{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T10:47:23Z","timestamp":1782902843101,"version":"3.54.5"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Carol Davila University of Medicine and Pharmacy, Bucharest, Romania"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic cancer remains one of the most aggressive digestive neoplasms, especially due to late diagnosis. The aim of our study was to investigate cytokeratin-19 fragments (CYFRA 21-1), osteopontin (OPN), and human epididymis protein 4 (HE4) clinical significance in pancreatic adenocarcinoma. Our research is a single-center cross-sectional prospective study that included sixty hospitalized patients diagnosed with pancreatic adenocarcinoma and fourteen controls. CYFRA 21-1, OPN, and HE4 were tested in all participants using Luminex x MAP technology. Serum CYFRA 21-1 levels were weakly correlated with those of OPN (r = 0.302; p = 0.009), HE4 (r = 0.485; p &lt; 0.001), and carbohydrate antigen (CA) 125 (r = 0.376; p = 0.037). Similarly to CA 19-9 and CA 125, the serum OPN levels were higher in patients with pancreatic cancer when compared to controls, 3.37 (1.84; 9.12) ng\/mL versus 1.59 (1.09; 2.51) ng\/mL; p = 0.003. However, in multivariate analysis, the OPN was not an independent predictor for pancreatic cancer. Further, the receiver operating characteristic (ROC) curve analysis identified CA 19-9 as the biomarker with the highest diagnostic accuracy, while CYFRA 21-1, OPN, and HE4 did not reach clinically meaningful results. Further, the CYFRA 21-1 levels were significantly higher in cases subjected to significant weight loss before admission.<\/jats:p>","DOI":"10.3390\/ijms27031562","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T10:35:37Z","timestamp":1770287737000},"page":"1562","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical Significance of Cytokeratin 19-Fragments (CYFRA 21-1), Osteopontin (OPN) and Human Epididymis Protein 4 (HE4) in Pancreatic Adenocarcinoma"],"prefix":"10.3390","volume":"27","author":[{"given":"Augustin Catalin","family":"Dima","sequence":"first","affiliation":[{"name":"Clinical Department 14, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Surgery 2, Carol Davila University Central Emergency Military Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3436-8041","authenticated-orcid":false,"given":"Daniel Vasile","family":"Balaban","sequence":"additional","affiliation":[{"name":"Clinical Department 5, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Gastroenterology, Carol Davila Central University Emergency Military Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iulia-Ioana","family":"Stanescu-Spinu","sequence":"additional","affiliation":[{"name":"Discipline of Physiology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana","family":"Teodorescu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Carol Davila Central University Emergency Military Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Manucu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Carol Davila Central University Emergency Military Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Ioana","family":"Coman","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Carol Davila Central University Emergency Military Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8743-3236","authenticated-orcid":false,"given":"Alina","family":"Dima","sequence":"additional","affiliation":[{"name":"Clinical Department 5, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cezar","family":"Betianu","sequence":"additional","affiliation":[{"name":"Department of Radiology, Doctor Carol Davila Central Military University Emergency Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihai","family":"Tanase","sequence":"additional","affiliation":[{"name":"Department of Surgery 2, Carol Davila University Central Emergency Military Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Miricescu","sequence":"additional","affiliation":[{"name":"Discipline of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5826-0815","authenticated-orcid":false,"given":"Mariana","family":"Jinga","sequence":"additional","affiliation":[{"name":"Clinical Department 5, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Gastroenterology, Carol Davila Central University Emergency Military Hospital, 010825 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catalin","family":"Carstoiu","sequence":"additional","affiliation":[{"name":"Clinical Department 14, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania"},{"name":"Department of Orthopedics and Traumatology, University Emergency Hospital, 050098 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wang, Q., Wang, H., Ding, Y., Wan, M., and Xu, M. (2022). The role of adipokines in pancreatic cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.926230"},{"key":"ref_2","first-page":"20200005","article-title":"CYFRA 21-1 in patients with suspected cancer: Evaluation of an optimal cutoff to assess the diagnostic efficacy and prognostic value","volume":"1","author":"Plata","year":"2020","journal-title":"Adv. Lab. Med.\/Av. En Med. De Lab."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Pergolizzi, R.G., and Brower, S.T. (2024). Molecular targets for the diagnosis and treatment of pancreatic cancer. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202407.2126.v1"},{"key":"ref_4","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Nolen, B.M., Brand, R.E., Prosser, D., Velikokhatnaya, L., Allen, P.J., Zeh, H.J., Grizzle, W.E., Lomakin, A., and Lokshin, A.E. (2014). Prediagnostic serum biomarkers as early detection tools for pancreatic cancer in a large prospective cohort study. PLoS ONE, 9, Correction in PLoS ONE\u00a02015, 10, e0117876.","DOI":"10.1371\/journal.pone.0117876"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.1007\/s00432-022-04112-z","article-title":"Serum biomarker panel diagnostics in pancreatic ductal adenocarcinoma: The clinical utility of soluble interleukins, IFN-\u03b3, TNF-\u03b1 and PD-1\/PD-L1 in comparison to established serum tumor markers","volume":"149","author":"Dorman","year":"2023","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1038\/bjc.2013.158","article-title":"Cytokeratin 19-fragments (CYFRA 21-1) as a novel serum biomarker for response and survival in patients with advanced pancreatic cancer","volume":"108","author":"Boeck","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1155\/2013\/196412","article-title":"Serum markers of intrahepatic cholangiocarcinoma","volume":"34","author":"Malaguarnera","year":"2013","journal-title":"Dis. Markers"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10732748241228037","DOI":"10.1177\/10732748241228037","article-title":"Cyfra 21.1: A Useful Tumour Marker in Pancreatic Ductal Adenocarcinoma: Cross-Sectional Study","volume":"31","author":"Kuttanchettiyar","year":"2024","journal-title":"Cancer Control"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Matuszczak, M., and Salagierski, M. (2020). Diagnostic and prognostic potential of biomarkers CYFRA 21.1, ERCC1, p53, FGFR3 and TATI in bladder cancers. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093360"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S35","DOI":"10.3233\/TUB-220023","article-title":"Oncology Biomarkers Section of the Catalan Association of Clinical Laboratory Science. Factors influencing blood tumor marker concentrations in the absence of neoplasia","volume":"46","author":"Auge","year":"2024","journal-title":"Tumor Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Liu, L., Xie, W., Xue, P., Wei, Z., Liang, X., and Chen, N. (2019). Diagnostic accuracy and prognostic applications of CYFRA 21-1 in head and neck cancer: A systematic review and meta-analysis. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0216561"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Sorino, C., Mondoni, M., Marchetti, G., Agati, S., Inchingolo, R., Mei, F., Flamini, S., Lococo, F., and Feller-Kopman, D. (2023). Pleural mesothelioma: Advances in blood and pleural biomarkers. J. Clin. Med., 12.","DOI":"10.3390\/jcm12227006"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Marstrand-Dauc\u00e9, L., Lorenzo, D., Chassac, A., Nicole, P., Couvelard, A., and Haumaitre, C. (2023). Acinar-to-ductal metaplasia (ADM): On the road to pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24129946"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.pan.2023.08.007","article-title":"Pancreatic ductal adenocarcinoma with acinar-to-ductal metaplasia-like cancer cells shows increased cellular proliferation","volume":"23","author":"Nishimon","year":"2023","journal-title":"Pancreatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"737","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":"ref_17","doi-asserted-by":"crossref","unstructured":"Amilca-Seba, K., Sabbah, M., Larsen, A.K., and Denis, J.A. (2021). Osteopontin as a regulator of colorectal cancer progression and its clinical applications. Cancers, 13.","DOI":"10.3390\/cancers13153793"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.21037\/gs-20-544","article-title":"Role of biomarkers for early detection of ovarian cancer recurrence","volume":"9","author":"Giampaolino","year":"2020","journal-title":"Gland Surg."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bastos, A.C.S.D.F., Gomes, A.V.P., Silva, G.R., Emerenciano, M., Ferreira, L.B., and Gimba, E.R.P. (2023). The intracellular and secreted sides of osteopontin and their putative physiopathological roles. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032942"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Hao, C., Lane, J., and Jiang, W.G. (2023). Osteopontin and cancer: Insights into its role in drug resistance. Biomedicines, 11.","DOI":"10.3390\/biomedicines11010197"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Moorman, H.R., Poschel, D., Klement, J.D., Lu, C., Redd, P.S., and Liu, K. (2020). Osteopontin: A key regulator of tumor progression and immunomodulation. Cancers, 12.","DOI":"10.3390\/cancers12113379"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1007\/s00432-024-06038-0","article-title":"Osteopontin: An indispensable component in common liver, pancreatic, and biliary related disease","volume":"150","author":"Liu","year":"2024","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1186\/s12935-020-01248-1","article-title":"HE4 overexpression decreases pancreatic cancer Capan-1 cell sensitivity to paclitaxel via cell cycle regulation","volume":"20","author":"Guo","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41598-020-79960-1","article-title":"The diagnostic value of human epididymis protein 4 for endometrial cancer is moderate","volume":"11","author":"Liu","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3892\/or.2015.4339","article-title":"Recombinant HE4 protein promotes proliferation of pancreatic and endometrial cancer cell lines","volume":"35","author":"Lu","year":"2016","journal-title":"Oncol. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Anastasi, E., Farina, A., Granato, T., Colaiacovo, F., Pucci, B., Tartaglione, S., and Angeloni, A. (2023). Recent insight about HE4 role in ovarian cancer oncogenesis. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202305.0967.v1"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1533033820971660","DOI":"10.1177\/1533033820971660","article-title":"Role of human epididymis protein 4 (HE4) in determining survival of patients with endometrial cancer: A meta-analysis","volume":"19","author":"He","year":"2020","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1158\/1055-9965.EPI-14-0447","article-title":"HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors: A systematic review","volume":"23","author":"Karlsen","year":"2014","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_29","first-page":"191","article-title":"Clinical significance of plasma osteopontin level as a biomarker of hepatocellular carcinoma","volume":"6","author":"Salem","year":"2013","journal-title":"Gastroenterol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"101951","DOI":"10.1016\/j.mcp.2024.101951","article-title":"Intrahepatic cholangiocarcinoma biomarkers: Towards early detection and personalized pharmacological treatments","volume":"73","author":"Capuozzo","year":"2024","journal-title":"Mol. Cell. Probes"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1002\/jcla.20208","article-title":"Diagnostic utility of pleural fluid carcinoembryonic antigen and CYFRA 21-1 in patients with pleural effusion: A systematic review and meta-analysis","volume":"21","author":"Gu","year":"2007","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/bjc.2017.45","article-title":"Carcinoembryonic antigen and cytokeratin-19 fragments for assessment of therapy response in non-small cell lung cancer: A systematic review and meta-analysis","volume":"116","author":"Holdenrieder","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S111","DOI":"10.3233\/TUB-230009","article-title":"Prognostic value of blood-based protein biomarkers in non-small cell lung cancer: A critical review and 2008\u20132022 update","volume":"46","author":"Trulson","year":"2024","journal-title":"Tumor Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Panda, V.K., Mishra, B., Nath, A.N., Butti, R., Yadav, A.S., Malhotra, D., Khanra, S., Mahapatra, S., Mishra, P., and Swain, B. (2024). Osteopontin: A key multifaceted regulator in tumor progression and immunomodulation. Biomedicines, 12.","DOI":"10.20944\/preprints202405.0835.v1"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/s41419-018-0391-6","article-title":"The role of osteopontin in the progression of solid organ tumour","volume":"9","author":"Zhao","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.3390\/ijms16022956","article-title":"Expression and diagnostic value of HE4 in pancreatic adenocarcinoma","volume":"16","author":"Huang","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1016\/j.humpath.2012.07.017","article-title":"Human epididymis protein 4 is up-regulated in gastric and pancreatic adenocarcinomas","volume":"44","author":"Nam","year":"2013","journal-title":"Hum. Pathol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"355","DOI":"10.3233\/TUB-211546","article-title":"Analysis of serum HE4 levels in various histologic subtypes of epithelial ovarian cancer and other malignant tumors","volume":"43","author":"Blackman","year":"2021","journal-title":"Tumor Biol."},{"key":"ref_39","first-page":"5618","article-title":"The value of serum HE4 in pancreatic adenocarcinoma diagnosis","volume":"10","author":"Ge","year":"2017","journal-title":"Int. J. Clin. Exp. Pathol"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"142","DOI":"10.5603\/NJO.2019.0026","article-title":"HE4\u2013not only an ovarian cancer biomarker\u2013a brief review","volume":"69","author":"Maksimiuk","year":"2019","journal-title":"Nowotwory J. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Huber, M., Brehm, C.U., Gress, T.M., Buchholz, M., Alashkar Alhamwe, B., Pogge von Strandmann, E., Slater, E.P., Bartsch, J.W., Bauer, C., and Lauth, M. (2020). The immune microenvironment in pancreatic cancer. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197307"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"57","DOI":"10.3892\/ijo.2020.5147","article-title":"High levels of human epididymis protein 4 mRNA and protein expression are associated with chemoresistance and a poor prognosis in pancreatic cancer","volume":"58","author":"Ohkuma","year":"2020","journal-title":"Int. J. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"James, N.E., Chichester, C., and Ribeiro, J.R. (2018). Beyond the biomarker: Understanding the diverse roles of human epididymis protein 4 in the pathogenesis of epithelial ovarian cancer. Front. Oncol., 8.","DOI":"10.3389\/fonc.2018.00124"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1562\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T10:38:02Z","timestamp":1770287882000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1562"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,5]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27031562"],"URL":"https:\/\/doi.org\/10.3390\/ijms27031562","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,5]]}}}