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PMID: 32492896 Published · epublish English Journal Article Review

Biomarkers in Hepatocellular Carcinoma: Diagnosis, Prognosis and Treatment Response Assessment.

Cells ·Vol. 9 ·No. 6 ·2020-00-01

Piñero F, Dirchwolf M, Pessôa MG

Abstract

Hepatocellular carcinoma (HCC) is one of the main cancer-related causes of death worldwide. Thus, there is a constant search for improvement in screening, diagnosis, and treatment strategies to improve the prognosis of this malignancy. The identification of useful biomarkers for surveillance and early HCC diagnosis is still deficient, with available serum biomarkers showing low sensitivity and heterogeneous specificity despite different cut-off points, even when assessed longitudinally, or with a combination of serum biomarkers. In contrast, HCC biomarkers used for prognostic (when associated with clinical outcomes) or predictive purposes (when associated with treatment response) may have an increased clinical role in the near future. Furthermore, some serum biomarkers are already implicated as a treatment selection tool, whether to provide access to certain therapies or to assess clinical benefit after treatment. In the present review we will discuss the clinical utility and foreseen future of HCC biomarkers implicated in surveillance, diagnosis, prognosis, and post-treatment assessment.

Keywords
biological liver cancer markers
MeSH Terms
Animals Biomarkers, Tumor/metabolism Carcinoma, Hepatocellular/diagnosis,metabolism,pathology,therapy Genomics Humans Liver Neoplasms/diagnosis,metabolism,pathology,therapy Neoplasm Staging Prognosis Treatment Outcome
Chemicals
Biomarkers, Tumor
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Piñero Federico ORCID
Hepatology and Liver Transplant Unit, Hospital Universitario Austral, School of Medicine, Austral University, Buenos Aires B1629AHJ, Argentina. | Latin American Liver Research Educational and Awareness Network (LALREAN), Buenos Aires B1629AHJ, Argentina.
Dirchwolf Melisa
Liver Unit, Hospital Privado de Rosario, Rosario 2000, Santa Fe, Argentina.
Pessôa Mário G
Division of Gastroenterology and Hepatology, University of São Paulo School of Medicine, São Paulo 05403-000, Brazil.
References (182)
182 references, click to expand
  1. Randomized controlled trial of screening for hepatocellular carcinoma.
    J Cancer Res Clin Oncol. 2004 Jul;130(7):417-22 PMID: 15042359
  2. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score).
    J Gastroenterol. 2003;38(3):207-15 PMID: 12673442
  3. The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015.
    JAMA Oncol. 2017 Dec 1;3(12):1683-1691 PMID: 28983565
  4. Clinicopathologic features of patients with hepatocellular carcinoma seropositive for alpha-fetoprotein-L3 and seronegative for des-gamma-carboxy prothrombin in comparison with those seropositive for des-gamma-carboxy prothrombin alone.
    J Gastroenterol Hepatol. 2002 Jul;17(7):772-8 PMID: 12121507
  5. Sorafenib in advanced hepatocellular carcinoma.
    N Engl J Med. 2008 Jul 24;359(4):378-90 PMID: 18650514
  6. GALAD Score for Hepatocellular Carcinoma Detection in Comparison with Liver Ultrasound and Proposal of GALADUS Score.
    Cancer Epidemiol Biomarkers Prev. 2019 Mar;28(3):531-538 PMID: 30464023
  7. Plasma microRNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma.
    J Clin Oncol. 2011 Dec 20;29(36):4781-8 PMID: 22105822
  8. Circulating Microbiota-Based Metagenomic Signature for Detection of Hepatocellular Carcinoma.
    Sci Rep. 2019 May 17;9(1):7536 PMID: 31101866
  9. Improved Detection of Hepatocellular Carcinoma by Using a Longitudinal Alpha-Fetoprotein Screening Algorithm.
    Clin Gastroenterol Hepatol. 2016 Mar;14(3):469-475.e2 PMID: 26260109
  10. Prognostic factors affecting survival at recurrence of hepatocellular carcinoma after living-donor liver transplantation: with special reference to neutrophil/lymphocyte ratio.
    Transplantation. 2013 Dec 15;96(11):1008-12 PMID: 24113512
  11. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
    Lancet Oncol. 2019 Feb;20(2):282-296 PMID: 30665869
  12. Molecular therapies and precision medicine for hepatocellular carcinoma.
    Nat Rev Clin Oncol. 2018 Oct;15(10):599-616 PMID: 30061739
  13. A different gut microbiome linked to inflammation found in cirrhotic patients with and without hepatocellular carcinoma.
