{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:20:50Z","timestamp":1783412450004,"version":"3.54.6"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Biliary tract cancer (BTC) exhibits diverse molecular characteristics. However, reliable biomarkers that predict therapeutic responses are yet to be discovered. We aimed to identify the molecular features of treatment responses to chemotherapy and immunotherapy in BTCs.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>We enrolled 121 advanced BTC patients (68 cholangiocarcinomas [33 intrahepatic, 35 extrahepatic], 41 gallbladder cancers, and 12 Ampulla of Vater cancers) whose specimens were analyzed by clinical sequencing platforms. All patients received first\u2010line palliative chemotherapy; 48 patients underwent programmed death 1 (PD\u20101)\/programmed death\u2010ligand 1 (PD\u2010L1) blockade therapy after failed chemotherapy. Molecular and histopathological characterization was performed using targeted sequencing and immunohistochemical staining to investigate treatment response\u2010associated biomarkers. Genomic analysis revealed a broad spectrum of mutational profiles according to anatomical location. Favorable responses to chemotherapy were observed in the small\u2010duct type compared with the large\u2010duct type intrahepatic cholangiocarcinoma, with frequent mutations in BRCA1\u2010associated protein\u20101\/isocitrate dehydrogenase 1\/2 and KRAS proto\u2010oncogene, GTPase\/SMAD family member 4 genes, respectively. The molecular features were further analyzed in BTCs, and transforming growth factor beta and DNA damage response pathway\u2010altered tumors exhibited poor and favorable chemotherapy responses, respectively. In PD\u20101\/PD\u2010L1 blockade\u2010treated patients, <jats:italic toggle=\"yes\">KRAS<\/jats:italic> alteration and chromosomal instability tumors were associated with resistance to immunotherapy. The majority of patients (95.0%) with these resistance factors show no clinical benefit to PD\u20101\/PD\u2010L1 blockade and low tumor mutational burdens. Low tumor\u2010infiltrating lymphocyte (TIL) density in tumors with these resistance factors indicated immune\u2010suppressive tumor microenvironments, whereas high intratumoral TIL density was associated with a favorable immunotherapy response.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>This study proposes predictive molecular features of chemotherapy and immunotherapy responses in advanced BTCs using clinical sequencing platforms. Our result provides an intuitive framework to guide the treatment of advanced BTCs benefiting from therapeutic agents based on the tumors\u2019 molecular features.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31862","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T02:36:38Z","timestamp":1619058998000},"page":"1914-1931","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":84,"title":["Molecular Characterization of Biliary Tract Cancer Predicts Chemotherapy and Programmed Death 1\/Programmed Death\u2010Ligand 1 Blockade Responses"],"prefix":"10.1097","volume":"74","author":[{"given":"Jihoon G.","family":"Yoon","sequence":"first","affiliation":[{"name":"Department of Pharmacology,Yonsei University College of Medicine,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Hwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology,Department of Internal Medicine,Yonsei University College of Medicine,Seoul,Republic of Korea"},{"name":"Pancreaticobiliary Cancer Clinic,Yonsei Cancer Center,Severance Hospital,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project,Yonsei University College of Medicine,Seoul,Republic of Korea"},{"name":"Department of Pathology,National Health Insurance Service Ilsan Hospital,Goyang,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hoguen","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project,Yonsei University College of Medicine,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Kyoung","family":"Hwang","sequence":"additional","affiliation":[{"name":"Pancreaticobiliary Cancer Clinic,Yonsei Cancer Center,Severance Hospital,Seoul,Republic of Korea"},{"name":"Division of Hepatobiliary and Pancreatic Surgery,Department of Surgery,Yonsei University College of Medicine,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang Moo","family":"Kang","sequence":"additional","affiliation":[{"name":"Pancreaticobiliary Cancer Clinic,Yonsei Cancer Center,Severance Hospital,Seoul,Republic of Korea"},{"name":"Division of Hepatobiliary and Pancreatic Surgery,Department of Surgery,Yonsei University College of Medicine,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo Jung","family":"Lee","sequence":"additional","affiliation":[{"name":"Pancreaticobiliary Cancer Clinic,Yonsei Cancer Center,Severance Hospital,Seoul,Republic of Korea"},{"name":"Division of Hepatobiliary and Pancreatic Surgery,Department of Surgery,Yonsei University College of Medicine,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beodeul","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology,Department