{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:20:47Z","timestamp":1790274047059,"version":"4.1.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:00:00Z","timestamp":1738627200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T00:00:00Z","timestamp":1738627200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Universit\u00e4tsklinikum des Saarlandes und Medizinische Fakult\u00e4t der Universit\u00e4t des Saarlandes"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Gastroenterol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The collagen-rich tumor stroma plays a crucial role in biliary tract cancer (BTC). Collagen biomarkers of type I collagen (reC1M), type III collagen (PRO-C3), type IV collagen (C4G), type VIII collagen (PRO-C8), type XI collagen (PRO-C11), type XVII collagen (PRO-C17) and type VIII collagen (TUM) may be used as potential non-invasive biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We measured the seven biomarkers of collagen turnover in sera of 72 patients with BTC at baseline and after first and second chemotherapy cycle (CTX). Markers were also assessed in sera of 50 healthy controls and compared to levels of patients at baseline. The diagnostic and prognostic value of the markers was evaluated for overall survival (OS) and progression-free survival (PFS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patients had a median age of 65 years (IQR 57\u201370), while healthy controls were younger, with a median age of 46 years (IQR 38\u201354). The majority of patients (62%) were diagnosed with intrahepatic bile duct adenocarcinoma. Except C4G, all collagen turnover markers were significantly (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) increased in serum from patients with BTC compared to healthy controls. PRO-C3 was the best marker to discriminate between patients with BTC and controls, reaching an area under a receiver operating characteristic (AUROC) of 0.98 (95% CI 0.95; 0.99) with a sensitivity (92%) and specificity (94%) balanced cutoff of 77.3 ng\/ml. Patients with high levels (cohort separated by median split) of PRO-C8 (HR 2.85, 95% CI 1.42; 5.73) followed by C3M (HR 2.33, 95% CI 1.2; 4.5), PRO-C3 (HR 3.09, 95% CI 1.5; 6.36) and CA 19\u20139 (HR 2.52, 95% CI 1.37; 4.64) as reference biomarker had a shorter OS. Notably, only the novel marker PRO-C8 was also predictive of PFS (HR 3.26, 95% CI 1.53; 6.95). Associations with survival outcomes remained significant after adjusting for relevant risk factors (CA 19\u20139 and CEA at baseline, age, presence of metastases, weight, height and gender).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The collagen turnover markers PRO-C8, C3M, PRO-C3 and the established biomarker CA 19\u20139 were prognostic for OS in patients with BTC while only PRO-C8 was also predictive for PFS. PRO-C3 showed the best diagnostic performance to discriminate between patients with BTC and controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Trial registration number and date of registration<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>NCT00661830 (NCT number)<\/jats:p>\n                    <jats:p>15 April 2008<\/jats:p>\n                    <jats:p>\n                      <jats:italic>Trial registry<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>The complete registry can found under:<\/jats:p>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/study\/NCT00661830?tab=table#administrative-information\" ext-link-type=\"uri\">https:\/\/clinicaltrials.gov\/study\/NCT00661830?tab=table#administrative-information<\/jats:ext-link>\n                      (last accessed 01\/2025)\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:italic>Principal investigator and study sponsor<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>Markus Moehler, MD<\/jats:p>\n                    <jats:p>Johannes Gutenberg University Mainz<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12876-025-03645-0","type":"journal-article","created":{"date-parts":[[2025,2,4]],"date-time":"2025-02-04T04:18:12Z","timestamp":1738642692000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Collagen turnover biomarkers to predict outcome of patients with biliary cancer"],"prefix":"10.1186","volume":"25","author":[{"given":"Leonard","family":"Kaps","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammed A.","family":"Genc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Moehler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Grabbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rn M.","family":"Schattenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Detlef","family":"Schuppan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasmus Sund","family":"Pedersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten A.","family":"Karsdal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Mildenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annett","family":"Maderer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Willumsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,4]]},"reference":[{"key":"3645_CR1","unstructured":"Kocher HM, Abraham AT, Bhattacharya S. 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The study was conducted in accordance with the Declaration of Helsinki.Ethics Committee at the State Medical Association of Rhineland-Palatinate approved the study to Department of Internal Medicine I, University Medical Centre Mainz, Mainz, Germany on april 2008.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"53"}}