{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T12:36:05Z","timestamp":1793018165093,"version":"4.5.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Apolipoprotein A2 isoforms (apoA2\u2011i) are clinically validated blood\u2011based biomarkers for the auxiliary diagnosis of pancreatic cancer. Emerging evidence also suggests that apoA2\u2011i may contribute to the detection of early\u2011stage pancreatic cancer, particularly in cohorts where CA19\u20119 shows limited sensitivity, although these applications remain investigational and require prospective validation. Beyond diagnostic applications, apoA2\u2011i reflect pancreatic exocrine physiology, linking biomarker biology with perioperative outcomes such as postoperative pancreatic fistula and steatotic liver disease. Because type 3c diabetes mellitus arises from exocrine dysfunction, emerging evidence suggests that exocrine\u2011based markers, including apoA2\u2011i, may contribute to future approaches for stratifying new\u2011onset diabetes, although current evidence remains preliminary. By integrating validated diagnostic roles with developing translational and physiological applications, this review outlines the evolving relevance of apoA2\u2011i within pancreatic oncology while emphasizing the need for prospective, multi-center validation and real-world data integration.<\/jats:p>","DOI":"10.3389\/fonc.2026.1902440","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:33:34Z","timestamp":1789644814000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ApoA2 isoforms as blood-based biomarkers reflecting pancreatic exocrine dysfunction for risk stratification and perioperative management of pancreatic cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Akira","family":"Matsushita","sequence":"first","affiliation":[{"name":"Department of Gastroenterological Surgery, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Murokawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junji","family":"Ueda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Kawano","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihisa","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Surgery, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Hasegawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Itokawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Molecular Prevention, Graduate School of Medicine, Nippon Medical School","place":["Tokyo, Japan"]},{"name":"Division of Molecular Prevention, Institute for Advanced Medical Science, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayumi","family":"Kashiro","sequence":"additional","affiliation":[{"name":"Department of Molecular Prevention, Graduate School of Medicine, Nippon Medical School","place":["Tokyo, Japan"]},{"name":"Division of Molecular Prevention, Institute for Advanced Medical Science, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazufumi","family":"Honda","sequence":"additional","affiliation":[{"name":"Department of Molecular Prevention, Graduate School of Medicine, Nippon Medical School","place":["Tokyo, Japan"]},{"name":"Division of Molecular Prevention, Institute for Advanced Medical Science, Nippon Medical School","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"16022","DOI":"10.1038\/nrdp.2016.22","article-title":"Pancreatic cancer","volume":"2","author":"Kleeff","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nature16965","article-title":"Genomic analyses identify molecular subtypes of pancreatic cancer","volume":"531","author":"Bailey","year":"2016","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.ccell.2017.07.007","article-title":"Integrated genomic characterization of pancreatic ductal adenocarcinoma","volume":"32","year":"2017","journal-title":"Cancer Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162024","article-title":"Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer","volume":"214","author":"\u00d6hlund","year":"2017","journal-title":"J Exp Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nature12040","article-title":"Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway","volume":"496","author":"Son","year":"2013","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.Can-14-2211","article-title":"Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein","volume":"75","author":"Kamphorst","year":"2015","journal-title":"Cancer Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-312078","article-title":"Myeloid cells are required for PD-1\/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer","volume":"66","author":"Zhang","year":"2017","journal-title":"Gut"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nature09515","article-title":"Distant metastasis occurs late during the genetic evolution of pancreatic cancer","volume":"467","author":"Yachida","year":"2010","journal-title":"Nature"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdr561","article-title":"The prognostic and predictive value of serum CA19.9 in pancreatic cancer","volume":"23","author":"Humphris","year":"2012","journal-title":"Ann Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/s1470-2045(13)70598-9","article-title":"Addressing overdiagnosis and overtreatment in cancer: a prescription for change","volume":"15","author":"Esserman","year":"2014","journal-title":"Lancet Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar3247","article-title":"Detection and localization of surgically resectable cancers with a multi-analyte blood test","volume":"359","author":"Cohen","year":"2018","journal-title":"Science"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-023-02072-w","article-title":"Clinical development of a blood biomarker using apolipoprotein-A2 isoforms for early detection of pancreatic cancer","volume":"59","author":"Kashiro","year":"2024","journal-title":"J Gastroenterol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.3390\/cancers17071071","article-title":"Evaluating the usefulness of the blood apolipoprotein A2 isoform index for pancreatic cancer diagnosis","volume":"17","author":"Shionoya","year":"2025","journal-title":"Cancers (Basel)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/jgh3.70375","article-title":"Clinical utility of the apolipoprotein A2 isoform index as a tumor marker for pancreatic cancer","volume":"10","author":"Hoshino","year":"2026","journal-title":"JGH Open"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.14309\/ctg.0000000000000856","article-title":"Risk stratification for Malignant potential of intraductal papillary mucinous neoplasms using the apolipoprotein-A2 isoforms blood test","volume":"16","author":"Hasegawa","year":"2025","journal-title":"Clin Transl Gastroenterol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"102","DOI":"10.21037\/hbsn-2025-325","article-title":"Monitoring with plasma apolipoprotein A2-isoforms can predict developing new-onset steatotic liver disease caused by pancreatic exocrine insufficiency following pancreatectomy","volume":"15","author":"Matsushita","year":"2026","journal-title":"HepatoBiliary Surg Nutr"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v32.i16.116238","article-title":"Plasma apolipoprotein A2 isoforms predict