{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:56:51Z","timestamp":1790704611314,"version":"4.1.0"},"reference-count":26,"publisher":"IMR Press","issue":"9","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br. J. Hosp. Med. (Lond)"],"abstract":"<jats:p>Aims\/Background: Gastric cancer remains a leading cause of cancer-related mortality worldwide. Helicobacter pylori (Hp) infection is a major risk factor, but the diagnostic performance of serum biomarkers may vary according to Hp infection status. This study aimed to evaluate the diagnostic value of serum human epididymis protein 4 (HE4), trefoil factor 3 (TFF3), and carbohydrate antigen 72-4 (CA72-4), individually and in combination, for gastric cancer stratified by Hp infection status using a propensity score-matched retrospective case-control design. Methods: This retrospective study was conducted at Jinshazhou Hospital of Guangzhou University of Chinese Medicine, from January 2022 to December 2025. Propensity score matching (1:1 nearest neighbor matching, caliper 0.1) was performed to balance age, sex, body mass index (BMI), smoking history, alcohol consumption history, chronic kidney disease, chronic liver disease, and Hp infection status between groups. After matching, 268 gastric cancer patients and 268 healthy controls were included. Serum levels of HE4, TFF3, and CA72-4 were measured. Between-group comparisons of each marker, stratified by Hp status, were performed. Logistic regression was used to construct combined diagnostic models, and receiver operating characteristic (ROC) curve analysis was performed to evaluate the area under the curve (AUC). Results: After matching, all covariates achieved good balance with standardized mean differences &lt;0.1. In the total population, serum levels of HE4, TFF3, and CA72-4 were significantly higher in the gastric cancer group than in the control group (all p &lt; 0.001). Multivariate logistic regression identified all three markers as independent risk factors for gastric cancer (HE4: odds ratio [OR] = 1.05, 95% confidence interval [CI]: 1.03\u20131.06; TFF3: OR = 1.19, 95% CI: 1.13\u20131.26; CA72-4: OR = 1.46, 95% CI: 1.34\u20131.62; all p &lt; 0.001). The combined model yielded an AUC of 0.899 (0.872\u20130.925) in the total population, significantly superior to any single marker (all p &lt; 0.001). After stratification by Hp status, the AUC of TFF3 was significantly higher in Hp-positive individuals than in Hp-negative individuals (p &lt; 0.001); no significant differences were observed for HE4 or CA72-4 between the two strata (p &gt; 0.05). Conclusion: The diagnostic value of serum HE4, TFF3, and CA72-4 for gastric cancer varies according to Hp infection status. In Hp-positive patients, TFF3 demonstrates significantly higher diagnostic performance compared with Hp-negative individuals. HE4 and CA72-4 demonstrate stable performance across Hp strata, with no statistically significant differences observed. The combined detection of these biomarkers demonstrates favorable diagnostic performance regardless of Hp status. These findings suggest that Hp status-stratified testing provides an auxiliary strategy for optimizing differential diagnosis of gastric cancer.<\/jats:p>","DOI":"10.31083\/bjhm52019","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:59:52Z","timestamp":1790701192000},"source":"Crossref","is-referenced-by-count":0,"title":["Diagnostic Value of Serum HE4, TFF3, and CA72-4 for Gastric Cancer Stratified by Helicobacter pylori Infection Status"],"prefix":"10.31083","volume":"87","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5338-4661","authenticated-orcid":true,"given":"Muyong","family":"Wang","sequence":"first","affiliation":[{"name":"Department of General Surgery, Jinshazhou Hospital of Guangzhou University of Chinese Medicine, 510168 Guangzhou, Guangdong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengke","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Health and Medicine, Dezhou University, 253023 Dezhou, Shandong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: a Cancer Journal for Clinicians. 