    Ann Hepatol. 2019 May - Jun;18(3):480-487 PMID: 31023615
  14. Early alpha-fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma.
    Cancer. 2010 Oct 1;116(19):4590-6 PMID: 20572033
  15. Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.
    Ann Oncol. 2018 Oct 1;29(10):2121-2128 PMID: 30165419
  16. Incidence of hepatocellular carcinoma and associated risk factors in hepatitis C-related advanced liver disease.
    Gastroenterology. 2009 Jan;136(1):138-48 PMID: 18848939
  17. Evidence Supporting LI-RADS Major Features for CT- and MR Imaging-based Diagnosis of Hepatocellular Carcinoma: A Systematic Review.
    Radiology. 2018 Jan;286(1):29-48 PMID: 29166245
  18. Triple positive tumor markers for hepatocellular carcinoma are useful predictors of poor survival.
    Ann Surg. 2011 Dec;254(6):984-91 PMID: 21606837
  19. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in american patients.
    Hepatology. 2003 May;37(5):1114-21 PMID: 12717392
  20. Circulating miR-21 serves as a serum biomarker for hepatocellular carcinoma and correlated with distant metastasis.
    Oncotarget. 2017 Jul 4;8(27):44050-44058 PMID: 28477010
  21. A Phase-1b study of tivantinib (ARQ 197) in adult patients with hepatocellular carcinoma and cirrhosis.
    Br J Cancer. 2013 Jan 15;108(1):21-4 PMID: 23287988
  22. Evidence-Based Diagnosis, Staging, and Treatment of Patients With Hepatocellular Carcinoma.
    Gastroenterology. 2016 Apr;150(4):835-53 PMID: 26795574
  23. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria.
    Gut. 2016 Jun;65(6):1035-41 PMID: 25804634
  24. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
    Lancet Oncol. 2009 Jan;10(1):25-34 PMID: 19095497
  25. Serum microRNA-1 and microRNA-122 are prognostic markers in patients with hepatocellular carcinoma.
    Eur J Cancer. 2013 Nov;49(16):3442-9 PMID: 23810247
  26. Lack of reduction in serum alpha-fetoprotein during treatment with direct antiviral agents predicts hepatocellular carcinoma development in a large cohort of patients with hepatitis C virus-related cirrhosis.
    J Viral Hepat. 2018 Dec;25(12):1493-1500 PMID: 30112854
  27. Overexpression of osteopontin is associated with intrahepatic metastasis, early recurrence, and poorer prognosis of surgically resected hepatocellular carcinoma.
    Cancer. 2003 Jul 1;98(1):119-27 PMID: 12833464
  28. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
    Lancet. 2017 Jun 24;389(10088):2492-2502 PMID: 28434648
  29. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma.
    Gut. 2019 Jun;68(6):1014-1023 PMID: 30045880
  30. Lens culinaris agglutinin-reactive alpha-fetoprotein and protein induced by vitamin K absence II are potential indicators of a poor prognosis: a histopathological study of surgically resected hepatocellular carcinoma.
    J Gastroenterol. 2007 Dec;42(12):962-8 PMID: 18085353
  31. Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: Analysis of two phase III studies.
    J Hepatol. 2017 Nov;67(5):999-1008 PMID: 28687477
  32. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
    Lancet Oncol. 2018 Jul;19(7):940-952 PMID: 29875066
  33. Clinical Impact of Genomic Diversity From Early to Advanced Hepatocellular Carcinoma.
    Hepatology. 2020 Jan;71(1):164-182 PMID: 31206197
  34. Lens culinaris agglutinin-reactive fraction of AFP is a useful prognostic biomarker for survival after repeat hepatic resection for HCC.
    J Gastroenterol Hepatol. 2011 Apr;26(4):731-8 PMID: 21155886
  35. The use and interpretation of competing risks regression models.
    Clin Cancer Res. 2012 Apr 15;18(8):2301-8 PMID: 22282466
  36. Utility of Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxy prothrombin, alone or in combination, as biomarkers for hepatocellular carcinoma.
    Clin Gastroenterol Hepatol. 2009 Jan;7(1):104-13 PMID: 18849011
  37. Early α-fetoprotein response as a predictor for clinical outcome after localized concurrent chemoradiotherapy for advanced hepatocellular carcinoma.
