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Prevention Strategies for Hepatocellular Carcinoma

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Hepatocellular Carcinoma

Part of the book series: Molecular and Translational Medicine ((MOLEMED))

Abstract

Hepatocellular carcinoma (HCC) occurs primarily in patients who have sustained years of chronic liver injury. Unfortunately, most patients are diagnosed with advanced disease when potentially curative surgical resection or liver transplant is no longer a therapeutic option and medical treatments for HCC are largely ineffective. Consequently, the average 5-year survival for HCC is less than 15%. The global burden of HCC is expected to increase in the coming decades as a result of an increasing population and the global rise of obesity and fatty liver disease as emerging HCC etiologies. Given this context, prevention efforts for HCC are urgently needed to reduce the incidence of this deadly disease. Primary prevention involves avoidance of exposure to risk factors for chronic liver disease, including toxins such as ethanol and certain chemicals, viral hepatitis through vaccination, and overweight or metabolic syndromes via lifestyle modification. National neonatal hepatitis B vaccination and reduced aflatoxin exposure have successfully reduced HCC incidence in traditionally endemic regions such as East Asia. Secondary prevention encompasses mitigation of risk factors in patients with baseline chronic liver disease. Multiple dietary and pharmaceutical agents have been suggested to have preventative potential in retrospective analyses, though few clinical trials have been performed. Finally, tertiary prevention represents interventions to reduce the risk of de novo HCC recurrence after curative resection of primary HCC tumor. In this chapter, we provide a comprehensive overview of chemopreventive strategies and discuss future directions.

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References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer. 2001;94(2):153–6.

    Article  CAS  PubMed  Google Scholar 

  2. El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;365(12):1118–27. https://doi.org/10.1056/NEJMra1001683.

    Article  CAS  PubMed  Google Scholar 

  3. Goldberg DS, Valderrama A, Kamalakar R, Sansgiry SS, Babajanyan S, Lewis JD. Hepatocellular carcinoma surveillance among cirrhotic patients with commercial health insurance. J Clin Gastroenterol. 2016;50(3):258–65. https://doi.org/10.1097/MCG.0000000000000411.

    Article  CAS  PubMed  Google Scholar 

  4. Palmer LB, Kappelman MD, Sandler RS, Hayashi PH. Surveillance for hepatocellular carcinoma in a Medicaid cirrhotic population. J Clin Gastroenterol. 2013;47(8):713–8. https://doi.org/10.1097/MCG.0b013e318286fd97.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Davila JA, Henderson L, Kramer JR, Kanwal F, Richardson PA, Duan Z, et al. Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus-infected veterans in the United States. Ann Intern Med. 2011;154(2):85–93. https://doi.org/10.7326/0003-4819-154-2-201101180-00006.

    Article  PubMed  Google Scholar 

  6. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108. https://doi.org/10.3322/caac.21262.

    Article  PubMed  Google Scholar 

  7. Choo SP, Tan WL, Goh BK, Tai WM, Zhu AX. Comparison of hepatocellular carcinoma in Eastern versus Western populations. Cancer. 2016;122(22):3430–46. https://doi.org/10.1002/cncr.30237.

    Article  PubMed  Google Scholar 

  8. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol. 2018;68(3):526–49. https://doi.org/10.1016/j.jhep.2017.09.016.

    Article  PubMed  Google Scholar 

  9. Hoshida Y, Fuchs BC, Tanabe KK. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges. Curr Cancer Drug Targets. 2012;12(9):1129–59.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Luo Z, Li L, Ruan B. Impact of the implementation of a vaccination strategy on hepatitis B virus infections in China over a 20-year period. Int J Infect Dis. 2012;16(2):e82–8. https://doi.org/10.1016/j.ijid.2011.10.009.

