PMID- 34796691 OWN - NLM STAT- MEDLINE DCOM- 20220502 LR - 20220502 IS - 2471-254X (Electronic) IS - 2471-254X (Linking) VI - 6 IP - 4 DP - 2022 Apr TI - Multimarker Panels for Detection of Early Stage Hepatocellular Carcinoma: A Prospective, Multicenter, Case-Control Study. PG - 679-691 LID - 10.1002/hep4.1847 [doi] AB - Hepatocellular carcinoma (HCC), the sixth most common cancer worldwide, has an incidence rate equal to mortality. Over 80% of HCC cases occur within a high-risk population, mainly patients with both cirrhosis and chronic hepatitis B or C. With a 5-year survival rate ranging from <16% for advanced HCC to >90% for early stage HCC, there is a high medical need for the early detection of HCC. In this study, we systematically evaluated biomarkers mentioned in international guidelines and peer-reviewed literature for HCC surveillance and diagnosis with the aim of identifying combinations that display high sensitivity and specificity for early stage HCC. Fifty biomarkers were measured in the first sample panel, panel A (n = 110), and subjected to univariate analysis. Of these, 35 biomarkers (38 assays) from panel A and an additional 13 biomarkers from the literature were prioritized for subsequent multivariate evaluation with lasso regression and exhaustive search of two- to four-biomarker combinations (panel B). Panel B included 1,081 samples from patients with HCC (n = 308) or with chronic liver diseases (n = 740). Among all patients, 61.0% had hepatitis B, 32.9% had hepatitis C, and 60.5% had cirrhosis; 40.6% of patients with HCC had early stage cancer. Protein induced by vitamin K absence-II (PIVKA-II; also known as des-gamma-carboxy prothrombin [DCP]) and alpha-fetoprotein (AFP) demonstrated the best clinical performance, both individually and in combination, and the addition of a third biomarker (Lens culinaris agglutinin-reactive fraction of AFP [AFP-L3], cartilage oligomeric matrix protein [COMP], insulin-like growth factor-binding protein 3 [IGFBP3], or matrix metalloproteinase 3 [MMP3]) further increased sensitivity for the detection of both early stage and all-stage HCC. The addition of age and sex to the three-biomarker panel resulted in an improved diagnostic performance. Conclusion: The combination of AFP and PIVKA-II, with either IGFBP3, COMP or MMP3, plus age and sex, demonstrated the best performance for the detection of early- and all-stage HCC. These novel panels performed similar to that of the GALAD score (sex [gender], age, plus serum levels of AFP, AFP-L3 and DCP [PIVKA-II]), a promising screening tool developed for HCC detection. CI - (c) 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. FAU - Piratvisuth, Teerha AU - Piratvisuth T AD - NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Hat Yai, Thailand. FAU - Tanwandee, Tawesak AU - Tanwandee T AD - Division of Gastroenterology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand. FAU - Thongsawat, Satawat AU - Thongsawat S AD - Department of Internal Medicine, Maharaj Nakorn Chiang Mai Hospital, Chiang Mai University, Chiang Mai, Thailand. FAU - Sukeepaisarnjaroen, Wattana AU - Sukeepaisarnjaroen W AD - Faculty of Medicine, Srinagarind Hospital, Khon Kaen University, Khon Kaen, Thailand. FAU - Esteban, Juan Ignacio AU - Esteban JI AD - Liver Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain. AD - Centro de Investigacion Biomedica en red de Enfermedades Hepaticas y Digestivas, Insituto de Salud Carlos III, Madrid, Spain. FAU - Bes, Marta AU - Bes M AD - Centro de Investigacion Biomedica en red de Enfermedades Hepaticas y Digestivas, Insituto de Salud Carlos III, Madrid, Spain. AD - Transfusion Safety Laboratory, Banc de Sang i Teixits, Barcelona, Spain. FAU - Kohler, Bruno AU - Kohler B AD - Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany. AD - Liver Cancer Center Heidelberg, Heidelberg, Germany. FAU - He, Ying AU - He Y AD - Roche Diagnostics GmbH, Penzberg, Germany. FAU - Swiatek-de Lange, Magdalena AU - Swiatek-de Lange M AD - Roche Diagnostics GmbH, Penzberg, Germany. FAU - Morgenstern, David AU - Morgenstern D AD - Roche Diagnostics Operations, Indianapolis, IN, USA. FAU - Chan, Henry Lik-Yuen AU - Chan HL AD - Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong. LA - eng PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20211119 PL - United States TA - Hepatol Commun JT - Hepatology communications JID - 101695860 RN - 0 (Biomarkers) RN - 0 (Protein Precursors) RN - 0 (alpha-Fetoproteins) RN - 9001-26-7 (Prothrombin) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) SB - IM MH - Biomarkers MH - *Carcinoma, Hepatocellular/diagnosis MH - Case-Control Studies MH - Humans MH - Liver Cirrhosis MH - *Liver Neoplasms/diagnosis MH - Matrix Metalloproteinase 3 MH - Prospective Studies MH - Protein Precursors MH - Prothrombin/metabolism MH - alpha-Fetoproteins/analysis PMC - PMC8948551 EDAT- 2021/11/20 06:00 MHDA- 2022/05/03 06:00 PMCR- 2021/11/19 CRDT- 2021/11/19 07:21 PHST- 2021/08/27 00:00 [revised] PHST- 2021/04/21 00:00 [received] PHST- 2021/09/28 00:00 [accepted] PHST- 2021/11/20 06:00 [pubmed] PHST- 2022/05/03 06:00 [medline] PHST- 2021/11/19 07:21 [entrez] PHST- 2021/11/19 00:00 [pmc-release] AID - HEP41847 [pii] AID - 10.1002/hep4.1847 [doi] PST - ppublish SO - Hepatol Commun. 2022 Apr;6(4):679-691. doi: 10.1002/hep4.1847. Epub 2021 Nov 19.