    Liver Int. 2011 Mar;31(3):369-76 PMID: 21083802
  38. Diagnostic and therapeutic potential of the gut microbiota in patients with early hepatocellular carcinoma.
    Ther Adv Med Oncol. 2019 May 10;11:1758835919848184 PMID: 31205505
  39. Prediction of recurrence of hepatocellular carcinoma after curative ablation using three tumor markers.
    Hepatology. 2006 Dec;44(6):1518-27 PMID: 17133456
  40. Assessment of treatment efficacy in hepatocellular carcinoma: Response rate, delay in progression or none of them.
    J Hepatol. 2017 Jun;66(6):1114-1117 PMID: 28284917
  41. Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria.
    Gastroenterology. 2012 Oct;143(4):986-94.e3; quiz e14-5 PMID: 22750200
  42. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation.
    Liver Transpl. 2005 Dec;11(12):1505-14 PMID: 16315294
  43. Utility of Liquid Biopsy Analysis in Detection of Hepatocellular Carcinoma, Determination of Prognosis, and Disease Monitoring: A Systematic Review.
    Clin Gastroenterol Hepatol. 2020 Apr 11;: PMID: 32289533
  44. Diagnostic accuracy of tumor markers for hepatocellular carcinoma: a systematic review.
    Hepatol Int. 2008 Mar;2(1):17-30 PMID: 19669276
  45. New serum markers of hepatocellular carcinoma.
    Semin Oncol. 2012 Aug;39(4):434-9 PMID: 22846860
  46. The detection of hepatocellular carcinoma using a prospectively developed and validated model based on serological biomarkers.
    Cancer Epidemiol Biomarkers Prev. 2014 Jan;23(1):144-53 PMID: 24220911
  47. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: results from the randomized phase III BRISK-FL study.
    J Clin Oncol. 2013 Oct 1;31(28):3517-24 PMID: 23980084
  48. Metroticket 2.0 Model for Analysis of Competing Risks of Death After Liver Transplantation for Hepatocellular Carcinoma.
    Gastroenterology. 2018 Jan;154(1):128-139 PMID: 28989060
  49. PIVKA-II is a useful tumor marker for recurrent hepatocellular carcinoma after surgical resection.
    Oncology. 2007;72 Suppl 1:52-7 PMID: 18087182
  50. Biomarkers Associated With Response to Regorafenib in Patients With Hepatocellular Carcinoma.
    Gastroenterology. 2019 May;156(6):1731-1741 PMID: 30738047
  51. Prognosis of hepatocellular carcinoma: the BCLC staging classification.
    Semin Liver Dis. 1999;19(3):329-38 PMID: 10518312
  52. Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma.
    Gastroenterology. 2014 Jun;146(7):1691-700.e3 PMID: 24583061
  53. Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis.
    Aliment Pharmacol Ther. 2009 Jul;30(1):37-47 PMID: 19392863
  54. Combinations of biomarkers and Milan criteria for predicting hepatocellular carcinoma recurrence after liver transplantation.
    Liver Transpl. 2015 May;21(5):599-606 PMID: 25789635
  55. Predictors of survival in patients with advanced hepatocellular carcinoma who permanently discontinued sorafenib.
    Hepatology. 2015 Sep;62(3):784-91 PMID: 25645399
  56. Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation.
    Transplantation. 2009 Feb 27;87(4):531-7 PMID: 19307789
  57. Role of the GALAD and BALAD-2 Serologic Models in Diagnosis of Hepatocellular Carcinoma and Prediction of Survival in Patients.
    Clin Gastroenterol Hepatol. 2016 Jun;14(6):875-886.e6 PMID: 26775025
  58. AFP, AFP-L3, DCP, and GP73 as markers for monitoring treatment response and recurrence and as surrogate markers of clinicopathological variables of HCC.
    J Gastroenterol. 2010 Dec;45(12):1272-82 PMID: 20625772
  59. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma.
    Clin Cancer Res. 2012 Apr 15;18(8):2290-300 PMID: 22374331
  60. A new approach to the use of α-fetoprotein as surveillance test for hepatocellular carcinoma in patients with cirrhosis.
    Br J Cancer. 2015 Jan 6;112(1):69-76 PMID: 25314061
  61. Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial.
    J Clin Oncol. 2020 Jan 20;38(3):193-202 PMID: 31790344
  62. Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma.
