{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T20:12:30Z","timestamp":1793736750241,"version":"4.6.1"},"reference-count":35,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"\n Importance<\/jats:title>\n \n Hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis remains suboptimal, with inadequate early-stage detection. \u03b1-Fetoprotein (AFP) demonstrates insufficient sensitivity. Circulating methylated septin 9 (\n SEPT9<\/jats:italic>\n ) has shown diagnostic promise.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To determine whether methylated\n SEPT9<\/jats:italic>\n improves detection of HCC when combined with AFP in patients with cirrhosis undergoing surveillance.\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n In this prospective, cross-sectional, diagnostic accuracy study, patients with cirrhosis undergoing routine HCC surveillance with ultrasonography and AFP were enrolled at 2 French academic centers from February 2018 through October 2024. HCC was diagnosed per international guidelines with centralized radiologic review, blinded to methylated\n SEPT9<\/jats:italic>\n results. Data were analyzed from October 2025 to January 2026.\n <\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n \n Plasma methylated\n SEPT9<\/jats:italic>\n was analyzed from 3 independent plasma aliquots and classified by number of positive replicates (single-positive, double-positive, or triple-positive). Serum AFP was evaluated at a threshold of 20 ng\/mL. Biomarkers were evaluated individually and in combination using disjunction logic (tier 1; maximizing sensitivity) or conjunction logic (tier 2; maximizing specificity).\n <\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n The primary outcome was the presence of HCC at enrollment. The primary end point was comparison of the area under the receiver operating characteristic curve (AUROC) between methylated\n SEPT9<\/jats:italic>\n and AFP. Secondary end points included diagnostic performance stratified by Barcelona Clinic Liver Cancer (BCLC) stage.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Among 574 participants, 414 (72.1%) were male, and the median (IQR) age was 63 (57-70) years. A total of 118 had HCC, including 51 (43.2%) with BCLC stage 0-A. Methylated\n SEPT9<\/jats:italic>\n outperformed AFP (AUROC: 0.79 [95% CI, 0.74-0.84] vs 0.71 [95% CI, 0.66-0.76], respectively;\n P<\/jats:italic>\n \u2009=\u2009.002; posterior probability of superiority &amp;gt;99.8%). Tier 1a (at least single-positive methylated\n SEPT9<\/jats:italic>\n or AFP &amp;gt;20 ng\/mL) achieved 87.8% (95% CI, 81.6-93.5) sensitivity and a negative likelihood ratio of 0.2 (95% CI, 0.1-0.3). Among 64 HCC cases missed by AFP, tier 1a recovered 50 (78%). For BCLC 0-A disease, tier 1a sensitivity was 74.5% (95% CI, 62.2-86.5) vs 23.5% (95% CI, 12.5-35.8) for AFP, 3.2-fold increase. Tier 2 (triple-positive methylated\n SEPT9<\/jats:italic>\n and AFP &amp;gt;20 ng\/mL) achieved 99.6% (95% CI, 98.9-100) specificity, a positive likelihood ratio of 76.0 (95% CI, 26.9-181.0), and a diagnostic odds ratio of 112.1 (95% CI, 37.8-294.7).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n In this diagnostic study, combining methylated\n SEPT9<\/jats:italic>\n with AFP substantially improved HCC detection in patients with cirrhosis, particularly for early-stage disease amenable to curative treatment. Prospective studies are needed to determine whether improved detection translates into survival benefit.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaoncol.2026.2157","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T15:35:49Z","timestamp":1783006549000},"page":"940","source":"Crossref","is-referenced-by-count":6,"title":["Circulating Methylated\n SEPT9<\/i>\n for Detection of Hepatocellular Carcinoma in Cirrhosis"],"prefix":"10.1001","volume":"12","author":[{"given":"Abderrahim","family":"Oussalah","sequence":"first","affiliation":[{"name":"Department of Genomic Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy, Nancy, France"},{"name":"INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, University of Lorraine, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u00ebl","family":"Silva Rodriguez","sequence":"additional","affiliation":[{"name":"Department of Genomic Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy, Nancy, France"},{"name":"INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, University of