    Article  PubMed  Google Scholar 

  11. Magnussen A, Parsi MA. Aflatoxins, hepatocellular carcinoma and public health. World J Gastroenterol. 2013;19(10):1508–12. https://doi.org/10.3748/wjg.v19.i10.1508.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Perumpail BJ, Khan MA, Yoo ER, Cholankeril G, Kim D, Ahmed A. Clinical epidemiology and disease burden of nonalcoholic fatty liver disease. World J Gastroenterol. 2017;23(47):8263–76. https://doi.org/10.3748/wjg.v23.i47.8263.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Kim NG, Nguyen PP, Dang H, Kumari R, Garcia G, Esquivel CO, et al. Temporal trends in disease presentation and survival of patients with hepatocellular carcinoma: a real-world experience from 1998 to 2015. Cancer. 2018;124(12):2588–98. https://doi.org/10.1002/cncr.31373.

    Article  PubMed  Google Scholar 

  14. Traussnigg S, Kienbacher C, Halilbasic E, Rechling C, Kazemi-Shirazi L, Hofer H, et al. Challenges and Management of Liver Cirrhosis: practical issues in the therapy of patients with cirrhosis due to NAFLD and NASH. Dig Dis. 2015;33(4):598–607. https://doi.org/10.1159/000375353.

    Article  PubMed  Google Scholar 

  15. Perricone G, Duvoux C, Berenguer M, Cortesi PA, Vinaixa C, Facchetti R, et al. Delisting HCV infected liver transplant candidates who improved after viral eradication: outcome 2 years after delisting. Liver Int. 2018;38(12):2170–7. https://doi.org/10.1111/liv.13878.

    Article  CAS  PubMed  Google Scholar 

  16. Simonetti RG, Camma C, Fiorello F, Politi F, D’Amico G, Pagliaro L. Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci. 1991;36(7):962–72.

    Article  CAS  PubMed  Google Scholar 

  17. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 2004;127(5 Suppl 1):S35–50.

    Article  PubMed  Google Scholar 

  18. Haukeland JW, Lorgen I, Schreiner LT, Frigstad SO, Brandsaeter B, Bjoro K, et al. Incidence rates and causes of cirrhosis in a Norwegian population. Scand J Gastroenterol. 2007;42(12):1501–8. https://doi.org/10.1080/00365520701478014.

    Article  PubMed  Google Scholar 

  19. Ding J, Wang H. Multiple interactive factors in hepatocarcinogenesis. Cancer Lett. 2014;346(1):17–23. https://doi.org/10.1016/j.canlet.2013.12.024.

    Article  CAS  PubMed  Google Scholar 

  20. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4):529–38. https://doi.org/10.1016/j.jhep.2006.05.013.

    Article  PubMed  Google Scholar 

  21. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340(10):745–50. https://doi.org/10.1056/NEJM199903113401001.

    Article  CAS  PubMed  Google Scholar 

  22. Tsai WL, Chung RT. Viral hepatocarcinogenesis. Oncogene. 2010;29(16):2309–24. https://doi.org/10.1038/onc.2010.36.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Branda M, Wands JR. Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma. Hepatology. 2006;43(5):891–902. https://doi.org/10.1002/hep.21196.

    Article  CAS  PubMed  Google Scholar 

  24. Hoshida Y, Fuchs BC, Bardeesy N, Baumert TF, Chung RT. Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma. J Hepatol. 2014;61(1 Suppl):S79–90. https://doi.org/10.1016/j.jhep.2014.07.010.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27(9):1485–91. https://doi.org/10.1200/JCO.2008.20.7753.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Inhibition of hepatocarcinogenesis by interferon therapy. Ann Intern Med. 1999;131(3):174–81.

    Article  CAS  PubMed  Google Scholar 

  27. Ishiguro S, Inoue M, Tanaka Y, Mizokami M, Iwasaki M, Tsugane S, et al. Impact of viral load of hepatitis C on the incidence of hepatocellular carcinoma: a population-based cohort study (JPHC Study). Cancer Lett. 2011;300(2):173–9. https://doi.org/10.1016/j.canlet.2010.10.002.