the development of pancreatic fistula following distal pancreatectomy","volume":"32","author":"Ono","year":"2026","journal-title":"World J Gastroenterol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.10.025","article-title":"Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma","volume":"22","author":"Kopp","year":"2012","journal-title":"Cancer Cell"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2009.12.005","article-title":"Pancreatic duct glands are distinct ductal compartments that react to chronic injury and mediate Shh-induced metaplasia","volume":"138","author":"Strobel","year":"2010","journal-title":"Gastroenterology"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/ueg2.12674","article-title":"European guidelines for the diagnosis and treatment of pancreatic exocrine insufficiency: UEG, EPC, EDS, ESPEN, ESPGHAN, ESDO, and ESPCG evidence-based recommendations","volume":"13","author":"Dominguez-Mu\u00f1oz","year":"2025","journal-title":"United Eur Gastroenterol J"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1578","DOI":"10.3390\/biomedicines10071578","article-title":"Apolipoprotein A-II, a player in multiple processes and diseases","volume":"10","author":"Florea","year":"2022","journal-title":"Biomedicines"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/srep15921","article-title":"Plasma biomarker for detection of early stage pancreatic cancer and risk factors for pancreatic Malignancy using antibodies for apolipoprotein-AII isoforms","volume":"5","author":"Honda","year":"2015","journal-title":"Sci Rep"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046908","article-title":"Altered plasma apolipoprotein modifications in patients with pancreatic cancer: protein characterization and multi-institutional validation","volume":"7","author":"Honda","year":"2012","journal-title":"PloS One"},{"key":"B25","doi-asserted-by":"publisher","first-page":"1920","DOI":"10.3390\/diagnostics14171920","article-title":"Potential of carbohydrate antigen 19-9 and serum apolipoprotein A2-isoforms in the diagnosis of stage 0 and IA pancreatic cancer","volume":"14","author":"Hanada","year":"2024","journal-title":"Diagnostics (Basel)"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(86)90930-3","article-title":"Comparison of the sensitivity and specificity of the CA19-9 and carcinoembryonic antigen assays in detecting cancer of the pancreas","volume":"90","author":"Steinberg","year":"1986","journal-title":"Gastroenterology"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.2147\/ott.S145708","article-title":"Diagnostic and prognostic value of carcinoembryonic antigen in pancreatic cancer: a systematic review and meta-analysis","volume":"10","author":"Meng","year":"2017","journal-title":"Onco Targets Ther"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1200\/jco.23.01573","article-title":"Using tumor marker gene variants to improve the diagnostic accuracy of DUPAN-2 and carbohydrate antigen 19-9 for pancreatic cancer","volume":"42","author":"Ando","year":"2024","journal-title":"J Clin Oncol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"7651","DOI":"10.3390\/ijms21207651","article-title":"Current status of circulating tumor DNA liquid biopsy in pancreatic cancer","volume":"21","author":"Grunvald","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aat4921","article-title":"Enhanced detection of circulating tumor DNA by fragment size analysis","volume":"10","author":"Mouliere","year":"2018","journal-title":"Sci Transl Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2025.104807","article-title":"Unveilling the potential of liquid biopsy in pancreatic cancer for molecular diagnosis and treatment guidance","volume":"212","author":"Toledano-Fonseca","year":"2025","journal-title":"Crit Rev Oncol Hematol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34287","article-title":"Urine biomarkers enable pancreatic cancer detection up to 2\u2009years before diagnosis","volume":"152","author":"Debernardi","year":"2023","journal-title":"Int J Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.jmoldx.2024.10.001","article-title":"A clinical laboratory improvement amendments\/college of american pathologists-compliant noninvasive laboratory-developed test for early detection of pancreatic ductal adenocarcinoma","volume":"27","author":"Tajbakhsh","year":"2025","journal-title":"J Mol Diagn"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aah5583","article-title":"Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers","volume":"9","author":"Kim","year":"2017","journal-title":"Sci Transl Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2021.103797","article-title":"Soluble AXL is a novel blood marker for early detection of pancreatic ductal adenocarcinoma and differential diagnosis from chronic pancreatitis","volume":"75","author":"Mart\u00ednez-Bosch","year":"2022","journal-title":"EBioMedicine"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nature14581","article-title":"Glypican-1 identifies cancer exosomes and detects early pancreatic cancer","volume":"523","author":"Melo","year":"2015","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.pan.2023.12.009","article-title":"International evidence-based Kyoto guidelines for the management of intraductal papillary mucinous neoplasm of the pancreas","volume":"24","author":"Ohtsuka","year":"2024","journal-title":"Pancreatology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.gastro.2005.05.007","article-title":"Probability of pancreatic cancer following diabetes: a population-based study","volume":"129","author":"Chari","year":"2005","journal-title":"Gastroenterology"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2025.06.025","article-title":"Risk of pancreatic cancer in glycemically defined new-onset diabetes: a prospective cohort study","volume":"170","author":"Chari","year":"2026","journal-title":"Gastroenterology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/s2468-1253(16)30106-6","article-title":"Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer","volume":"1","author":"Hart","year":"2016","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v19.i42.7276","article-title":"Diagnosis and treatment of diabetes mellitus in chronic pancreatitis","volume":"19","author":"Ewald","year":"2013","journal-title":"World J Gastroenterol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/5738614","article-title":"Clinical significance of plasma apolipoprotein-AII isoforms as a marker of pancreatic exocrine disorder for patients with pancreatic adenocarcinoma undergoing chemoradiotherapy, paying attention to pancreatic morphological changes","volume":"2019","author":"Hayasaki","year":"2019","journal-title":"BioMed Res Int"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1902440\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T12:13:27Z","timestamp":1793016807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1902440\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":42,"alternative-id":["10.3389\/fonc.2026.1902440"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1902440","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]},"article-number":"1902440"}}