{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T22:56:19Z","timestamp":1769640979615,"version":"3.49.0"},"update-to":[{"DOI":"10.1371\/journal.pntd.0013441","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000}}],"reference-count":28,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82260573"],"award-info":[{"award-number":["82260573"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013076","name":"National Major Science and Technology Projects of China","doi-asserted-by":"publisher","award":["2017ZX10203207"],"award-info":[{"award-number":["2017ZX10203207"]}],"id":[{"id":"10.13039\/501100013076","id-type":"DOI","asserted-by":"publisher"}]},{"name":"High-level innovation team and outstanding scholar program in Guangxi Colleges and Universities, \u201c139\u201d projects for training high-level medical science talents from Guangxi","award":["G201903001"],"award-info":[{"award-number":["G201903001"]}]},{"name":"The Key Research and Development Project of Guangxi","award":["AB20297009, AA18221001, AB18050020"],"award-info":[{"award-number":["AB20297009, AA18221001, AB18050020"]}]},{"name":"The Key Laboratory of Early Prevention and Treatment for Regional High-Frequency Tumor, Ministry of Education\/Guangxi, Independent Research Project","award":["GKE2017-ZZ02, GKE2018-KF02, GKE2019-ZZ07"],"award-info":[{"award-number":["GKE2017-ZZ02, GKE2018-KF02, GKE2019-ZZ07"]}]},{"name":"Development and application of medical and health appropriate technology in Guangxi","award":["S2019039"],"award-info":[{"award-number":["S2019039"]}]},{"DOI":"10.13039\/501100012543","name":"Youth Science Foundation of Guangxi Medical University","doi-asserted-by":"publisher","award":["GXMUYSF202321"],"award-info":[{"award-number":["GXMUYSF202321"]}],"id":[{"id":"10.13039\/501100012543","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Self-funded Scientific Research Project of the Health and Family Planning Commission of Guangxi Zhuang Autonomous Region","award":["Z-A20240412"],"award-info":[{"award-number":["Z-A20240412"]}]},{"name":"Self-funded Scientific Research Project of the Health Commission of Guangxi Zhuang Autonomous Region","award":["Z-A20221082"],"award-info":[{"award-number":["Z-A20221082"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Hepatocellular carcinoma (HCC) prognosis is poor in East Asia. The impact of <jats:italic><jats:italic>Clonorchis sinensis<\/jats:italic><\/jats:italic> (<jats:italic><jats:italic>C.sinensis<\/jats:italic><\/jats:italic>) infection, a known carcinogen for cholangiocarcinoma, on HCC prognosis after curative resection in co-endemic regions is unclear. This study aimed to evaluate the independent association of <jats:italic><jats:italic>C.sinensis<\/jats:italic><\/jats:italic> infection with overall survival (OS) and recurrence-free survival (RFS) after curative HCC resection.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>This retrospective, multicenter cohort study included 1386 patients undergoing R0 hepatectomy for HCC (2011\u20132021) in Guangxi, China (312 <jats:italic><jats:italic>C.sinensis<\/jats:italic><\/jats:italic>-positive, 1074 <jats:italic><jats:italic>C.sinensis<\/jats:italic><\/jats:italic>-negative). Associations were assessed using multivariable Cox regression and propensity score methods (1:1 PSM [primary], 1:3 PSM, IPTW) for multivariable adjustment for confounding. To assess robustness, additional sensitivity analyses including doubly robust estimation and E-value analysis were performed. Causal mediation analysis evaluated the role of microvascular invasion (MVI) on OS.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p><jats:italic><jats:italic>C.sinensis<\/jats:italic><\/jats:italic> prevalence was 22.5%; median follow-up was 88 months. Significant baseline imbalances were observed. After the primary 1:1 PSM adjustment (N\u2009=\u2009530), which achieved generally good balance (19\/21 covariates SMD\u2009&lt;\u20090.1), <jats:italic><jats:italic>C.sinensis<\/jats:italic><\/jats:italic> infection was significantly associated with poorer OS (adjusted Hazard Ratio [aHR], 1.55; 95% CI, 1.20\u20132.01; P\u2009&lt;\u20090.001) and RFS (aHR, 1.63; 95% CI, 1.30\u20132.04; P\u2009&lt;\u20090.001). The adverse OS association was robust across multivariable Cox and other propensity score sensitivity analyses (all P\u2009&lt;\u20090.05). However, the RFS association was inconsistent across methods: while PSM analyses showed a significant association, this was not confirmed in multivariable Cox (P\u2009=\u20090.36), IPTW (P\u2009=\u20090.20), or doubly robust estimation (P\u2009=\u20090.27) analyses. After comprehensive covariate adjustment, MVI was found to significantly mediate the <jats:italic><jats:italic>C.sinensis<\/jats:italic><\/jats:italic>-OS association (Natural Indirect Effect P\u2009=\u20090.006), explaining approximately 12.7% (P\u2009=\u20090.020) of the total effect.