    Article  CAS  PubMed  Google Scholar 

  28. Lee MH, Yang HI, Lu SN, Jen CL, Yeh SH, Liu CJ, et al. Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study. J Clin Oncol. 2010;28(30):4587–93. https://doi.org/10.1200/JCO.2010.29.1500.

    Article  PubMed  Google Scholar 

  29. Gravitz L. Introduction: a smouldering public-health crisis. Nature. 2011;474(7350):S2–4. https://doi.org/10.1038/474S2a.

    Article  CAS  PubMed  Google Scholar 

  30. Smith BD, Morgan RL, Beckett GA, Falck-Ytter Y, Holtzman D, Teo CG, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012;61(RR-4):1–32.

    PubMed  Google Scholar 

  31. Alter MJ, Hadler SC, Judson FN, Mares A, Alexander WJ, Hu PY, et al. Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus infection. JAMA. 1990;264(17):2231–5.

    Article  CAS  PubMed  Google Scholar 

  32. Rein DB, Wittenborn JS, Weinbaum CM, Sabin M, Smith BD, Lesesne SB. Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States. Dig Liver Dis. 2011;43(1):66–72. https://doi.org/10.1016/j.dld.2010.05.006.

    Article  PubMed  Google Scholar 

  33. Ray RB, Steele R, Meyer K, Ray R. Transcriptional repression of p53 promoter by hepatitis C virus core protein. J Biol Chem. 1997;272(17):10983–6.

    Article  CAS  PubMed  Google Scholar 

  34. Cho J, Baek W, Yang S, Chang J, Sung YC, Suh M. HCV core protein modulates Rb pathway through pRb down-regulation and E2F-1 up-regulation. Biochim Biophys Acta. 2001;1538(1):59–66.

    Article  CAS  PubMed  Google Scholar 

  35. Bandiera S, Billie Bian C, Hoshida Y, Baumert TF, Zeisel MB. Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma. Curr Opin Virol. 2016;20:99–105. https://doi.org/10.1016/j.coviro.2016.09.010.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Irshad M, Dhar I. Hepatitis C virus core protein: an update on its molecular biology, cellular functions and clinical implications. Med Princ Pract. 2006;15(6):405–16. https://doi.org/10.1159/000095485.

    Article  CAS  PubMed  Google Scholar 

  37. Lerat H, Higgs M, Pawlotsky JM. Animal models in the study of hepatitis C virus-associated liver pathologies. Expert Rev Gastroenterol Hepatol. 2011;5(3):341–52. https://doi.org/10.1586/egh.11.14.

    Article  PubMed  Google Scholar 

  38. Hara Y, Yanatori I, Ikeda M, Kiyokage E, Nishina S, Tomiyama Y, et al. Hepatitis C virus core protein suppresses mitophagy by interacting with parkin in the context of mitochondrial depolarization. Am J Pathol. 2014;184(11):3026–39. https://doi.org/10.1016/j.ajpath.2014.07.024.

    Article  CAS  PubMed  Google Scholar 

  39. Bruno S, Shiffman ML, Roberts SK, Gane EJ, Messinger D, Hadziyannis SJ, et al. Efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis. Hepatology. 2010;51(2):388–97. https://doi.org/10.1002/hep.23340.

    Article  CAS  PubMed  Google Scholar 

  40. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1207–17. https://doi.org/10.1056/NEJMoa1009482.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405–16. https://doi.org/10.1056/NEJMoa1012912.

    Article  CAS  PubMed  Google Scholar 

  42. Manns M, Marcellin P, Poordad F, de Araujo ES, Buti M, Horsmans Y, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2014;384(9941):414–26. https://doi.org/10.1016/S0140-6736(14)60538-9.

    Article  CAS  PubMed  Google Scholar 

  43. Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368(20):1878–87. https://doi.org/10.1056/NEJMoa1214853.

    Article  CAS  PubMed  Google Scholar 

  44. Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014;370(20):1879–88. https://doi.org/10.1056/NEJMoa1402355.

