Semin. Radiat. Oncol"},{"key":"2025102407200524000_2025.10.20.25338395v1.54","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-05-0074"},{"key":"2025102407200524000_2025.10.20.25338395v1.55","doi-asserted-by":"crossref","unstructured":"Thomas, R. , Wang, W. & Su, D. M . Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging. Immunity & ageing : I & A 17, (2020).","DOI":"10.1186\/s12979-020-0173-8"},{"key":"2025102407200524000_2025.10.20.25338395v1.56","doi-asserted-by":"crossref","unstructured":"Chaudhry, M. S. , Velardi, E. , Dudakov, J. A. & van den Brink, M. R. Thymus: the next (re)generation. Immunological reviews 271, (2016).","DOI":"10.1111\/imr.12418"},{"key":"2025102407200524000_2025.10.20.25338395v1.57","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41698-024-00781-w","article-title":"Diversity of TCR repertoire predicts recurrence after CRT followed by durvalumab in patients with NSCLC","volume":"9","year":"2025","journal-title":"NPJ Precis. Oncol"},{"key":"2025102407200524000_2025.10.20.25338395v1.58","doi-asserted-by":"crossref","first-page":"4238","DOI":"10.1038\/s41467-023-39874-8","article-title":"Impact of TMB\/PD-L1 expression and pneumonitis on chemoradiation and durvalumab response in stage III NSCLC","volume":"14","year":"2023","journal-title":"Nat. Commun"},{"key":"2025102407200524000_2025.10.20.25338395v1.59","doi-asserted-by":"crossref","first-page":"102101","DOI":"10.1016\/j.xcrm.2025.102101","article-title":"Low T cell diversity associates with poor outcome in bladder cancer: A comprehensive longitudinal analysis of the T cell receptor repertoire","volume":"6","year":"2025","journal-title":"Cell Rep. Med"},{"key":"2025102407200524000_2025.10.20.25338395v1.60","doi-asserted-by":"crossref","unstructured":"Hopkins, A. C. , et al. T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma. JCI Insight 3, (2018).","DOI":"10.1172\/jci.insight.122092"},{"key":"2025102407200524000_2025.10.20.25338395v1.61","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/s41587-024-02232-0","article-title":"Identification of clinically relevant T cell receptors for personalized T cell therapy using combinatorial algorithms","volume":"43","year":"2025","journal-title":"Nat. Biotechnol"},{"key":"2025102407200524000_2025.10.20.25338395v1.62","unstructured":"Girotto, G. et al. Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non\u2013Small Cell Lung Cancer: The Phase III PACIFIC-2 Study. Journal of Clinical Oncology (2025)."},{"key":"2025102407200524000_2025.10.20.25338395v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.radonc.2019.11.015"},{"key":"2025102407200524000_2025.10.20.25338395v1.64","doi-asserted-by":"crossref","first-page":"586449","DOI":"10.3389\/fonc.2020.586449","article-title":"Consolidation Immunotherapy After Platinum-Based Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer-Cross-Sectional Study of Eligibility and Administration Rates","volume":"10","year":"2020","journal-title":"Front Oncol"},{"key":"2025102407200524000_2025.10.20.25338395v1.65","doi-asserted-by":"publisher","DOI":"10.1038\/nature14292"},{"key":"2025102407200524000_2025.10.20.25338395v1.66","doi-asserted-by":"crossref","unstructured":"O\u2019Leary, C. L. , Pierce, N. , Patel, S. P. & Naidoo, J . Immune-Related Toxicity in NSCLC: Current State-of-the-Art and Emerging Clinical Challenges. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 19, (2024).","DOI":"10.1016\/j.jtho.2023.11.018"},{"key":"2025102407200524000_2025.10.20.25338395v1.67","doi-asserted-by":"crossref","unstructured":"Meraz-Mu\u00f1oz, A. et al. Acute kidney injury associated with immune checkpoint inhibitor therapy: incidence, risk factors and outcomes. J Immunother Cancer 8, (2020).","DOI":"10.1136\/jitc-2019-000467"},{"key":"2025102407200524000_2025.10.20.25338395v1.68","doi-asserted-by":"crossref","unstructured":"Sakata, Y. et al. The association between tumor burden and severe immune-related adverse events in non-small cell lung cancer patients responding to immune-checkpoint inhibitor treatment. Lung cancer (Amsterdam, Netherlands) 130, (2019).","DOI":"10.1016\/j.lungcan.2019.02.011"},{"key":"2025102407200524000_2025.10.20.25338395v1.69","doi-asserted-by":"crossref","first-page":"1758835920926822","DOI":"10.1177\/1758835920926822","article-title":"A review of radiation-induced lymphopenia in patients with esophageal cancer: an immunological perspective for radiotherapy","volume":"12","year":"2020","journal-title":"Therapeutic Advances in Medical