of Internal Medicine,Yonsei University College of Medicine,Seoul,Republic of Korea"},{"name":"Pancreaticobiliary Cancer Clinic,Yonsei Cancer Center,Severance Hospital,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choong\u2010kun","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology,Department of Internal Medicine,Yonsei University College of Medicine,Seoul,Republic of Korea"},{"name":"Pancreaticobiliary Cancer Clinic,Yonsei Cancer Center,Severance Hospital,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Goo","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,Yonsei University College of Medicine,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Cheol","family":"Chung","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology,Department of Internal Medicine,Yonsei University College of Medicine,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Jin","family":"Choi","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology,Department of Internal Medicine,Yonsei University College of Medicine,Seoul,Republic of Korea"},{"name":"Pancreaticobiliary Cancer Clinic,Yonsei Cancer Center,Severance Hospital,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Nyun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project,Yonsei University College of Medicine,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,7,29]]},"reference":[{"key":"hep31862-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","article-title":"Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS\u2010CCA)","volume":"13","year":"2016","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep31862-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"104","DOI":"10.5009\/gnl18105","article-title":"Incidence and overall survival of biliary tract cancers in South Korea from 2006 to 2015: using the national health information database","volume":"13","year":"2019","journal-title":"Gut Liv"},{"key":"hep31862-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","volume":"362","year":"2010","journal-title":"N Engl J Med"},{"key":"hep31862-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/ng.3375","article-title":"Genomic spectra of biliary tract cancer","volume":"47","year":"2015","journal-title":"Nat Genet"},{"key":"hep31862-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"3657","DOI":"10.1002\/cncr.30247","article-title":"Next\u2010generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance","volume":"122","year":"2016","journal-title":"Cancer"},{"key":"hep31862-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1158\/2159-8290.CD-17-0368","article-title":"Whole\u2010genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma","volume":"7","year":"2017","journal-title":"Cancer Discov"},{"key":"hep31862-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.jhep.2018.01.009","article-title":"Genomic characterization of biliary tract cancers identifies driver genes and predisposing mutations","volume":"68","year":"2018","journal-title":"J Hepatol"},{"key":"hep31862-bib-0008-20250824","doi-asserted-by":"crossref","first-page":"4154","DOI":"10.1158\/1078-0432.CCR-18-0078","article-title":"Comprehensive molecular profiling of intrahepatic and extrahepatic cholangiocarcinomas: potential targets for intervention","volume":"24","year":"2018","journal-title":"Clin Cancer Res"},{"key":"hep31862-bib-0009-20250824","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1002\/hep.31110","article-title":"Genomic characterization of cholangiocarcinoma in primary sclerosing cholangitis reveals therapeutic opportunities","volume":"72","year":"2020","journal-title":"Hepatology"},{"key":"hep31862-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s13045-015-0155-z","article-title":"HER2\/neu\u2010directed therapy for biliary tract cancer","volume":"8","year":"2015","journal-title":"J Hematol Oncol"},{"key":"hep31862-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/S2468-1253(19)30189-X","article-title":"Safety and activity of ivosidenib in patients with IDH1\u2010mutant advanced cholangiocarcinoma: a phase 1 study","volume":"4","year":"2019","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"hep31862-bib-0012-20250824","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1200\/JCO.2019.37.4_suppl.187","article-title":"Efficacy and safety of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600E mutated biliary tract cancer (BTC): a cohort of the ROAR basket trial","volume":"37","year":"2019","journal-title":"J Clin Oncol"},{"key":"hep31862-bib-0013-20250824","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/S1470-2045(20)30157-1","article-title":"Ivosidenib in IDH1\u2010mutant, chemotherapy\u2010refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double\u2010blind, placebo\u2010controlled, phase 3 study","volume":"21","year":"2020","journal-title":"Lancet Oncol"},{"key":"hep31862-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1097\/PAS.0000000000000670","article-title":"Distinct clinicopathologic and genetic features of 2 histologic subtypes of intrahepatic cholangiocarcinoma","volume":"40","year":"2016","journal-title":"Am J Surg Pathol"},{"key":"hep31862-bib-0015-20250824","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.jhep.2020.03.008","article-title":"Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma","volume":"73","year":"2020","journal-title":"J Hepatol"},{"issue":"Suppl. 