    Article  CAS  PubMed  Google Scholar 

  45. Lawitz E, Sulkowski MS, Ghalib R, Rodriguez-Torres M, Younossi ZM, Corregidor A, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet. 2014;384(9956):1756–65. https://doi.org/10.1016/S0140-6736(14)61036-9.

    Article  CAS  PubMed  Google Scholar 

  46. Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D, et al. Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 2014;370(17):1594–603. https://doi.org/10.1056/NEJMoa1315722.

    Article  CAS  PubMed  Google Scholar 

  47. Puoti M, Foster GR, Wang S, Mutimer D, Gane E, Moreno C, et al. High SVR12 with 8-week and 12-week glecaprevir/pibrentasvir therapy: an integrated analysis of HCV genotype 1-6 patients without cirrhosis. J Hepatol. 2018;69(2):293–300. https://doi.org/10.1016/j.jhep.2018.03.007.

    Article  CAS  PubMed  Google Scholar 

  48. Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour H Jr, et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386(10003):1537–45. https://doi.org/10.1016/s0140-6736(15)00349-9.

    Article  CAS  PubMed  Google Scholar 

  49. Hezode C, Asselah T, Reddy KR, Hassanein T, Berenguer M, Fleischer-Stepniewska K, et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. Lancet. 2015;385(9986):2502–9. https://doi.org/10.1016/s0140-6736(15)60159-3.

    Article  CAS  PubMed  Google Scholar 

  50. Forns X, Lawitz E, Zeuzem S, Gane E, Bronowicki JP, Andreone P, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology. 2014;146(7):1669–79.e3. https://doi.org/10.1053/j.gastro.2014.02.051.

    Article  CAS  PubMed  Google Scholar 

  51. Jacobson IM, Lawitz E, Gane EJ, Willems BE, Ruane PJ, Nahass RG, et al. Efficacy of 8 weeks of sofosbuvir, velpatasvir, and voxilaprevir in patients with chronic HCV infection: 2 phase 3 randomized trials. Gastroenterology. 2017;153(1):113–22. https://doi.org/10.1053/j.gastro.2017.03.047.

    Article  CAS  PubMed  Google Scholar 

  52. Izumi N. Efficacy of daclatasvir in hepatitis C virus. Expert Rev Anti-Infect Ther. 2014;12(9):1025–31. https://doi.org/10.1586/14787210.2014.942282.

    Article  CAS  PubMed  Google Scholar 

  53. Toyoda H, Atsukawa M, Takaguchi K, Senoh T, Michitaka K, Hiraoka A, et al. Real-world virological efficacy and safety of elbasvir and grazoprevir in patients with chronic hepatitis C virus genotype 1 infection in Japan. J Gastroenterol. 2018;53(12):1276–84. https://doi.org/10.1007/s00535-018-1473-z.

    Article  CAS  PubMed  Google Scholar 

  54. Bourliere M, Bronowicki JP, de Ledinghen V, Hezode C, Zoulim F, Mathurin P, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis. 2015;15(4):397–404. https://doi.org/10.1016/s1473-3099(15)70050-2.

    Article  CAS  PubMed  Google Scholar 

  55. Ahmed H, Abushouk AI, Menshawy A, Mohamed A, Negida A, Loutfy SA, et al. Safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin for treatment of hepatitis C virus genotype 1: a systematic review and meta-analysis. Clin Drug Investig. 2017;37(11):1009–23. https://doi.org/10.1007/s40261-017-0565-5.

    Article  PubMed  Google Scholar 

  56. Chayama K, Suzuki F, Karino Y, Kawakami Y, Sato K, Atarashi T, et al. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis. J Gastroenterol. 2018;53(4):557–65. https://doi.org/10.1007/s00535-017-1391-5.

    Article  PubMed  Google Scholar 

  57. Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373(27):2599–607. https://doi.org/10.1056/NEJMoa1512610.

