{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:40:07Z","timestamp":1786700407459,"version":"build-2736575974"},"reference-count":43,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Brain metastasis (BM) is a major cause of mortality in limited\u2010stage small\u2010cell lung cancer (LS\u2010SCLC). Prophylactic cranial irradiation (PCI) reduces BM incidence but carries neurotoxicity and lacks individualized risk assessment. Here, we developed BraMARS, an explainable deep learning model that estimates future BM risk from routine H&amp;E\u2010stained whole\u2010slide images of resected LS\u2010SCLC. BraMARS demonstrates robust discriminatory performance across independent cohorts, with AUCs ranging from 0.738 to 0.944, and stratifies patients into high\u2010risk and low\u2010risk groups with significantly different disease\u2010free survival, overall survival, and brain metastasis\u2010free survival. Retrospective simulation shows BraMARS\u2010guided risk stratification could reduce PCI exposure in 19.3% of low\u2010risk predicted patients while improving identification of high\u2010risk\u2010predicted patients by 84.4%. Histopathologic attribution and proteomic analyses linked higher scores to distinct tissue patterns and programs involving mitochondrial metabolism, reactive\u2010oxygen\u2010species detoxification, and DNA repair. Overall, BraMARS provides a biologically interpretable histopathology\u2010based framework for estimating subsequent BM risk in resected LS\u2010SCLC, with potential to support individualized intracranial risk assessment, intensified MRI surveillance, and hypothesis generation for prospective BM\u2010prevention strategies.<\/jats:p>","DOI":"10.1002\/advs.77075","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:21:46Z","timestamp":1786699306000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["BraMARS: An Interpretable Histopathology\u2010Driven Deep Learning Model for Brain Metastasis Risk Stratification in Surgically Resected Limited\u2010Stage SCLC"],"prefix":"10.1002","author":[{"given":"Zijian","family":"Yang","sequence":"first","affiliation":[{"name":"Institute of Genomic Medicine School of Biomedical Engineering Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taolue","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine School of Biomedical Engineering Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6868-2752","authenticated-orcid":false,"given":"Shilong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Radiation Oncology Harbin Medical University Cancer Hospital  Harbin People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zicheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine School of Biomedical Engineering Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9986-6397","authenticated-orcid":false,"given":"Yibo","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine School of Biomedical Engineering Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1355-1050","authenticated-orcid":false,"given":"Bo","family":"Yu","sequence":"additional","affiliation":[{"name":"AMG Nephrology Avera McKennan Hospital  Sioux Falls South Dakota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaishuai","family":"Gao","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine School of Biomedical Engineering Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine School of Biomedical Engineering Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pathology National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9987-9024","authenticated-orcid":false,"given":"Meng","family":"Zhou","sequence":"additional","affiliation":[{"name":"Institute of Genomic Medicine School of Biomedical Engineering Wenzhou Medical University  Wenzhou People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010020\u201000235\u20100"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.87"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2022.166557"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572\u2010018\u20100055\u2010y"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noac118"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.1929"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctro.2022.02.002"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.2147\/ijgm.S342009"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13014\u2010025\u201002644\u20105"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.889161"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2025.15011"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr\u20102025\u2010326"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202013122"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.7555\/JBR.38.20240293"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199908123410703"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prro.2020.02.009"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43856\u2010024\u201000445\u20107"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201080425\u2010y"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cllc.2018.09.014"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41746\u2010024\u201001003\u20100"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.21037\/tcr\u201024\u20101147"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12672\u2010023\u201000837\u20106"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032\u2010022\u201001900\u2010y"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201008575\u20107"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010025\u201000848\u20101"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1101\/2024.07.29.605595"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr\u201019\u2010547"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2021.11.033"},{"issue":"21","key":"e_1_2_11_30_1","first-page":"4760","article-title":"Elevated DNA Repair Capacity is Associated With Intrinsic Resistance of Lung Cancer to Chemotherapy","volume":"55","author":"Zeng\u2010Rong N.","year":"1995","journal-title":"Cancer Research"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.313"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556\u2010023\u201001241\u20106"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noae219"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202402716"},{"issue":"4","key":"e_1_2_11_35_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.xcrm.2026.102713","article-title":"Single\u2010Cell Spatial Transcriptomics Reveals Tumor Microenvironment Heterogeneity in Primary and Lymph Node\u2010Metastatic Small Cell Lung Cancer","volume":"7","author":"Zhang Z.","year":"2026","journal-title":"Cell Reports Medicine"},{"key":"e_1_2_11_36_1","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1007\/978-3-031-43907-0_57","volume-title":"Medical Image Computing and Computer Assisted Intervention \u2013 MICCAI 2023","author":"Fillioux L.","year":"2023"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.media.2022.102559"},{"key":"e_1_2_11_38_1","doi-asserted-by":"crossref","first-page":"35971","DOI":"10.52202\/068431-2607","article-title":"On the Parameterization and Initialization of Diagonal State Space Models","author":"Gu A.","year":"2022","journal-title":"Advances in neural information processing systems 35"},{"key":"e_1_2_11_39_1","first-page":"1474","article-title":"HiPPO: Recurrent Memory with Optimal Polynomial Projections","volume":"33","author":"Gu A.","year":"2020","journal-title":"Advances in Neural Information Processing Systems"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2026.102143"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1101\/2020.07.21.214205"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010019\u201009234\u20106"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.04.014"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77075","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.77075","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77075","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:21:48Z","timestamp":1786699308000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.77075"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":43,"alternative-id":["10.1002\/advs.77075"],"URL":"https:\/\/doi.org\/10.1002\/advs.77075","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]},"assertion":[{"value":"2026-01-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e77075"}}