2021; 71: 209\u2013249.","DOI":"10.3322\/caac.21660"},{"key":"ref2","doi-asserted-by":"publisher","unstructured":"Li M, Cao S, Xu RH. Global trends and epidemiological shifts in gastrointestinal cancers: insights from the past four decades. Cancer Communications. 2025; 45: 774\u2013788.","DOI":"10.1002\/cac2.70017"},{"key":"ref3","doi-asserted-by":"publisher","unstructured":"Park JY, Georges D, Alberts CJ, Bray F, Clifford G, Baussano I. Global lifetime estimates of expected and preventable gastric cancers across 185 countries. Nature Medicine. 2025; 31: 3020\u20133027.","DOI":"10.1038\/s41591-025-03793-6"},{"key":"ref4","doi-asserted-by":"publisher","unstructured":"Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet. 2020; 396: 635\u2013648.","DOI":"10.1016\/S0140-6736(20)31288-5"},{"key":"ref5","doi-asserted-by":"publisher","unstructured":"Ajani JA, D'Amico TA, Almhanna K, Bentrem DJ, Chao J, Das P, et al. Gastric Cancer, Version 3.2016, NCCN Clinical Practice Guidelines in Oncology. Journal of the National Comprehensive Cancer Network. 2016; 14: 1286\u20131312.","DOI":"10.6004\/jnccn.2016.0137"},{"key":"ref6","doi-asserted-by":"publisher","unstructured":"Or\u0103\u0219eanu A, Brisc MC, Maghiar OA, Popa H, Brisc CM, \u0218olea SF, et al. Landscape of Innovative Methods for Early Diagnosis of Gastric Cancer: A Systematic Review. Diagnostics. 2023; 13: 3608.","DOI":"10.3390\/diagnostics13243608"},{"key":"ref7","doi-asserted-by":"publisher","unstructured":"Feng F, Tian Y, Xu G, Liu Z, Liu S, Zheng G, et al. Diagnostic and prognostic value of CEA, CA19-9, AFP and CA125 for early gastric cancer. BMC Cancer. 2017; 17: 737.","DOI":"10.1186\/s12885-017-3738-y"},{"key":"ref8","doi-asserted-by":"publisher","unstructured":"Sun HT. Helicobacter pylori-related serum indicators: Cutting-edge advances to enhance the efficacy of gastric cancer screening. World Journal of Gastrointestinal Oncology. 2025; 17: 100739.","DOI":"10.4251\/wjgo.v17.i3.100739"},{"key":"ref9","unstructured":"Correa P. Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Research. 1992; 52: 6735\u20136740."},{"key":"ref10","doi-asserted-by":"publisher","unstructured":"Han Z, Liu J, Zhang W, Kong Q, Wan M, Lin M, et al. Cardia and non-cardia gastric cancer risk associated with Helicobacter pylori in East Asia and the West: A systematic review, meta-analysis, and estimation of population attributable fraction. Helicobacter. 2023; 28: e12950.","DOI":"10.1111\/hel.12950"},{"key":"ref11","doi-asserted-by":"publisher","unstructured":"Riquelme A, Silva F, Reyes D, Latorre G. Chronic Atrophic Gastritis and Intestinal Metaplasia: A Latin American Perspective. The Korean Journal of Helicobacter and Upper Gastrointestinal Research. 2024; 24: 218\u2013230.","DOI":"10.7704\/kjhugr.2024.0017"},{"key":"ref12","doi-asserted-by":"publisher","unstructured":"Yang XT, Niu PQ, Li XF, Sun MM, Wei W, Chen YQ, et al. Differential cytokine expression in gastric tissues highlights helicobacter pylori's role in gastritis. Scientific Reports. 2024; 14: 7683.","DOI":"10.1038\/s41598-024-58407-x"},{"key":"ref13","doi-asserted-by":"publisher","unstructured":"Matsuda K, Yamauchi K, Matsumoto T, Sano K, Yamaoka Y, Ota H. Quantitative analysis of the effect of Helicobacter pylori on the expressions of SOX2, CDX2, MUC2, MUC5AC, MUC6, TFF1, TFF2, and TFF3 mRNAs in human gastric carcinoma cells. Scandinavian Journal of Gastroenterology. 2008; 43: 25\u201333.","DOI":"10.1080\/00365520701579795"},{"key":"ref14","doi-asserted-by":"publisher","unstructured":"Guo YD, Wang JH, Lu H, Li XN, Song WW, Zhang XD, et al. The human epididymis protein 4 acts as a prognostic factor and promotes progression of gastric cancer. Tumour Biology. 2015; 36: 2457\u20132464.","DOI":"10.1007\/s13277-014-2858-0"},{"key":"ref15","doi-asserted-by":"publisher","unstructured":"\u00d6ks\u00fcz P, Diniz G, Akata T, Koca Y, Ayaz D. Correlation of Human Epididymis Protein 4 Expression with Clinicopathologic Parameters in Gastric Carcinomas. Hamidiye Medical Journal. 2025; 6: 59\u201366.","DOI":"10.4274\/hamidiyemedj.galenos.2025.15010"},{"key":"ref16","doi-asserted-by":"publisher","unstructured":"Jing D, Jin J, Mei Z, Zhu Q, Lu Y, Wang X. Effects of Helicobacter pylori infection and interleukin 6 on the expression of ITIH4 in human gastric cancer cells. Translational Cancer Research. 