Lorraine, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Conroy","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Mercy Hospital, Metz, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mouni","family":"Bensenane","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Liver Diseases, University Hospital of Nancy, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Rousseau","sequence":"additional","affiliation":[{"name":"Methodology, Data Management and Statistics Unit, University Hospital of Nancy, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmet","family":"Ayav","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary Surgery, University Hospital of Nancy, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Louis","family":"Gu\u00e9ant","sequence":"additional","affiliation":[{"name":"Joan Klein Jacobs Center for Precision Nutrition and Health, Cornell University, Ithaca, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houda","family":"Camara","sequence":"additional","affiliation":[{"name":"Methodology, Data Management and Statistics Unit, University Hospital of Nancy, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Baumann","sequence":"additional","affiliation":[{"name":"Methodology, Data Management and Statistics Unit, University Hospital of Nancy, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Laurent","sequence":"additional","affiliation":[{"name":"Department of Radiology, University Hospital of Nancy, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Pierre","family":"Bronowicki","sequence":"additional","affiliation":[{"name":"INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, University of Lorraine, Nancy, France"},{"name":"Department of Gastroenterology and Liver Diseases, University Hospital of Nancy, Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"SEPT9_CROSS Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"N\/A","given":"Vincent","family":"Haghnejad","sequence":"additional","affiliation":[{"name":"for the SEPT9_CROSS Study Group"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"N\/A","given":"Claire","family":"Geist","sequence":"additional","affiliation":[{"name":"for the SEPT9_CROSS Study Group"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"N\/A","given":"Raphaelle","family":"Riffault","sequence":"additional","affiliation":[{"name":"for the SEPT9_CROSS Study Group"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"N\/A","given":"Abdelbasset","family":"Nani","sequence":"additional","affiliation":[{"name":"for the SEPT9_CROSS Study Group"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"N\/A","given":"Julien","family":"Levy","sequence":"additional","affiliation":[{"name":"for the SEPT9_CROSS Study Group"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"N\/A","given":"Jonas","family":"Callet","sequence":"additional","affiliation":[{"name":"for the SEPT9_CROSS Study Group"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"3","key":"coi260031r1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"issue":"6","key":"coi260031r2","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1097\/HEP.0000000000000466","article-title":"AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma.","volume":"78","author":"Singal","year":"2023","journal-title":"Hepatology"},{"issue":"10504","key":"coi260031r3","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/S0140-6736(25)01042-6","article-title":"The Lancet Commission on addressing the global hepatocellular carcinoma burden: comprehensive strategies from prevention to treatment.","volume":"406","author":"Chan","year":"2025","journal-title":"Lancet"},{"issue":"15","key":"coi260031r4","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1056\/NEJMra1713263","article-title":"Hepatocellular carcinoma.","volume":"380","author":"Villanueva","year":"2019","journal-title":"N Engl J Med"},{"issue":"2","key":"coi260031r5","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.jhep.2024.08.028","article-title":"EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma.","volume":"82","author":"European Association for the Study of the Liver","year":"2025","journal-title":"J Hepatol"},{"issue":"6","key":"coi260031r6","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1053\/j.gastro.2018.01.064","article-title":"Surveillance imaging and alpha fetoprotein for early detection of hepatocellular carcinoma in patients with cirrhosis: a