    N Engl J Med. 2018 Jul 05;379(1):54-63 PMID: 29972759
  63. Clinical features of hepatocellular carcinoma that occur after sustained virological response to interferon for chronic hepatitis C.
    J Gastroenterol Hepatol. 2006 Jan;21(1 Pt 1):122-8 PMID: 16706823
  64. GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis.
    Clin Gastroenterol Hepatol. 2020 Mar;18(3):728-735.e4 PMID: 31712073
  65. Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial.
    J Hepatol. 2016 May;64(5):1090-1098 PMID: 26809111
  66. Alpha-fetoprotein, des-gamma carboxyprothrombin, and lectin-bound alpha-fetoprotein in early hepatocellular carcinoma.
    Gastroenterology. 2009 Jul;137(1):110-8 PMID: 19362088
  67. Validation of miRNA prognostic power in hepatocellular carcinoma using expression data of independent datasets.
    Sci Rep. 2018 Jun 15;8(1):9227 PMID: 29907753
  68. The clinical course of cirrhosis. Population based studies and the need of personalized medicine.
    J Hepatol. 2014 Feb;60(2):241-2 PMID: 24211741
  69. EASL and AASLD recommendations for the diagnosis of HCC to the test of daily practice.
    Liver Int. 2017 Oct;37(10):1515-1525 PMID: 28346737
  70. Identification of metastasis-related microRNAs in hepatocellular carcinoma.
    Hepatology. 2008 Mar;47(3):897-907 PMID: 18176954
  71. Screening for liver cancer: results of a randomised controlled trial in Qidong, China.
    J Med Screen. 2003;10(4):204-9 PMID: 14738659
  72. Differences in the impact of prognostic factors for hepatocellular carcinoma over time.
    Cancer Sci. 2017 Dec;108(12):2438-2444 PMID: 28945309
  73. Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion for liver transplantation in patients with hepatocellular carcinoma meeting the Milan criteria.
    Liver Transpl. 2014 Aug;20(8):945-51 PMID: 24797281
  74. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update.
    Hepatol Int. 2017 Jul;11(4):317-370 PMID: 28620797
  75. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade.
    J Clin Oncol. 2015 Feb 20;33(6):550-8 PMID: 25512453
  76. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients.
    Cancer. 2002 Mar 15;94(6):1760-9 PMID: 11920539
  77. Alpha-foetoprotein: further evidence to add a biological marker to refine Milan criteria.
    Liver Int. 2016 Nov;36(11):1580-1581 PMID: 27744652
  78. Surveillance for Hepatocellular Carcinoma: Does the Place Where Ultrasound Is Performed Impact Its Effectiveness?
    Dig Dis Sci. 2019 Mar;64(3):718-728 PMID: 30511199
  79. Des-γ-carboxyprothrombin may be a promising biomarker to determine the therapeutic efficacy of sorafenib for hepatocellular carcinoma.
    Dig Dis. 2011;29(3):321-5 PMID: 21829024
  80. Linifanib versus Sorafenib in patients with advanced hepatocellular carcinoma: results of a randomized phase III trial.
    J Clin Oncol. 2015 Jan 10;33(2):172-9 PMID: 25488963
  81. Relationship between baseline hepatic status and outcome, and effect of sorafenib on liver function: SHARP trial subanalyses.
    J Hepatol. 2012 May;56(5):1080-8 PMID: 22245896
  82. Elevated alpha-fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders.
    Clin Liver Dis. 2015 May;19(2):309-23 PMID: 25921665
  83. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
    Lancet. 2018 Mar 24;391(10126):1163-1173 PMID: 29433850
  84. Significance of des-gamma-carboxy prothrombin in selection criteria for living donor liver transplantation for hepatocellular carcinoma.
    Am J Transplant. 2009 Oct;9(10):2362-71 PMID: 19656125
  85. Risk factors for hepatocellular carcinoma may impair the performance of biomarkers: a comparison of AFP, DCP, and AFP-L3.
    Cancer Biomark. 2007;3(2):79-87 PMID: 17522429
  86. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the Scientific Registry of Transplant Recipients database.
    Hepatology. 2009 Mar;49(3):832-8 PMID: 19152426
  87. Epidemiology and surveillance of hepatocellular carcinoma.
    Liver Cancer. 2012 Jun;1(1):2-14 PMID: 24159567
  88. National Experience on Down-Staging of Hepatocellular Carcinoma Before Liver Transplant: Influence of Tumor Burden, Alpha-Fetoprotein, and Wait Time.
