{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T16:41:12Z","timestamp":1770914472520,"version":"3.50.1"},"reference-count":42,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Otolaryngol Head Neck Surg"],"published-print":{"date-parts":[[2026,2,1]]},"abstract":"<jats:sec id=\"ab-ooi250077-4\">\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>Improved methods are needed to predict recurrence in oral cavity squamous cell carcinoma (OCSCC). However, to date, no metabolome studies have fully explored the prediction of OCSCC relapse patterns and survival.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ooi250077-5\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To identify serum metabolites associated with OCSCC recurrence and develop and validate a prognostic scoring system.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ooi250077-6\">\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>This retrospective cohort study was conducted at a single tertiary academic center and enrolled patients with histologically confirmed, surgically resected first primary advanced-stage OCSCC from betel quid\u2013chewing areas. Patients underwent primary surgery between February 2007 and May 2018, with follow-up data systematically collected through a prospectively maintained institutional registry. Data were analyzed from December 2024 to September 2025.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ooi250077-7\">\n                    <jats:title>Exposures<\/jats:title>\n                    <jats:p>Preoperative serum metabolomic profiling was performed using liquid chromatography\u2013mass spectrometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ooi250077-8\">\n                    <jats:title>Main Outcomes and Measures<\/jats:title>\n                    <jats:p>Identification of metabolites predictive of relapse and survivals; development and validation of the MetaboScore.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ooi250077-9\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Of 228 included patients, 216 (94.7%) were male, and the mean (SD) age at OCSCC onset was 51.9 (10.8) years. A total of 19 metabolites associated with relapse were included in the MetaboScore. A threshold score of 11 or greater was associated with a higher risk of relapse, including local recurrence (22 of 79 [27.8%] vs 5 of 149 [3.4%]), regional recurrence (19 [24.1%] vs 10 [6.7%]), and distant metastasis (29 [36.7%] vs 21 [14.1%]) compared with scores less than 11. Patients with scores of 11 or greater had worse 5-year disease-free survival (38% [95% CI, 28-51] vs 83% [95% CI, 77-89]; difference, 45 percentage points; 95% CI, 32-57) and disease-specific survival (58% [95% CI, 48-70] vs 85% [95% CI, 79-91]; difference, 27 percentage points; 95% CI, 14-40). Multivariable analysis confirmed the independent prognostic value of the MetaboScore (local recurrence: hazard ratio [HR], 14.84; 95% CI, 5.45-40.40; regional recurrence: HR, 4.22; 95% CI, 1.94-9.15; distant metastases: HR, 2.53; 95% CI, 1.42-4.50; disease-free survival: HR, 4.40; 95% CI, 2.71-7.15; disease-specific survival: HR, 3.04; 95% CI, 1.76-5.25). Notably, the MetaboScore provided additional prognostic information beyond pN3b status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-ooi250077-10\">\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>In this cohort study, a high MetaboScore was associated with local recurrence, regional recurrence, and distant metastasis, even after conventional staging was applied, in OCSCC. Its derivation from a cohort predominantly composed of male patients with betel quid exposure and advanced-stage disease warrants caution. Prospective validation in more diverse populations comprising different etiologies, disease stages, and demographic characteristics will be essential before broad clinical implementation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamaoto.2025.4267","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T16:31:03Z","timestamp":1764865863000},"page":"172","source":"Crossref","is-referenced-by-count":0,"title":["Serum Metabolomics for Prognostic Stratification in Resected Advanced-Stage Oral Cavity Cancer"],"prefix":"10.1001","volume":"152","author":[{"given":"Eric Yi-Liang","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology and Proton Therapy Center, Chang Gung Memorial Hospital, Linkou and Chang Gung University, Taoyuan City, Taiwan, Republic of China"},{"name":"Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taoyuan City, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-Yu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu-Hang","family":"Ng","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung-Ming","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia-Hsun","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chih-Hua","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Radiology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiang-Fu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung-Jan","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzu-Chen","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nai-Ming","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Ta","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"10","reference":[{"issue":"10","key":"ooi250077r1","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1001\/jamaoncol.2023.2960","article-title":"The global, regional, and national burden of adult lip, oral, and pharyngeal cancer in 204 countries and territories: a systematic analysis for the Global Burden of Disease Study 2019.","volume":"9","author":"Cunha","year":"2023","journal-title":"JAMA Oncol"},{"issue":"3","key":"ooi250077r2","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":"10318","key":"ooi250077r3","doi-asserted-by":"publisher","first-page":"2289","DOI":"10.1016\/S0140-6736(21)01550-6","article-title":"Head and neck cancer.","volume":"398","author":"Mody","year":"2021","journal-title":"Lancet"},{"issue":"S2","key":"ooi250077r4","doi-asserted-by":"publisher","first-page":"S83","DOI":"10.1017\/S0022215116000499","article-title":"Oral cavity and lip cancer: United Kingdom National Multidisciplinary Guidelines.","volume":"130","author":"Kerawala","year":"2016","journal-title":"J Laryngol Otol"},{"issue":"5","key":"ooi250077r6","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1016\/j.ijrobp.2019.08.058","article-title":"Precision adjuvant therapy based on detailed pathologic risk factors for resected oral cavity squamous cell carcinoma: long-term outcome comparison of CGMH and NCCN guidelines.","volume":"106","author":"Lin","year":"2020","journal-title":"Int J Radiat Oncol Biol Phys"},{"issue":"5","key":"ooi250077r7","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1007\/s00784-024-05644-z","article-title":"Improved recurrence rates and progression-free survival in primarily surgically treated oral squamous cell carcinoma\u2014results from a German tertiary medical center.","volume":"28","author":"Struckmeier","year":"2024","journal-title":"Clin Oral Investig"},{"key":"ooi250077r8","doi-asserted-by":"publisher","first-page":"E1544","DOI":"10.1002\/hed.24276","article-title":"Association between multidisciplinary team care approach and survival rates in patients with oral cavity squamous cell carcinoma.","volume":"38","author":"Liao","year":"2016","journal-title":"Head Neck"},{"issue":"5","key":"ooi250077r9","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1016\/j.cell.2008.08.026","article-title":"Metabolic phenotyping in health and disease.","volume":"134","author":"Holmes","year":"2008","journal-title":"Cell"},{"issue":"5","key":"ooi250077r10","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation.","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ooi250077r11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103529","article-title":"In situ DESI-MSI lipidomic profiles of mucosal margin of oral squamous cell carcinoma.","volume":"70","author":"Yang","year":"2021","journal-title":"EBioMedicine"},{"key":"ooi250077r12","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.ebiom.2019.10.005","article-title":"Amino acids signatures of distance-related surgical margins of oral squamous cell carcinoma.","volume":"48","author":"Yang","year":"2019","journal-title":"EBioMedicine"},{"issue":"1","key":"ooi250077r13","doi-asserted-by":"publisher","first-page":"8588","DOI":"10.1038\/s41598-023-34808-2","article-title":"Plasma metabolomics of oral squamous cell carcinomas based on NMR and MS approaches provides biomarker identification and survival prediction.","volume":"13","author":"Polachini","year":"2023","journal-title":"Sci Rep"},{"issue":"28","key":"ooi250077r14","doi-asserted-by":"publisher","first-page":"16167","DOI":"10.1073\/pnas.2001395117","article-title":"Oral squamous cell carcinoma diagnosed from saliva metabolic profiling.","volume":"117","author":"Song","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ooi250077r15","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2023.101672","article-title":"Identification