meta-analysis.","volume":"154","author":"Tzartzeva","year":"2018","journal-title":"Gastroenterology"},{"issue":"1","key":"coi260031r7","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1111\/j.1365-2036.2009.04014.x","article-title":"Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis.","volume":"30","author":"Singal","year":"2009","journal-title":"Aliment Pharmacol Ther"},{"issue":"10","key":"coi260031r8","doi-asserted-by":"publisher","first-page":"2925","DOI":"10.1002\/hep4.2045","article-title":"Comparison of a multitarget blood test to ultrasound and alpha-fetoprotein for hepatocellular carcinoma surveillance: results of a network meta-analysis.","volume":"6","author":"Singal","year":"2022","journal-title":"Hepatol Commun"},{"issue":"11","key":"coi260031r9","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1056\/NEJMra072067","article-title":"Epigenetics in cancer.","volume":"358","author":"Esteller","year":"2008","journal-title":"N Engl J Med"},{"issue":"6","key":"coi260031r10","doi-asserted-by":"publisher","first-page":"1945","DOI":"10.1002\/hep.27732","article-title":"DNA methylation-based prognosis and epidrivers in hepatocellular carcinoma.","volume":"61","author":"Villanueva","year":"2015","journal-title":"Hepatology"},{"key":"coi260031r11","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.ebiom.2018.03.029","article-title":"Plasma mSEPT9: a novel circulating cell-free DNA-based epigenetic biomarker to diagnose hepatocellular carcinoma.","volume":"30","author":"Oussalah","year":"2018","journal-title":"EBioMedicine"},{"issue":"11","key":"coi260031r12","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1016\/S0895-4356(03)00206-3","article-title":"Assessment of the accuracy of diagnostic tests: the cross-sectional study.","volume":"56","author":"Knottnerus","year":"2003","journal-title":"J Clin Epidemiol"},{"key":"coi260031r13","doi-asserted-by":"publisher","first-page":"h5527","DOI":"10.1136\/bmj.h5527","article-title":"STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies.","volume":"351","author":"Bossuyt","year":"2015","journal-title":"BMJ"},{"issue":"1","key":"coi260031r14","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1002\/hep.29086","article-title":"AASLD guidelines for the treatment of hepatocellular carcinoma.","volume":"67","author":"Heimbach","year":"2018","journal-title":"Hepatology"},{"issue":"1","key":"coi260031r15","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.jhep.2018.03.019","article-title":"EASL Clinical Practice Guidelines: management of hepatocellular carcinoma.","volume":"69","author":"European Association for the Study of the Liver","year":"2018","journal-title":"J Hepatol"},{"issue":"3","key":"coi260031r16","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1148\/radiol.2018181494","article-title":"Liver Imaging Reporting and Data System (LI-RADS) version 2018: imaging of hepatocellular carcinoma in at-risk patients.","volume":"289","author":"Chernyak","year":"2018","journal-title":"Radiology"},{"issue":"1","key":"coi260031r17","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s00261-017-1291-4","article-title":"LI-RADS major features: CT, MRI with extracellular agents, and MRI with hepatobiliary agents.","volume":"43","author":"Santillan","year":"2018","journal-title":"Abdom Radiol (NY)"},{"issue":"2","key":"coi260031r18","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1136\/gutjnl-2012-304149","article-title":"Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer.","volume":"63","author":"Church","year":"2014","journal-title":"Gut"},{"issue":"9","key":"coi260031r19","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1038\/s41587-021-00857-z","article-title":"Evaluating the analytical validity of circulating tumor DNA sequencing assays for precision oncology.","volume":"39","author":"Deveson","year":"2021","journal-title":"Nat Biotechnol"},{"issue":"5","key":"coi260031r20","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/S1470-2045(25)00139-1","article-title":"Clinical validation of droplet digital PCR assays in detecting BRAFV600-mutant circulating tumour DNA as a prognostic biomarker in patients with resected stage III melanoma receiving adjuvant therapy (COMBI-AD): a biomarker analysis from a double-blind, randomised phase 3 trial.","volume":"26","author":"Syeda","year":"2025","journal-title":"Lancet Oncol"},{"issue":"3","key":"coi260031r21","doi-asserted-by":"publisher","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"issue":"1","key":"coi260031r23","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1111\/apt.13841","article-title":"Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis.","volume":"45","author":"Simmons","year":"2017","journal-title":"Aliment