    Hepatology. 2020 Mar;71(3):943-954 PMID: 31344273
  89. Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study.
    Lancet Oncol. 2012 Aug;13(8):817-26 PMID: 22738799
  90. Significance of alpha-fetoprotein and des-gamma-carboxy prothrombin in patients with hepatocellular carcinoma undergoing hepatectomy.
    Ann Surg Oncol. 2009 Oct;16(10):2795-804 PMID: 19669841
  91. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.
    Semin Liver Dis. 2010 Feb;30(1):52-60 PMID: 20175033
  92. High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: a prospective study.
    Oncol Rep. 2004 May;11(5):1077-84 PMID: 15069550
  93. A global view of hepatocellular carcinoma: trends, risk, prevention and management.
    Nat Rev Gastroenterol Hepatol. 2019 Oct;16(10):589-604 PMID: 31439937
  94. A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients.
    Hepatology. 1995 Sep;22(3):802-7 PMID: 7544756
  95. LI-RADS (Liver Imaging Reporting and Data System): summary, discussion, and consensus of the LI-RADS Management Working Group and future directions.
    Hepatology. 2015 Mar;61(3):1056-65 PMID: 25041904
  96. Screening and surveillance-principles and practice.
    Br J Radiol. 2018 Oct;91(1090):20180200 PMID: 29589964
  97. Clinical utility of AFP-L3% measurement in North American patients with HCV-related cirrhosis.
    Am J Gastroenterol. 2007 Oct;102(10):2196-205 PMID: 17617202
  98. Validation of a new prognostic staging system for hepatocellular carcinoma: the JIS score compared with the CLIP score.
    Hepatology. 2004 Dec;40(6):1396-405 PMID: 15565571
  99. Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma.
    Gut. 2012 Oct;61(10):1481-7 PMID: 22287594
  100. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.
    N Engl J Med. 2020 May 14;382(20):1894-1905 PMID: 32402160
  101. Alpha-fetoprotein response after locoregional therapy for hepatocellular carcinoma: oncologic marker of radiologic response, progression, and survival.
    J Clin Oncol. 2009 Dec 1;27(34):5734-42 PMID: 19805671
  102. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.
    N Engl J Med. 1996 Mar 14;334(11):693-9 PMID: 8594428
  103. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
    Lancet. 2017 Jan 7;389(10064):56-66 PMID: 27932229
  104. SEARCH: a phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma.
    J Clin Oncol. 2015 Feb 20;33(6):559-66 PMID: 25547503
  105. Clinical advantage of highly sensitive on-chip immunoassay for fucosylated fraction of alpha-fetoprotein in patients with hepatocellular carcinoma.
    Dig Dis Sci. 2010 Dec;55(12):3576-83 PMID: 20407827
  106. Protein induced by vitamin K absence or antagonist II as a prognostic marker in hepatocellular carcinoma. Comparison with alpha-fetoprotein.
    Cancer. 1994 May 15;73(10):2464-71 PMID: 7513601
  107. Serum insulin-like growth factor I evaluation as a useful tool for predicting the risk of developing hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a prospective study.
    Cancer. 2002 Dec 15;95(12):2539-45 PMID: 12467068
  108. Identification of liver transplant candidates with hepatocellular carcinoma and a very low dropout risk: implications for the current organ allocation policy.
    Liver Transpl. 2013 Dec;19(12):1343-53 PMID: 24285611
  109. Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C Trial.
    J Hepatol. 2005 Sep;43(3):434-41 PMID: 16136646
  110. Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis.
    J Hepatol. 2019 Sep;71(3):543-552 PMID: 31176752
  111. Prediction of recurrence of hepatocellular carcinoma after curative hepatectomy using preoperative Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein.
    Hepatol Res. 2012 Sep;42(9):887-94 PMID: 22524419
  112. Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials.
    Br J Cancer. 2019 Aug;121(4):340-343 PMID: 31285588
  113. Prediction of vascular invasion in hepatocellular carcinoma by next-generation des-r-carboxy prothrombin.
    Br J Cancer. 2016 Jan 12;114(1):53-8 PMID: 26679378
  114. Racial disparities in alpha-fetoprotein testing and alpha-fetoprotein status associated with the diagnosis and outcome of hepatocellular carcinoma patients.