Oncology"},{"key":"2025102407200524000_2025.10.20.25338395v1.70","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13671"},{"key":"2025102407200524000_2025.10.20.25338395v1.71","doi-asserted-by":"crossref","unstructured":"Palmer, D. B . The effect of age on thymic function. Frontiers in immunology 4, (2013).","DOI":"10.3389\/fimmu.2013.00316"},{"key":"2025102407200524000_2025.10.20.25338395v1.72","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.2517-6161.1977.tb01600.x","article-title":"Maximum Likelihood from Incomplete Data Via the EM Algorithm","volume":"39","year":"1977","journal-title":"J. R. Stat. Soc"},{"key":"2025102407200524000_2025.10.20.25338395v1.73","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/s42256-019-0048-x","article-title":"Stop explaining black box machine learning models for high stakes decisions and use interpretable models instead. Nat","volume":"1","year":"2019","journal-title":"Mach. Intell"},{"key":"2025102407200524000_2025.10.20.25338395v1.74","first-page":"e745","article-title":"The false hope of current approaches to explainable artificial intelligence in health care. Lancet Digit","volume":"3","year":"2021","journal-title":"Health"},{"key":"2025102407200524000_2025.10.20.25338395v1.75","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adg1487"},{"key":"2025102407200524000_2025.10.20.25338395v1.76","doi-asserted-by":"crossref","unstructured":"McFarland, R. D. , Douek, D. C. , Koup, R. A. & Picker, L. J . Identification of a human recent thymic emigrant phenotype. Proceedings of the National Academy of Sciences of the United States of America 97, (2000).","DOI":"10.1073\/pnas.070061597"},{"key":"2025102407200524000_2025.10.20.25338395v1.77","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/s41592-021-01201-8","article-title":"High-throughput and single-cell T cell receptor sequencing technologies","volume":"18","year":"2021","journal-title":"Nature Methods"},{"key":"2025102407200524000_2025.10.20.25338395v1.78","doi-asserted-by":"publisher","DOI":"10.1101\/2024.11.19.24317497"},{"key":"2025102407200524000_2025.10.20.25338395v1.79","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-101721-064501"},{"key":"2025102407200524000_2025.10.20.25338395v1.80","doi-asserted-by":"crossref","unstructured":"Fedorov, A. et al. 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magnetic resonance imaging 30, (2012).","DOI":"10.1016\/j.mri.2012.05.001"},{"key":"2025102407200524000_2025.10.20.25338395v1.81","doi-asserted-by":"crossref","first-page":"112004","DOI":"10.1016\/j.ejrad.2025.112004","article-title":"Automated segmentation by SCA-UNet can be directly used for radiomics diagnosis of thymic epithelial tumors","volume":"185","year":"2025","journal-title":"Eur. J. Radiol"},{"key":"2025102407200524000_2025.10.20.25338395v1.82","unstructured":"Goodfellow, I. , Bengio, Y. , Courville, A. & Bengio, Y. Deep Learning. vol. 1 (MIT press Cambridge, 2016)."},{"key":"2025102407200524000_2025.10.20.25338395v1.83","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1667\/RR4554.1","article-title":"Late Effects of Exposure to Ionizing Radiation and Age on Human Thymus Morphology and Function","volume":"187","year":"2017","journal-title":"Radiat. Res"},{"key":"2025102407200524000_2025.10.20.25338395v1.84","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00911-8"},{"key":"2025102407200524000_2025.10.20.25338395v1.85","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/978-1-59745-395-0_8","article-title":"Thymus organogenesis and development of the thymic stroma","volume":"380","year":"2007","journal-title":"Methods Mol. Biol"},{"key":"2025102407200524000_2025.10.20.25338395v1.86","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.athoracsur.2013.07.121","article-title":"What is the prevalence of a \u2018nontherapeutic\u2019 thymectomy?","volume":"97","year":"2014","journal-title":"Ann. Thorac. Surg"},{"key":"2025102407200524000_2025.10.20.25338395v1.87","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2010.08.005"},{"key":"2025102407200524000_2025.10.20.25338395v1.88","unstructured":"Wong, H. E. , Ortiz, J. J. G. , Guttag, J. & Dalca, A. V . MultiverSeg: Scalable Interactive Segmentation of Biomedical Imaging Datasets with In-Context Guidance. (2024)."}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.10.20.25338395","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:49:14Z","timestamp":1768510154000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.10.20.25338395"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":88,"URL":"https:\/\/doi.org\/10.1101\/2025.10.20.25338395","relation":{},"subject":[],"published":{"date-parts":[[2025,10,22]]},"subtype":"preprint"}}