Pharmacol Ther"},{"issue":"9","key":"coi260031r24","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1002\/lt.25202","article-title":"Predictors of ultrasound failure to detect hepatocellular carcinoma.","volume":"24","author":"Samoylova","year":"2018","journal-title":"Liver Transpl"},{"issue":"7","key":"coi260031r25","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1007\/s11606-011-1952-x","article-title":"Utilization of hepatocellular carcinoma surveillance among American patients: a systematic review.","volume":"27","author":"Singal","year":"2012","journal-title":"J Gen Intern Med"},{"issue":"7","key":"coi260031r26","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.23504","article-title":"Barriers to surveillance for hepatocellular carcinoma in a multicenter cohort.","volume":"5","author":"Parikh","year":"2022","journal-title":"JAMA Netw Open"},{"issue":"20","key":"coi260031r27","doi-asserted-by":"publisher","first-page":"1888","DOI":"10.1056\/NEJMra2200923","article-title":"Liver transplantation.","volume":"389","author":"Lucey","year":"2023","journal-title":"N Engl J Med"},{"issue":"10360","key":"coi260031r28","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1016\/S0140-6736(22)01200-4","article-title":"Hepatocellular carcinoma.","volume":"400","author":"Vogel","year":"2022","journal-title":"Lancet"},{"issue":"11","key":"coi260031r29","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/S0895-4356(03)00177-X","article-title":"The diagnostic odds ratio: a single indicator of test performance.","volume":"56","author":"Glas","year":"2003","journal-title":"J Clin Epidemiol"},{"issue":"3","key":"coi260031r30","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1002\/hep.32185","article-title":"GALAD demonstrates high sensitivity for HCC surveillance in a cohort of patients with cirrhosis.","volume":"75","author":"Singal","year":"2022","journal-title":"Hepatology"},{"issue":"1","key":"coi260031r31","doi-asserted-by":"publisher","first-page":"E22","DOI":"10.1097\/HEP.0000000000001589","article-title":"Performance of a multi-target blood test versus ultrasound in detecting early hepatocellular carcinoma: results from the ALTUS prospective study.","volume":"83","author":"John","year":"2026","journal-title":"Hepatology"},{"issue":"14","key":"coi260031r32","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1002\/cncr.28706","article-title":"Determinants of alpha-fetoprotein levels in patients with hepatocellular carcinoma: implications for its clinical use.","volume":"120","author":"Giannini","year":"2014","journal-title":"Cancer"},{"issue":"6","key":"coi260031r33","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1002\/ijc.33898","article-title":"Comprehensive clinicopathologic study of alpha fetoprotein-expression in a large cohort of patients with hepatocellular carcinoma.","volume":"150","author":"Ridder","year":"2022","journal-title":"Int J Cancer"},{"issue":"3","key":"coi260031r34","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1002\/hep4.1469","article-title":"Novel liquid biopsy test based on a sensitive methylated SEPT9 assay for diagnosing hepatocellular carcinoma.","volume":"4","author":"Kotoh","year":"2020","journal-title":"Hepatol Commun"},{"issue":"1","key":"coi260031r35","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1093\/toxsci\/kfq307","article-title":"Mitochondrial prohibitins and septin 9 are implicated in the onset of rat hepatocarcinogenesis.","volume":"119","author":"Kakehashi","year":"2011","journal-title":"Toxicol Sci"},{"key":"coi260031r22","unstructured":"Oussalah? A. Interactive Fagan nomogram for hepatocellular carcinoma diagnosis using methylated SEPT9 and alpha-fetoprotein. Accessed January 25, 2026. https:\/\/zenodo.org\/records\/18365627"}],"container-title":["JAMA Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamaoncology\/articlepdf\/2850971\/jamaoncology_oussalah_2026_oi_260031_1789560637.08464.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T15:00:42Z","timestamp":1789657242000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamaoncology\/fullarticle\/2850971"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":35,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamaoncol.2026.2157","relation":{},"ISSN":["2374-2437"],"issn-type":[{"value":"2374-2437","type":"print"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}