    Cancer Med. 2019 Nov;8(15):6614-6623 PMID: 31517445
  115. Surveillance Imaging and Alpha Fetoprotein for Early Detection of Hepatocellular Carcinoma in Patients With Cirrhosis: A Meta-analysis.
    Gastroenterology. 2018 May;154(6):1706-1718.e1 PMID: 29425931
  116. Ultrasonographic surveillance of hepatocellular carcinoma in cirrhosis: a randomized trial comparing 3- and 6-month periodicities.
    Hepatology. 2011 Dec;54(6):1987-97 PMID: 22144108
  117. A comprehensive study of epigenetic alterations in hepatocellular carcinoma identifies potential therapeutic targets.
    J Hepatol. 2019 Jul;71(1):78-90 PMID: 30880225
  118. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics.
    Semin Cancer Biol. 2018 Oct;52(Pt 2):117-124 PMID: 29229461
  119. Time of hepatocellular carcinoma recurrence after liver resection and alpha-fetoprotein are important prognostic factors for salvage liver transplantation.
    Liver Transpl. 2014 Sep;20(9):1057-63 PMID: 24862741
  120. Performance of PIVKA-II for early hepatocellular carcinoma diagnosis and prediction of microvascular invasion.
    J Hepatol. 2015 Apr;62(4):848-54 PMID: 25450201
  121. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.
    Gut. 2019 Jun;68(6):1065-1075 PMID: 30108162
  122. Usefulness of alpha-fetoprotein response in patients treated with sorafenib for advanced hepatocellular carcinoma.
    J Hepatol. 2012 Jul;57(1):101-7 PMID: 22414760
  123. Longitudinal Assessment of Three Serum Biomarkers to Detect Very Early-Stage Hepatocellular Carcinoma.
    Hepatology. 2019 May;69(5):1983-1994 PMID: 30153338
  124. Diagnostic Evaluation of Des-Gamma-Carboxy Prothrombin versus α-Fetoprotein for Hepatitis B Virus-Related Hepatocellular Carcinoma in China: A Large-Scale, Multicentre Study.
    PLoS One. 2016 Apr 12;11(4):e0153227 PMID: 27070780
  125. Complications and competing risks of death in compensated viral cirrhosis (ANRS CO12 CirVir prospective cohort).
    Hepatology. 2015 Sep;62(3):737-50 PMID: 25678021
  126. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population.
    Hepatology. 1995 Aug;22(2):432-8 PMID: 7543434
  127. Prognostic value of α-fetoprotein and des-γ-carboxy prothrombin responses in patients with hepatocellular carcinoma treated with transarterial chemoembolization.
    BMC Cancer. 2013 Jan 03;13:5 PMID: 23282286
  128. Validation of serological models for staging and prognostication of HCC in patients from a Japanese nationwide survey.
    J Gastroenterol. 2017 Oct;52(10):1112-1121 PMID: 28224228
  129. Liver transplantation for hepatocellular carcinoma: evaluation of the alpha-fetoprotein model in a multicenter cohort from Latin America.
    Liver Int. 2016 Nov;36(11):1657-1667 PMID: 27169841
  130. PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy.
    J Hepatol. 2016 Apr;64(4):800-6 PMID: 26678008
  131. AASLD guidelines for the treatment of hepatocellular carcinoma.
    Hepatology. 2018 Jan;67(1):358-380 PMID: 28130846
  132. Circulating miR-148/152 family as potential biomarkers in hepatocellular carcinoma.
    Tumour Biol. 2016 Apr;37(4):4945-53 PMID: 26531720
  133. A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire.
    J Hepatol. 1999 Jul;31(1):133-41 PMID: 10424293
  134. Des-gamma-carboxyprothrombin, alpha-fetoprotein and AFP-L3 in patients with chronic hepatitis, cirrhosis and hepatocellular carcinoma.
    J Gastroenterol Hepatol. 2008 Oct;23(10):1541-8 PMID: 18422961
  135. Clinical utility of highly sensitive Lens culinaris agglutinin-reactive alpha-fetoprotein in hepatocellular carcinoma patients with alpha-fetoprotein <20 ng/mL.
    Cancer Sci. 2011 May;102(5):1025-31 PMID: 21244578
  136. GP73, a resident Golgi glycoprotein, is a novel serum marker for hepatocellular carcinoma.
    J Hepatol. 2005 Dec;43(6):1007-12 PMID: 16137783
  137. Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma.
