{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T01:19:57Z","timestamp":1787620797112,"version":"build-2736575974"},"reference-count":23,"publisher":"American Medical Association (AMA)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Surg"],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"\n Importance<\/jats:title>\n Neoadjuvant chemoradiotherapy is recommended for clinical stage II (T2N0) esophageal squamous cell carcinoma (ESCC) with high-risk features such as tumor size 3 cm or greater, lymphovascular invasion (LVI), and poor differentiation. However, these criteria have limited predictive value, and there is an unmet need for more accurate preoperative risk stratification tools.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To evaluate whether preoperative detection of circulating tumor DNA (ctDNA) is associated with nodal upstaging and postoperative recurrence in patients with clinical stage I (T1b) or T2N0 ESCC.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n This cohort study included 2 independent cohorts in Seoul, Korea: Samsung Medical Center (SMC; n\u2009=\u200950), with data from January 2015 through December 2019, and Yonsei University Severance Hospital (YUSH; n\u2009=\u200924), with data from January 2023 through December 2024. All patients had T1b or T2N0 ESCC, underwent radical esophagectomy and lymph node dissection without neoadjuvant therapy, and provided tumor and preoperative plasma samples for tumor-informed ctDNA sequencing.<\/jats:p>\n <\/jats:sec>\n \n Exposure<\/jats:title>\n Presence or absence of ctDNA in preoperative plasma samples.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n \n Primary outcomes were pathologic nodal upstaging and survival (recurrence-free survival [RFS] and overall survival [OS]). Associations between ctDNA status and outcomes were analyzed using \u03c7\n 2<\/jats:sup>\n , logistic regression, and Cox proportional hazard models.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n In the SMC cohort, the median (IQR) age was 68 (60-74) years, and 47 participants (94%) were male; in the YUSH cohort, the median (IQR) age was 67 (61-69) years, and 21 participants (87.5%) were male. Preoperative ctDNA was detected in 36 patients (48.6%) (27 [54.0%] in SMC and 9 [37.5%] in YUSH). Detection was more frequent in T2N0 than T1b: 26 [57.8%] vs 1 [20.0%] in SMC and 9 [42.9%] vs 0 in YUSH. Over a median (IQR) follow-up of 37.7 (24.9-49.6) months, patients with positive ctDNA results had worse RFS (hazard ratio [HR], 4.15; 95% CI, 1.54-11.22;\n P<\/jats:italic>\n \u2009=\u2009.005) and OS (HR, 4.02; 95% CI, 1.50-10.74;\n P<\/jats:italic>\n \u2009=\u2009.006). Among patients with T2N0 disease\u2014a subgroup where neoadjuvant therapy decisions remain uncertain\u2014ctDNA positivity predicted occult nodal metastasis with a positive predictive value of 100% (95% CI, 71.51-100) in the SMC cohort and 88.89% (95% CI, 51.75-99.72) in the YUSH cohort. Preoperative ctDNA remained significantly associated with nodal metastasis (odds ratio [OR], 19.98; 3.90-211.42;\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001), outperforming guideline-based criteria (LVI, poor differentiation, tumor size \u22653 cm). Adding ctDNA to models with guideline risk factors improved the area under the receiver operating characteristic curve from 0.66 to 0.91 (\n P<\/jats:italic>\n \u2009=\u2009.048) in the SMC cohort, and showed consistent performance in the YUSH cohort (from 0.67 to 0.89;\n P<\/jats:italic>\n \u2009=\u2009.03).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Preoperative ctDNA detection was significantly associated with occult nodal metastasis and recurrence risk in clinical N0 early-stage ESCC in this study. Among patients with T2N0 ESCC, ctDNA may serve as a complementary biomarker to inform neoadjuvant treatment escalation and support more personalized therapeutic strategies.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamasurg.2025.6755","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T16:30:25Z","timestamp":1771432225000},"page":"370","source":"Crossref","is-referenced-by-count":2,"title":["Preoperative Circulating Tumor DNA Detection and Risk Stratification in Esophageal Squamous Cell Carcinoma"],"prefix":"10.1001","volume":"161","author":[{"given":"Tae Hee","family":"Hong","sequence":"first","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Gi","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Yong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung Jo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongsoo","family":"Kyung","sequence":"additional","affiliation":[{"name":"IMBdx, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwang-Phil","family":"Kim","sequence":"additional","affiliation":[{"name":"IMBdx, Seoul, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Ho","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Gu","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong Jeong","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junghee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea"},{"name":"Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Ho","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong Soo","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young Mog","family":"Shim","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se-Hoon","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea"},{"name":"Division of Hematology-Oncology, Department of Internal Medicine, Sungkyunkwan University, Samsung Medical Center, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae Joon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Yonsei University College of Medicine, Severance Hospital, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong Kwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea"},{"name":"Department of Clinical Research Design and Evaluation, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"2","key":"soi250103r1","doi-asserted-by":"publisher","first-page":"119","DOI":"10.21037\/acs.2017.03.14","article-title":"8th edition AJCC\/UICC staging of cancers of the esophagus and esophagogastric junction: application to clinical practice.","volume":"6","author":"Rice","year":"2017","journal-title":"Ann Cardiothorac Surg"},{"issue":"4","key":"soi250103r2","doi-asserted-by":"publisher","first-page":"393","DOI":"10.6004\/jnccn.2023.0019","article-title":"Esophageal and esophagogastric junction cancers, version 2.2023, NCCN clinical practice guidelines in oncology.","volume":"21","author":"Ajani","year":"2023","journal-title":"J Natl Compr Canc Netw"},{"issue":"23","key":"soi250103r3","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.1200\/JCO.20.00866","article-title":"Treatment of locally advanced esophageal carcinoma: ASCO guideline.","volume":"38","author":"Shah","year":"2020","journal-title":"J Clin Oncol"},{"issue":"4","key":"soi250103r4","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.tige.2023.06.001","article-title":"Accuracy of endoscopic biopsies for determining tumor grade in pre-resection evaluation of esophageal adenocarcinoma.","volume":"25","author":"Shah","year":"2023","journal-title":"Tech Innov Gastrointest Endosc"},{"issue":"2","key":"soi250103r5","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1093\/ejcts\/ezt607","article-title":"Clinical stage T1-T2N0M0 oesophageal cancer: accuracy of clinical staging and predictive factors for lymph node metastasis.","volume":"46","author":"Shin","year":"2014","journal-title":"Eur J Cardiothorac Surg"},{"issue":"1","key":"soi250103r6","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1016\/j.jtcvs.2021.10.033","article-title":"Risk prediction of occult lymph node metastasis in patients with clinical T1 through T2 N0 esophageal squamous cell carcinoma.","volume":"164","author":"Yun","year":"2022","journal-title":"J Thorac Cardiovasc Surg"},{"issue":"10","key":"soi250103r7","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1016\/j.annonc.2022.07.003","article-title":"Oesophageal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up.","volume":"33","author":"Obermannov\u00e1","year":"2022","journal-title":"Ann Oncol"},{"issue":"4","key":"soi250103r8","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1016\/j.annonc.2020.12.010","article-title":"Longitudinal tracking of 97 esophageal adenocarcinomas using liquid biopsy sampling.","volume":"32","author":"Ococks","year":"2021","journal-title":"Ann Oncol"},{"issue":"4","key":"soi250103r9","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/nrc.2017.7","article-title":"Liquid biopsies come of age: towards implementation of circulating tumour DNA.","volume":"17","author":"Wan","year":"2017","journal-title":"Nat Rev Cancer"},{"issue":"7655","key":"soi250103r10","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1038\/nature22364","article-title":"Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.","volume":"545","author":"Abbosh","year":"2017","journal-title":"Nature"},{"issue":"11","key":"soi250103r11","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.1016\/j.jtho.2024.07.002","article-title":"Clinical utility of tumor-na\u00efve presurgical circulating tumor