1","key":"hep31862-bib-0016-20250824","first-page":"7","article-title":"Anatomical, histomorphological and molecular classification of cholangiocarcinoma","volume":"39","year":"2019","journal-title":"Liver Int"},{"key":"hep31862-bib-0017-20250824","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.hpb.2018.07.021","article-title":"Histological and molecular characterization of intrahepatic bile duct cancers suggests an expanded definition of perihilar cholangiocarcinoma","volume":"21","year":"2019","journal-title":"HPB (Oxford)"},{"key":"hep31862-bib-0018-20250824","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: the next horizon in mechanisms and management","volume":"17","year":"2020","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep31862-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1158\/2159-8290.CD-17-0245","article-title":"New horizons for precision medicine in biliary tract cancers","volume":"7","year":"2017","journal-title":"Cancer Discov"},{"key":"hep31862-bib-0020-20250824","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1056\/NEJMc1713444","article-title":"Tumor mutational burden and response rate to PD\u20101 inhibition","volume":"377","year":"2017","journal-title":"N Engl J Med"},{"key":"hep31862-bib-0021-20250824","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.aan6733","article-title":"Mismatch repair deficiency predicts response of solid tumors to PD\u20101 blockade","volume":"357","year":"2017","journal-title":"Science"},{"key":"hep31862-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1126\/science.aao4572","article-title":"Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy","volume":"359","year":"2018","journal-title":"Science"},{"key":"hep31862-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1200\/JCO.2018.78.2276","article-title":"T\u2010cell\u2010inflamed gene\u2010expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE\u2010028","volume":"37","year":"2019","journal-title":"J Clin Oncol"},{"key":"hep31862-bib-0024-20250824","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1002\/ijc.33013","article-title":"Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: results from the KEYNOTE\u2010158 and KEYNOTE\u2010028 studies","volume":"147","year":"2020","journal-title":"Int J Cancer"},{"key":"hep31862-bib-0025-20250824","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.celrep.2018.03.076","article-title":"Genomic and molecular landscape of DNA damage repair deficiency across The Cancer Genome Atlas","volume":"23","year":"2018","journal-title":"Cell Rep"},{"key":"hep31862-bib-0026-20250824","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1038\/s41467-018-05228-y","article-title":"The therapeutic significance of mutational signatures from DNA repair deficiency in cancer","volume":"9","year":"2018","journal-title":"Nat Commun"},{"key":"hep31862-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"1050","DOI":"10.1038\/s41467-017-01018-0","article-title":"Genomic landscape associated with potential response to anti\u2010CTLA\u20104 treatment in cancers","volume":"8","year":"2017","journal-title":"Nat Commun"},{"key":"hep31862-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nrc3245","article-title":"The immune contexture in human tumours: impact on clinical outcome","volume":"12","year":"2012","journal-title":"Nat Rev Cancer"},{"key":"hep31862-bib-0029-20250824","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)","volume":"45","year":"2009","journal-title":"Eur J Cancer"},{"key":"hep31862-bib-0030-20250824","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13073-018-0531-8","article-title":"Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations","volume":"10","year":"2018","journal-title":"Genome Med"},{"key":"hep31862-bib-0031-20250824","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.jmoldx.2018.09.008","article-title":"Somatic tumor variant filtration strategies to optimize tumor\u2010only molecular profiling using targeted next\u2010generation sequencing panels","volume":"21","year":"2019","journal-title":"J Mol Diagn"},{"key":"hep31862-bib-0032-20250824","article-title":"A computational approach to distinguish somatic vs. germline origin of genomic alterations from deep sequencing of cancer specimens without a matched normal","volume":"14","year":"2018","journal-title":"PLoS Comput Biol"},{"key":"hep31862-bib-0033-20250824","article-title":"CNVkit: genome\u2010wide copy number detection and visualization from targeted DNA sequencing","volume":"12","year":"2016","journal-title":"PLoS Comput Biol"},{"key":"hep31862-bib-0034-20250824","article-title":"TopHat\u2010Fusion: an algorithm for discovery of novel fusion