    Gastroenterology. 2011 May;140(5):1501-12.e2 PMID: 21320499
  138. Detection of Circulating Tumor Cells and Their Implications as a Biomarker for Diagnosis, Prognostication, and Therapeutic Monitoring in Hepatocellular Carcinoma.
    Hepatology. 2020 Feb 4;: PMID: 32017145
  139. Phases of biomarker development for early detection of cancer.
    J Natl Cancer Inst. 2001 Jul 18;93(14):1054-61 PMID: 11459866
  140. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study.
    Lancet Oncol. 2013 Jan;14(1):55-63 PMID: 23182627
  141. Prognostic significance of simultaneous measurement of three tumor markers in patients with hepatocellular carcinoma.
    Clin Gastroenterol Hepatol. 2006 Jan;4(1):111-7 PMID: 16431313
  142. Correlation between Early Tumor Marker Response and Imaging Response in Patients with Advanced Hepatocellular Carcinoma Treated with Lenvatinib.
    Oncology. 2019;97(2):75-81 PMID: 31242488
  143. Phase 2 study of pembrolizumab and circulating biomarkers to predict anticancer response in advanced, unresectable hepatocellular carcinoma.
    Cancer. 2019 Oct 15;125(20):3603-3614 PMID: 31251403
  144. Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial.
    J Hepatol. 2019 Apr;70(4):684-691 PMID: 30529387
  145. Are There Upper Limits in Tumor Burden for Down-Staging of Hepatocellular Carcinoma to Liver Transplant? Analysis of the All-Comers Protocol.
    Hepatology. 2019 Oct;70(4):1185-1196 PMID: 30779440
  146. Identifying patients at higher risk of hepatocellular carcinoma recurrence after liver transplantation in a multicenter cohort study from Argentina.
    Eur J Gastroenterol Hepatol. 2016 Apr;28(4):421-7 PMID: 26684693
  147. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial.
    J Clin Oncol. 2013 Nov 10;31(32):4067-75 PMID: 24081937
  148. Biomarker-based prognosis in hepatocellular carcinoma: validation and extension of the BALAD model.
    Br J Cancer. 2014 Apr 15;110(8):2090-8 PMID: 24691419
  149. Preoperative diagnosis and prediction of hepatocellular carcinoma: Radiomics analysis based on multi-modal ultrasound images.
    BMC Cancer. 2018 Nov 12;18(1):1089 PMID: 30419849
  150. Biology and significance of alpha-fetoprotein in hepatocellular carcinoma.
    Liver Int. 2019 Dec;39(12):2214-2229 PMID: 31436873
  151. Diagnosis and staging of hepatocellular carcinoma (HCC): current guidelines.
    Eur J Radiol. 2018 Apr;101:72-81 PMID: 29571804
  152. Prognostic significance of Lens culinaris agglutinin A-reactive alpha-fetoprotein in small hepatocellular carcinomas.
    Gastroenterology. 1996 Oct;111(4):996-1001 PMID: 8831594
  153. Met as a therapeutic target in HCC: facts and hopes.
    J Hepatol. 2014 Feb;60(2):442-52 PMID: 24045150
  154. The utility of Lens culinaris agglutinin-reactive alpha-fetoprotein in the diagnosis of hepatocellular carcinoma: evaluation in a United States referral population.
    Clin Gastroenterol Hepatol. 2007 Mar;5(3):394-402; quiz 267 PMID: 17368240
  155. Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival.
    J Hepatol. 2010 Aug;53(2):291-7 PMID: 20483497
  156. Staging hepatocellular carcinoma by a novel scoring system (BALAD score) based on serum markers.
    Clin Gastroenterol Hepatol. 2006 Dec;4(12):1528-36 PMID: 17162244
  157. Frequency of elevated hepatocellular carcinoma (HCC) biomarkers in patients with advanced hepatitis C.
    Am J Gastroenterol. 2012 Jan;107(1):64-74 PMID: 21931376
  158. Prognostic significance of glypican-3 in hepatocellular carcinoma: a meta-analysis.
    BMC Cancer. 2014 Feb 18;14:104 PMID: 24548704
  159. Prognostic significance of glypican-3 expression in hepatocellular carcinoma: A meta-analysis.
    Medicine (Baltimore). 2018 Jan;97(4):e9702 PMID: 29369198
  160. Novel Lens culinaris agglutinin-reactive fraction of α-fetoprotein: a biomarker of hepatocellular carcinoma recurrence in patients with low α-fetoprotein concentrations.