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Concurrent <jats:italic><jats:italic>C.sinensis<\/jats:italic><\/jats:italic> infection is an independent risk factor for reduced OS after curative HCC resection in this endemic cohort. We recommend routine preoperative screening for <jats:italic><jats:italic>C.sinensis<\/jats:italic><\/jats:italic> to improve risk stratification and guide postoperative management.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0013441","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T17:59:58Z","timestamp":1757008798000},"page":"e0013441","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Impact of Clonorchis sinensis infection on long-term survival after curative resection for hepatocellular carcinoma: A multicenter cohort study"],"prefix":"10.1371","volume":"19","author":[{"given":"Shuang","family":"Shen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5452-1736","authenticated-orcid":true,"given":"Guodong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haojie","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jindu","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiayin","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huijie","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huaiyue","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1360-0783","authenticated-orcid":true,"given":"Ze","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bangde","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"issue":"10360","key":"pntd.0013441.ref001","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S0140-6736(22)01200-4","article-title":"Hepatocellular carcinoma","volume":"400","author":"A Vogel","year":"2022","journal-title":"Lancet"},{"issue":"2","key":"pntd.0013441.ref002","first-page":"115","article-title":"Cancer statistics in China, 2015","volume":"66","author":"W Chen","year":"2016","journal-title":"CA Cancer J Clin"},{"issue":"16","key":"pntd.0013441.ref003","first-page":"67","article-title":"Analysis of the epidemiological characteristics and disease burden of malignant tumors in Guangxi","volume":"1","author":"Z Zhou","year":"2024","journal-title":"Chinese Journal of Oncology Prevention and Treatment"},{"issue":"13","key":"pntd.0013441.ref004","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1002\/bjs.10677","article-title":"Randomized clinical trial of hepatic resection versus radiofrequency ablation for early-stage hepatocellular carcinoma","volume":"104","author":"KKC Ng","year":"2017","journal-title":"Br J Surg"},{"issue":"6","key":"pntd.0013441.ref005","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.jhep.2014.01.027","article-title":"Prediction of aggressiveness in early-stage hepatocellular carcinoma for selection of surgical resection","volume":"60","author":"S-W Suh","year":"2014","journal-title":"J Hepatol"},{"issue":"10020","key":"pntd.0013441.ref006","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1016\/S0140-6736(15)60313-0","article-title":"Clonorchiasis","volume":"387","author":"M Qian","year":"2016","journal-title":"Lancet"},{"issue":"11","key":"pntd.0013441.ref007","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.1016\/j.pt.2021.05.011","article-title":"Clonorchis sinensis","volume":"37","author":"M-B Qian","year":"2021","journal-title":"Trends Parasitol"},{"issue":"11","key":"pntd.0013441.ref008","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1111\/jfd.13245","article-title":"Prevalence of Clonorchis sinensis infection in fish in South-East Asia: A systematic review and meta-analysis","volume":"43","author":"Y Zhang","year":"2020","journal-title":"J Fish Dis"},{"key":"pntd.0013441.ref009","first-page":"1","article-title":"Biological agents","volume":"100","author":"IARC Working Group on the Evaluation of Carcinogenic Risks to Humans","year":"2012","journal-title":"IARC Monogr Eval Carcinog Risks Hum"},{"issue":"1","key":"pntd.0013441.ref010","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s13071-021-04717-2","article-title":"Transcriptomic profiling of three-dimensional cholangiocyte spheroids long term exposed to repetitive Clonorchis sinensis excretory-secretory products","volume":"14","author":"J-W Kim","year":"2021","journal-title":"Parasit Vectors"},{"issue":"12","key":"pntd.0013441.ref011","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/j.pt.2024.10.012","article-title":"Mechanistic insights into liver-fluke-induced bile-duct cancer","volume":"40","author":"MJ Smout","year":"2024","journal-title":"Trends Parasitol"},{"issue":"12","key":"pntd.0013441.ref012","doi-asserted-by":"crossref","first-page":"3403","DOI":"10.1007\/s00436-022-07699-x","article-title":"Clonorchis sinensis infection contributes to hepatocellular carcinoma progression in rat","volume":"121","author":"Y Qi","year":"2022","journal-title":"Parasitol Res"},{"key":"pntd.0013441.ref013","doi-asserted-by":"crossref","first-page":"1526699","DOI":"10.3389\/fimmu.2025.1526699","article-title":"Clonorchis sinensis-infected hepatocellular carcinoma exhibits distinct tumor microenvironment and molecular features","volume":"16","author":"J Chen","year":"2025","journal-title":"Front