    Article  CAS  PubMed  Google Scholar 

  58. Foster GR, Afdhal N, Roberts SK, Brau N, Gane EJ, Pianko S, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med. 2015;373(27):2608–17. https://doi.org/10.1056/NEJMoa1512612.

    Article  CAS  PubMed  Google Scholar 

  59. Klibanov OM, Gale SE, Santevecchi B. Ombitasvir/paritaprevir/ritonavir and dasabuvir tablets for hepatitis C virus genotype 1 infection. Ann Pharmacother. 2015;49(5):566–81. https://doi.org/10.1177/1060028015570729.

    Article  CAS  PubMed  Google Scholar 

  60. McCombs J, Matsuda T, Tonnu-Mihara I, Saab S, Hines P, L’Italien G, et al. The risk of long-term morbidity and mortality in patients with chronic hepatitis C: results from an analysis of data from a Department of Veterans Affairs Clinical Registry. JAMA Intern Med. 2014;174(2):204–12. https://doi.org/10.1001/jamainternmed.2013.12505.

    Article  PubMed  Google Scholar 

  61. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158(5 Pt 1):329–37. https://doi.org/10.7326/0003-4819-158-5-201303050-00005.

    Article  PubMed  Google Scholar 

  62. Ioannou GN, Green PK, Berry K. HCV eradication induced by direct-acting antiviral agents reduces the risk of hepatocellular carcinoma. J Hepatol. 2017; https://doi.org/10.1016/j.jhep.2017.08.030.

  63. Li DK, Chung RT. Impact of hepatitis C virus eradication on hepatocellular carcinogenesis. Cancer. 2015;121(17):2874–82. https://doi.org/10.1002/cncr.29528.

    Article  PubMed  Google Scholar 

  64. Hepatitis B. World Health Organization. 2017. http://www.who.int/news-room/fact-sheets/detail/hepatitis-b.

  65. Franco E, Bagnato B, Marino MG, Meleleo C, Serino L, Zaratti L. Hepatitis B: epidemiology and prevention in developing countries. World J Hepatol. 2012;4(3):74–80. https://doi.org/10.4254/wjh.v4.i3.74.

    Article  PubMed Central  PubMed  Google Scholar 

  66. McMahon JB. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49(S5):S45–55. https://doi.org/10.1002/hep.22898.

    Article  CAS  PubMed  Google Scholar 

  67. Chih-Lin L, Jia-Horng K. Risk stratification for hepatitis B virus related hepatocellular carcinoma. J Gastroenterol Hepatol. 2013;28(1):10–7. https://doi.org/10.1111/jgh.12010.

    Article  CAS  Google Scholar 

  68. Paganelli M, Stephenne X, Sokal EM. Chronic hepatitis B in children and adolescents. J Hepatol. 2012;57(4):885–96. https://doi.org/10.1016/j.jhep.2012.03.036.

    Article  PubMed  Google Scholar 

  69. Mittal S, El-Serag HB. Epidemiology of HCC: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–6. https://doi.org/10.1097/MCG.0b013e3182872f29.

    Article  PubMed Central  PubMed  Google Scholar 

  70. Do AL, Wong CR, Nguyen LH, Nguyen VG, Trinh H, Nguyen MH. Hepatocellular carcinoma incidence in noncirrhotic patients with chronic hepatitis B and patients with cirrhosis of all etiologies. J Clin Gastroenterol. 2014;48(7):644–9. https://doi.org/10.1097/mcg.0000000000000015.

    Article  PubMed  Google Scholar 

  71. Sung W-K, Zheng H, Li S, Chen R, Liu X, Li Y, et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet. 2012;44:765. https://doi.org/10.1038/ng.2295; https://www.nature.com/articles/ng.2295#supplementary-information.