transcripts","volume":"12","year":"2011","journal-title":"Genome Biol"},{"key":"hep31862-bib-0035-20250824","article-title":"GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy\u2010number alteration in human cancers","volume":"12","year":"2011","journal-title":"Genome Biol"},{"key":"hep31862-bib-0036-20250824","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/ng0506-500","article-title":"GenePattern 2.0","volume":"38","year":"2006","journal-title":"Nat Genet"},{"key":"hep31862-bib-0037-20250824","doi-asserted-by":"crossref","first-page":"5696","DOI":"10.1038\/ncomms6696","article-title":"Mutational landscape of intrahepatic cholangiocarcinoma","volume":"5","year":"2014","journal-title":"Nat Commun"},{"key":"hep31862-bib-0038-20250824","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1101\/gr.239244.118","article-title":"Maftools: efficient and comprehensive analysis of somatic variants in cancer","volume":"28","year":"2018","journal-title":"Genome Res"},{"key":"hep31862-bib-0039-20250824","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1038\/modpathol.2013.241","article-title":"Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features","volume":"27","year":"2014","journal-title":"Mod Pathol"},{"key":"hep31862-bib-0040-20250824","article-title":"Cholangiocarcinoma with FGFR genetic aberrations: a unique clinical phenotype","year":"2018","journal-title":"JCO Precision Oncol"},{"key":"hep31862-bib-0041-20250824","doi-asserted-by":"crossref","first-page":"3906","DOI":"10.1016\/j.febslet.2013.10.035","article-title":"BAP1 is phosphorylated at serine 592 in S\u2010phase following DNA damage","volume":"587","year":"2013","journal-title":"FEBS Lett"},{"key":"hep31862-bib-0042-20250824","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1038\/s41388-017-0077-z","article-title":"Wild\u2010type and mutated IDH1\/2 enzymes and therapy responses","volume":"37","year":"2018","journal-title":"Oncogene"},{"key":"hep31862-bib-0043-20250824","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s12943-017-0587-x","article-title":"BAP1 dependent expression of long non\u2010coding RNA NEAT\u20101 contributes to sensitivity to gemcitabine in cholangiocarcinoma","volume":"16","year":"2017","journal-title":"Mol Cancer"},{"key":"hep31862-bib-0044-20250824","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1016\/j.ejca.2012.12.002","article-title":"Role of crosstalk between interleukin\u20106 and transforming growth factor\u2010beta 1 in epithelial\u2010mesenchymal transition and chemoresistance in biliary tract cancer","volume":"49","year":"2013","journal-title":"Eur J Cancer"},{"key":"hep31862-bib-0045-20250824","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1001\/jamaoncol.2020.0930","article-title":"A phase 2 multi\u2010institutional study of nivolumab for patients with advanced refractory biliary tract cancer","volume":"6","year":"2020","journal-title":"JAMA Oncol"},{"key":"hep31862-bib-0046-20250824","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/s41416-018-0199-2","article-title":"Mismatch repair deficiency is a rare but putative therapeutically relevant finding in non\u2010liver fluke associated cholangiocarcinoma","volume":"120","year":"2019","journal-title":"Br J Cancer"},{"key":"hep31862-bib-0047-20250824","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.ccell.2019.02.008","article-title":"KRAS\u2010IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer","volume":"35","year":"2019","journal-title":"Cancer Cell"},{"key":"hep31862-bib-0048-20250824","doi-asserted-by":"crossref","first-page":"4520","DOI":"10.1200\/JCO.2020.38.15_suppl.4520","article-title":"Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) +\/\u2010 tremelimumab (T) and gemcitabine\/cisplatin (GemCis) in chemo\u2010naive advanced biliary tract cancer (aBTC)","volume":"38","year":"2020","journal-title":"J Clin Oncol"},{"key":"hep31862-bib-0049-20250824","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/nm.4333","article-title":"Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients","volume":"23","year":"2017","journal-title":"Nat Med"},{"key":"hep31862-bib-0050-20250824","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1093\/annonc\/mdz205","article-title":"Optimizing panel\u2010based tumor mutational burden (TMB) measurement","volume":"30","year":"2019","journal-title":"Ann Oncol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.31862","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.31862","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31862","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T23:11:20Z","timestamp":1756077080000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.31862"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,29]]},"references-count":50,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.31862","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,29]]},"assertion":[{"value":"2020-08-24","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-09","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}