DNA detection in early-stage NSCLC.","volume":"19","author":"Hong","year":"2024","journal-title":"J Thorac Oncol"},{"key":"soi250103r12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2025.115237","article-title":"Association of pre-surgical circulating tumor DNA detection, use of sublobar resection with risk of recurrence in stage I non-small cell lung cancer.","volume":"217","author":"Hong","year":"2025","journal-title":"Eur J Cancer"},{"issue":"1","key":"soi250103r13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10388-016-0551-7","article-title":"Japanese classification of esophageal cancer, 11th edition: part I.","volume":"14","author":"Japan Esophageal Society","year":"2017","journal-title":"Esophagus"},{"issue":"3","key":"soi250103r14","doi-asserted-by":"publisher","first-page":"765","DOI":"10.4143\/crt.2023.1294","article-title":"Analytical and clinical validation of a highly sensitive NGS-based ctDNA assay with real-world concordance in non\u2013small cell lung cancer.","volume":"56","author":"Yi","year":"2024","journal-title":"Cancer Res Treat"},{"issue":"18","key":"soi250103r15","doi-asserted-by":"publisher","first-page":"4437","DOI":"10.1158\/1078-0432.CCR-18-0143","article-title":"False-positive plasma genotyping due to clonal hematopoiesis.","volume":"24","author":"Hu","year":"2018","journal-title":"Clin Cancer Res"},{"issue":"1","key":"soi250103r16","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.jmoldx.2016.10.002","article-title":"Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists.","volume":"19","author":"Li","year":"2017","journal-title":"J Mol Diagn"},{"issue":"5","key":"soi250103r17","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejso.2025.109625","article-title":"Clinical value of preoperative circulating tumor DNA before surgery in patients with esophageal squamous cell carcinoma.","volume":"51","author":"Kobayashi","year":"2025","journal-title":"Eur J Surg Oncol"},{"issue":"4","key":"soi250103r18","doi-asserted-by":"publisher","DOI":"10.1111\/1759-7714.70017","article-title":"Exploring the clinical value of perioperative ctDNA-based detection of molecular residual disease in patients with esophageal squamous cell carcinoma.","volume":"16","author":"Li","year":"2025","journal-title":"Thorac Cancer"},{"key":"soi250103r19","doi-asserted-by":"publisher","DOI":"10.1200\/PO.22.00420","article-title":"Analysis of circulating tumor DNA to predict risk of recurrence in patients with esophageal and gastric cancers.","volume":"6","author":"Huffman","year":"2022","journal-title":"JCO Precis Oncol"},{"issue":"3","key":"soi250103r20","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1053\/j.gastro.2019.10.039","article-title":"Circulating tumor DNA analysis for detection of minimal residual disease after chemoradiotherapy for localized esophageal cancer.","volume":"158","author":"Azad","year":"2020","journal-title":"Gastroenterology"},{"issue":"11","key":"soi250103r21","doi-asserted-by":"publisher","first-page":"1141","DOI":"10.1001\/jamasurg.2023.4395","article-title":"Circulating tumor DNA dynamics as prognostic markers in locally advanced and metastatic esophageal squamous cell carcinoma.","volume":"158","author":"Ng","year":"2023","journal-title":"JAMA Surg"},{"issue":"10447","key":"soi250103r22","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/S0140-6736(24)00745-1","article-title":"Doublet chemotherapy, triplet chemotherapy, or doublet chemotherapy combined with radiotherapy as neoadjuvant treatment for locally advanced oesophageal cancer (JCOG1109 NExT): a randomised, controlled, open-label, phase 3 trial.","volume":"404","author":"Kato","year":"2024","journal-title":"Lancet"},{"issue":"5","key":"soi250103r23","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1001\/jamasurg.2025.0220","article-title":"Neoadjuvant chemoradiotherapy vs chemoimmunotherapy for esophageal squamous cell carcinoma.","volume":"160","author":"Guo","year":"2025","journal-title":"JAMA Surg"}],"container-title":["JAMA Surgery"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamasurgery\/articlepdf\/2845372\/jamasurgery_hong_2026_oi_250103_1773954891.46465.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T15:00:49Z","timestamp":1775660449000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamasurgery\/fullarticle\/2845372"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":23,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamasurg.2025.6755","relation":{},"ISSN":["2168-6254"],"issn-type":[{"value":"2168-6254","type":"print"}],"subject":[],"published":{"date-parts":[[2026,4,1]]}}}