2020; 9: 4656\u20134665.","DOI":"10.21037\/tcr-20-1766"},{"key":"ref17","doi-asserted-by":"publisher","unstructured":"Zhao J, Tian W, Zhang X, Dong S, Shen Y, Gao X, et al. The diagnostic value of serum trefoil factor 3 and pepsinogen combination in chronic atrophic gastritis: a retrospective study based on a gastric cancer screening cohort in the community population. Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals. 2024; 29: 384\u2013392.","DOI":"10.1080\/1354750X.2024.2400927"},{"key":"ref18","doi-asserted-by":"publisher","unstructured":"Latorre G, Pizarro M, Ford JS, G\u00e1ndara V, Mu\u00f1oz G, Araya JC, et al. Evaluation of trefoil factor 3 as a non-invasive biomarker of gastric intestinal metaplasia and gastric cancer in a high-risk population. Gastroenterologia Y Hepatologia. 2023; 46: 411\u2013418.","DOI":"10.1016\/j.gastrohep.2022.04.004"},{"key":"ref19","doi-asserted-by":"publisher","unstructured":"Wang H, Jin W, Wan C, Zhu C. Diagnostic value of combined detection of CA72-4, CA19-9, and carcinoembryonic antigen comparing to CA72-4 alone in gastric cancer: a systematic review and meta-analysis. Translational Cancer Research. 2022; 11: 848\u2013856.","DOI":"10.21037\/tcr-22-537"},{"key":"ref20","doi-asserted-by":"publisher","unstructured":"Hu PJ, Chen MY, Wu MS, Lin YC, Shih PH, Lai CH, et al. Clinical Evaluation of CA72-4 for Screening Gastric Cancer in A Healthy Population: A Multicenter Retrospective Study. Cancers. 2019; 11: 733.","DOI":"10.3390\/cancers11050733"},{"key":"ref21","doi-asserted-by":"publisher","unstructured":"Shen W, Zhou H, Li L, Liu W, Lou Q, Tong CY, et al. Promising protein biomarkers for early gastric cancer: clinical performance of combined detection. Clinical Chemistry and Laboratory Medicine. 2025; 63: 1864\u20131875.","DOI":"10.1515\/cclm-2024-1510"},{"key":"ref22","doi-asserted-by":"publisher","unstructured":"Zhang CX, Wu CT, Xiao L, Tang SH. The diagnostic and clinicopathological value of trefoil factor 3 in patients with gastric cancer: a systematic review and meta-analysis. Biomarkers: Biochemical Indicators of Exposure, Response, and Susceptibility to Chemicals. 2021; 26: 95\u2013102.","DOI":"10.1080\/1354750X.2020.1871411"},{"key":"ref23","doi-asserted-by":"publisher","unstructured":"O'Brien VP, Jackson LK, Frick JP, Rodriguez Martinez AE, Jones DS, Johnston CD, et al. Helicobacter pylori Chronic Infection Selects for Effective Colonizers of Metaplastic Glands. mbio. 2023; 14: e0311622.","DOI":"10.1128\/mbio.03116-22"},{"key":"ref24","doi-asserted-by":"publisher","unstructured":"O'Neal RL, Nam KT, LaFleur BJ, Barlow B, Nozaki K, Lee HJ, et al. Human epididymis protein 4 is up-regulated in gastric and pancreatic adenocarcinomas. Human Pathology. 2013; 44: 734\u2013742.","DOI":"10.1016\/j.humpath.2012.07.017"},{"key":"ref25","doi-asserted-by":"publisher","unstructured":"Qiu M, Zou S, Yu Z, Nian X. Clinical utility of human epididymis protein 4. Critical Reviews in Clinical Laboratory Sciences. 2025; 62: 510\u2013534.","DOI":"10.1080\/10408363.2025.2512467"},{"key":"ref26","doi-asserted-by":"publisher","unstructured":"Shimada H, Noie T, Ohashi M, Oba K, Takahashi Y. Clinical significance of serum tumor markers for gastric cancer: a systematic review of literature by the Task Force of the Japanese Gastric Cancer Association. Gastric Cancer. 2014; 17: 26\u201333.","DOI":"10.1007\/s10120-013-0259-5"}],"container-title":["British Journal of Hospital Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/BJHM\/87\/9\/10.31083\/BJHM52019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:00:58Z","timestamp":1790701258000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/BJHM\/87\/9\/10.31083\/BJHM52019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":26,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026]]}},"alternative-id":["S1759-7390(26)03915-0"],"URL":"https:\/\/doi.org\/10.31083\/bjhm52019","relation":{},"ISSN":["1750-8460","1759-7390"],"issn-type":[{"value":"1750-8460","type":"print"},{"value":"1759-7390","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]},"article-number":"52019"}}