of novel prognostic indicators for oral squamous cell carcinoma based on proteomics and metabolomics.","volume":"33","author":"Yao","year":"2023","journal-title":"Transl Oncol"},{"issue":"19","key":"ooi250077r16","doi-asserted-by":"publisher","first-page":"6627","DOI":"10.1002\/cam4.4195","article-title":"Poor tumor differentiation is an independent adverse prognostic variable in patients with locally advanced oral cavity cancer\u2014comparison with pathological risk factors according to the NCCN guidelines.","volume":"10","author":"Lee","year":"2021","journal-title":"Cancer Med"},{"issue":"3","key":"ooi250077r17","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1007\/s11306-025-02259-7","article-title":"Recommendations for sample selection, collection and preparation for NMR-based metabolomics studies of blood.","volume":"21","author":"Emwas","year":"2025","journal-title":"Metabolomics"},{"key":"ooi250077r18","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.cca.2013.11.008","article-title":"Standardization of collection requirements for fasting samples: for the Working Group on Preanalytical Phase (WG-PA) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM).","volume":"432","author":"Simundic","year":"2014","journal-title":"Clin Chim Acta"},{"key":"ooi250077r19","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2023.106366","article-title":"Indications for elective neck dissection in cT1N0M0 oral cavity cancer according to the AJCC eight edition: a nationwide study.","volume":"140","author":"Chien","year":"2023","journal-title":"Oral Oncol"},{"key":"ooi250077r20","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.910158","article-title":"Towards an improved pathological node classification for prognostic stratification of patients with oral cavity squamous cell carcinoma: results from a nationwide registry study.","volume":"12","author":"Kang","year":"2022","journal-title":"Front Oncol"},{"issue":"4","key":"ooi250077r23","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1214\/aos\/1176345976","article-title":"Cox\u2019s regression model for counting processes: a large sample study.","volume":"10","author":"Andersen","year":"1982","journal-title":"Ann Stat"},{"issue":"1","key":"ooi250077r25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization paths for generalized linear models via coordinate descent.","volume":"33","author":"Friedman","year":"2010","journal-title":"J Stat Softw"},{"issue":"4","key":"ooi250077r26","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/(SICI)1097-0258(19970228)16:4<385::AID-SIM380>3.0.CO;2-3","article-title":"The lasso method for variable selection in the Cox model.","volume":"16","author":"Tibshirani","year":"1997","journal-title":"Stat Med"},{"issue":"1","key":"ooi250077r27","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.2517-6161.1996.tb02080.x","article-title":"Regression shrinkage and selection via the lasso.","volume":"58","author":"Tibshirani","year":"2018","journal-title":"J R Stat Soc B"},{"key":"ooi250077r28","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.oraloncology.2018.09.021","article-title":"Pathological risk factors stratification in pN3b oral cavity squamous cell carcinoma: focus on the number of positive nodes and extranodal extension.","volume":"86","author":"Liao","year":"2018","journal-title":"Oral Oncol"},{"issue":"11","key":"ooi250077r29","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.3390\/cancers13112709","article-title":"Prognostic genetic biomarkers based on oncogenic signaling pathways for outcome prediction in patients with oral cavity squamous cell carcinoma.","volume":"13","author":"Fan","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"1","key":"ooi250077r30","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1007\/s00259-019-04453-x","article-title":"A combined analysis of maximum standardized uptake value on FDG-PET, genetic markers, and clinicopathological risk factors in the prognostic stratification of patients with resected oral cavity squamous cell carcinoma.","volume":"47","author":"Liao","year":"2020","journal-title":"Eur J Nucl Med Mol Imaging"},{"issue":"7536","key":"ooi250077r31","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/nature14129","article-title":"Comprehensive genomic characterization of head and neck squamous cell carcinomas.","volume":"517","author":"Cancer Genome