    Int J Clin Oncol. 2012 Aug;17(4):373-9 PMID: 21847534
  161. Surveillance for hepatocellular carcinoma.
    Best Pract Res Clin Gastroenterol. 2016 Dec;30(6):1001-1010 PMID: 27938779
  162. An assessment of benefits and harms of hepatocellular carcinoma surveillance in patients with cirrhosis.
    Hepatology. 2017 Apr;65(4):1196-1205 PMID: 27775821
  163. Detection of hepatocellular cancer during screening of 1125 patients with chronic hepatitis virus infection.
    J Chemother. 1997 Apr;9(2):151-2 PMID: 9176768
  164. Preoperative radiomics nomogram for microvascular invasion prediction in hepatocellular carcinoma using contrast-enhanced CT.
    Eur Radiol. 2019 Jul;29(7):3595-3605 PMID: 30770969
  165. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.
    J Hepatol. 2013 Jul;59(1):81-8 PMID: 23466307
  166. Correcting for lead time and length bias in estimating the effect of screen detection on cancer survival.
    Am J Epidemiol. 2008 Jul 1;168(1):98-104 PMID: 18504245
  167. Identification of soluble NH2-terminal fragment of glypican-3 as a serological marker for early-stage hepatocellular carcinoma.
    Cancer Res. 2004 Apr 1;64(7):2418-23 PMID: 15059894
  168. Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size.
    Am J Gastroenterol. 2006 Sep;101(9):2038-43 PMID: 16848811
  169. Circulating Tumor DNA and Hepatocellular Carcinoma.
    Semin Liver Dis. 2019 Nov;39(4):452-462 PMID: 31226727
  170. Response to therapy as a criterion for awarding priority to patients with hepatocellular carcinoma awaiting liver transplantation.
    Ann Surg Oncol. 2010 Sep;17(9):2290-302 PMID: 20217249
  171. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients.
    Aliment Pharmacol Ther. 2014 May;39(10):1180-93 PMID: 24654740
  172. Molecular therapies for HCC: Looking outside the box.
    J Hepatol. 2020 Feb;72(2):342-352 PMID: 31954496
  173. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status.
    J Hepatol. 2001 Apr;34(4):570-5 PMID: 11394657
  174. Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo-controlled study.
    Lancet Oncol. 2018 May;19(5):682-693 PMID: 29625879
  175. A new laboratory-based algorithm to predict development of hepatocellular carcinoma in patients with hepatitis C and cirrhosis.
    Gastroenterology. 2014 May;146(5):1249-55.e1 PMID: 24462733
  176. Disease Progression in Patients With Hepatitis C Virus Infection Treated With Direct-Acting Antiviral Agents.
    Clin Gastroenterol Hepatol. 2020 Feb 28;: PMID: 32113892
  177. Post-ablation des-gamma-carboxy prothrombin level predicts prognosis in hepatitis B-related hepatocellular carcinoma.
    Liver Int. 2016 Apr;36(4):580-7 PMID: 26503910
  178. Diagnosis of Hepatic Nodules in Patients at Risk for Hepatocellular Carcinoma: LI-RADS Probability Versus Certainty.
    Gastroenterology. 2019 Mar;156(4):860-862 PMID: 30776351
  179. Clinical evaluation of lens culinaris agglutinin-reactive alpha-fetoprotein and des-gamma-carboxy prothrombin in histologically proven hepatocellular carcinoma in the United States.
    Dig Dis Sci. 2007 Mar;52(3):776-82 PMID: 17253135
  180. Evaluation methods for pretransplant oncologic markers and their prognostic impacts in patient undergoing living donor liver transplantation for hepatocellular carcinoma.
    Transpl Int. 2014 Apr;27(4):391-8 PMID: 24472068
  181. Radiomics-based classification of hepatocellular carcinoma and hepatic haemangioma on precontrast magnetic resonance images.
    BMC Med Imaging. 2019 Mar 11;19(1):23 PMID: 30866850
  182. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators.
    Hepatology. 1998 Sep;28(3):751-5 PMID: 9731568
Article Info
Journal
Cells
Abbr.
Cells
ISSN
2073-4409
DOI
10.3390/cells9061370
Published
2020-00-01
Epub
2020-00-01
Language
English
Region
Switzerland
NLM ID
101600052
PMCID
PMC7349517
Subset
IM
External Links
PubMed source DOI: 10.3390/cells9061370 PMC Full Text View journal details
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