Immunol"},{"issue":"10","key":"pntd.0013441.ref014","doi-asserted-by":"crossref","first-page":"2645","DOI":"10.1007\/s00436-017-5572-1","article-title":"Clonorchis sinensis infection and co-infection with the hepatitis B virus are important factors associated with cholangiocarcinoma and hepatocellular carcinoma","volume":"116","author":"Y Shi","year":"2017","journal-title":"Parasitol Res"},{"issue":"6","key":"pntd.0013441.ref015","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1172\/JCI91786","article-title":"HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis","volume":"128","author":"C Hernandez","year":"2018","journal-title":"J Clin Invest"},{"issue":"5","key":"pntd.0013441.ref016","first-page":"538","article-title":"Interpretation of Diagnostic Criteria for Clonorchiasis","volume":"29","author":"C Ying-Dan","year":"2017","journal-title":"Zhongguo Xue Xi Chong Bing Fang Zhi Za Zhi"},{"issue":"6","key":"pntd.0013441.ref017","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.jhep.2005.11.040","article-title":"Cholangiocarcinoma and Clonorchis sinensis infection: a case-control study in Korea","volume":"44","author":"D Choi","year":"2006","journal-title":"J Hepatol"},{"issue":"1","key":"pntd.0013441.ref018","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3748\/wjg.15.86","article-title":"Prevalence of clonorchiasis in patients with gastrointestinal disease: a Korean nationwide multicenter survey","volume":"15","author":"HG Kim","year":"2009","journal-title":"World J Gastroenterol"},{"issue":"2","key":"pntd.0013441.ref019","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3347\/kjp.2007.45.2.77","article-title":"Imaging diagnosis of clonorchiasis","volume":"45","author":"D Choi","year":"2007","journal-title":"Korean J Parasitol"},{"issue":"6","key":"pntd.0013441.ref020","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1097\/EDE.0000000000000742","article-title":"Doubly Robust Additive Hazards Models to Estimate Effects of a Continuous Exposure on Survival","volume":"28","author":"Y Wang","year":"2017","journal-title":"Epidemiology"},{"issue":"5","key":"pntd.0013441.ref021","doi-asserted-by":"crossref","DOI":"10.1097\/EDE.0000000000000864","article-title":"Web Site and R Package for Computing E-values","volume":"29","author":"MB Mathur","year":"2018","journal-title":"Epidemiology"},{"key":"pntd.0013441.ref022","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1146\/annurev.psych.58.110405.085542","article-title":"Mediation analysis","volume":"58","author":"DP MacKinnon","year":"2007","journal-title":"Annu Rev Psychol"},{"issue":"3","key":"pntd.0013441.ref023","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1097\/EDE.0000000000000651","article-title":"Causal Mediation Analysis of Survival Outcome with Multiple Mediators","volume":"28","author":"Y-T Huang","year":"2017","journal-title":"Epidemiology"},{"issue":"1","key":"pntd.0013441.ref024","article-title":"Effects of Clonorchis sinensis combined with Hepatitis B virus infection on the prognosis of patients with Hepatocellular Carcinoma following Hepatectomy","volume":"17","author":"Y-K Li","year":"2023","journal-title":"PLoS Negl Trop Dis"},{"issue":"11","key":"pntd.0013441.ref025","article-title":"Clonorchis sinensis infection contributes to hepatocellular carcinoma progression via enhancing angiogenesis","volume":"18","author":"C Wei","year":"2024","journal-title":"PLoS Negl Trop Dis"},{"issue":"1","key":"pntd.0013441.ref026","article-title":"Clonorchis sinensis infection amplifies hepatocellular carcinoma stemness, predicting unfavorable prognosis","volume":"18","author":"Q Lin","year":"2024","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0013441.ref027","doi-asserted-by":"crossref","first-page":"1489077","DOI":"10.3389\/fimmu.2024.1489077","article-title":"Serum proteomic and metabolomic profiling of hepatocellular carcinoma patients co-infected with Clonorchis sinensis","volume":"15","author":"Z Tang","year":"2025","journal-title":"Front Immunol"},{"issue":"12","key":"pntd.0013441.ref028","doi-asserted-by":"crossref","first-page":"2354","DOI":"10.1136\/gutjnl-2023-330691","article-title":"Changing prevalence of chronic hepatitis B virus infection in China between 1973 and 2021: a systematic literature review and meta-analysis of 3740 studies and 231 million people","volume":"72","author":"Z Liu","year":"2023","journal-title":"Gut"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0013441","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T00:00:00Z","timestamp":1757376000000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0013441","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T17:54:53Z","timestamp":1757440493000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0013441"}},"subtitle":[],"editor":[{"given":"Elise M.","family":"O'Connell","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,4]]},"references-count":28,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9,4]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0013441","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0013441","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,4]]}}}