Atlas","year":"2015","journal-title":"Nature"},{"issue":"12","key":"ooi250077r32","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1158\/1940-6207.CAPR-24-0124","article-title":"Oncogenic HRAS induces metformin resistance in head and neck cancer by promoting glycolytic metabolism.","volume":"17","author":"Wu","year":"2024","journal-title":"Cancer Prev Res (Phila)"},{"issue":"7","key":"ooi250077r33","doi-asserted-by":"crossref","first-page":"140","DOI":"10.3390\/metabo9070140","article-title":"Metabolic regulation of glycolysis and AMP activated protein kinase pathways during black raspberry-mediated oral cancer chemoprevention.","volume":"9","author":"Knobloch","year":"2019","journal-title":"Metabolites"},{"issue":"10","key":"ooi250077r34","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s11306-020-01727-6","article-title":"Metabolic landscape of oral squamous cell carcinoma.","volume":"16","author":"Vit\u00f3rio","year":"2020","journal-title":"Metabolomics"},{"key":"ooi250077r35","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.aca.2018.10.070","article-title":"Integrated analyses utilizing metabolomics and transcriptomics reveal perturbation of the polyamine pathway in oral cavity squamous cell carcinoma.","volume":"1050","author":"Hsu","year":"2019","journal-title":"Anal Chim Acta"},{"issue":"2","key":"ooi250077r36","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1111\/odi.14432","article-title":"Metabolic profiling analysis of head and neck squamous cell carcinoma.","volume":"30","author":"Ohashi","year":"2024","journal-title":"Oral Dis"},{"issue":"11","key":"ooi250077r37","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1021\/pr200800w","article-title":"Magic angle spinning NMR-based metabolic profiling of head and neck squamous cell carcinoma tissues.","volume":"10","author":"Somashekar","year":"2011","journal-title":"J Proteome Res"},{"key":"ooi250077r38","doi-asserted-by":"crossref","first-page":"526","DOI":"10.3389\/fphys.2016.00526","article-title":"Metabolomics of head and neck cancer: a mini-review.","volume":"7","author":"Shin","year":"2016","journal-title":"Front Physiol"},{"issue":"14","key":"ooi250077r39","doi-asserted-by":"crossref","first-page":"2925","DOI":"10.1158\/1078-0432.CCR-23-3608","article-title":"Plasma metabolic profiles-based prediction of induction chemotherapy efficacy in nasopharyngeal carcinoma: results of a bidirectional clinical trial.","volume":"30","author":"Tang","year":"2024","journal-title":"Clin Cancer Res"},{"issue":"2","key":"ooi250077r40","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.cell.2014.09.035","article-title":"Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects.","volume":"159","author":"Yore","year":"2014","journal-title":"Cell"},{"issue":"1","key":"ooi250077r41","first-page":"1","article-title":"Prevalence rates of areca\/betel quid chewing in counties of Taiwan.","volume":"18","author":"Yang","year":"2002","journal-title":"Taiwan J Oral Med Health Sci"},{"key":"ooi250077r21","volume-title":"Analysis of Longitudinal Data","author":"Diggle","year":"1994"},{"key":"ooi250077r22","doi-asserted-by":"crossref","DOI":"10.1002\/9781118625590","volume-title":"Applied Regression Analysis","author":"Draper","year":"1998"},{"key":"ooi250077r24","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4757-3294-8","volume-title":"Modeling Survival Data: Extending the Cox Model","author":"Therneau","year":"2000"},{"key":"ooi250077r5","unstructured":"National Comprehensive Cancer Network. Head and Neck Cancers (Version 5.2025). Accessed September 1, 2025. https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/head-and-neck.pdf"},{"key":"ooi250077r42","unstructured":"Taiwan Cancer Registry. 2007-2022 Annual report. Accessed September 1, 2025. https:\/\/www.hpa.gov.tw\/Pages\/TopicList.aspx?nodeid=269"}],"container-title":["JAMA Otolaryngology\u2013Head &amp; Neck Surgery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamaotolaryngology\/articlepdf\/2841805\/jamaotolaryngology_shen_2025_oi_250077_1770606661.5278.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T16:01:15Z","timestamp":1770912075000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamaotolaryngology\/fullarticle\/2841805"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,1]]},"references-count":42,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,2,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamaoto.2025.4267","relation":{},"ISSN":["2168-6181"],"issn-type":[{"value":"2168-6181","type":"print"}],"subject":[],"published":{"date-parts":[[2026,2,1]]}}}