    Article  CAS  PubMed  Google Scholar 

  72. Jiang S, Yang Z, Li W, Li X, Wang Y, Zhang J, et al. Re-evaluation of the carcinogenic significance of hepatitis B virus integration in hepatocarcinogenesis. PLoS One. 2012;7(9):e40363. https://doi.org/10.1371/journal.pone.0040363.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Seeger C, Mason WS. Molecular biology of hepatitis B virus infection. Virology. 2015;479–480:672–86. https://doi.org/10.1016/j.virol.2015.02.031.

    Article  CAS  PubMed  Google Scholar 

  74. Ganem D, Prince AM. Hepatitis B virus infection—natural history and clinical consequences. N Engl J Med. 2004;350(11):1118–29. https://doi.org/10.1056/NEJMra031087.

    Article  CAS  PubMed  Google Scholar 

  75. Tian Y, Xiao X, Gong X, Peng F, Xu Y, Jiang Y, et al. HBx promotes cell proliferation by disturbing the cross-talk between miR-181a and PTEN. Sci Rep. 2017;7:40089. https://doi.org/10.1038/srep40089.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Dan Y, Zhang Y, Cheng L, Ma J, Xi Y, Yang L, et al. Hepatitis B virus X protein (HBx)-induced abnormalities of nucleic acid metabolism revealed by 1H-NMR-based metabonomics. Sci Rep. 2016;6:24430. https://doi.org/10.1038/srep24430.

    Article  CAS  Google Scholar 

  77. Muroyama R, Kato N, Yoshida H, Otsuka M, Moriyama M, Wang Y, et al. Nucleotide change of codon 38 in the X gene of hepatitis B virus genotype C is associated with an increased risk of hepatocellular carcinoma. J Hepatol. 2006;45(6):805–12. https://doi.org/10.1016/j.jhep.2006.07.025.

    Article  CAS  PubMed  Google Scholar 

  78. Ringelhan M, O’Connor T, Protzer U, Heikenwalder M. The direct and indirect roles of HBV in liver cancer: prospective markers for HCC screening and potential therapeutic targets. J Pathol. 2015;235(2):355–67. https://doi.org/10.1002/path.4434.

    Article  CAS  PubMed  Google Scholar 

  79. Schillie S, Vellozzi C, Reingold A, Harris A, Haber P, Ward JW, et al. Prevention of hepatitis B virus infection in the United States: recommendations of the advisory committee on immunization practices. MMWR Recomm Rep. 2018;67(1):1–31. https://doi.org/10.15585/mmwr.rr6701a1.

    Article  PubMed Central  PubMed  Google Scholar 

  80. Nayagam S, Thursz M, Sicuri E, Conteh L, Wiktor S, Low-Beer D, et al. Requirements for global elimination of hepatitis B: a modelling study. Lancet Infect Dis. 2016;16(12):1399–408. https://doi.org/10.1016/s1473-3099(16)30204-3.

    Article  PubMed  Google Scholar 

  81. Chang M-H, Chen C-J, Lai M-S, Hsu H-M, Wu T-C, Kong M-S, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med. 1997;336(26):1855–9. https://doi.org/10.1056/nejm199706263362602.

    Article  CAS  PubMed  Google Scholar 

  82. Nelson NP, Easterbrook PJ, McMahon BJ. Epidemiology of hepatitis B virus infection and impact of vaccination on disease. Clin Liver Dis. 2016;20(4):607–28. https://doi.org/10.1016/j.cld.2016.06.006.

    Article  PubMed Central  PubMed  Google Scholar 

  83. Childs L, Roesel S, Tohme RA. Status and progress of hepatitis B control through vaccination in the South-East Asia region, 1992-2015. Vaccine. 2018;36(1):6–14. https://doi.org/10.1016/j.vaccine.2017.11.027.

    Article  PubMed  Google Scholar 

  84. European Association for the Study of the Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167–85. https://doi.org/10.1016/j.jhep.2012.02.010.

    Article  Google Scholar 

  85. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261–83. https://doi.org/10.1002/hep.28156.

    Article  PubMed  Google Scholar 

  86. Zhang Y-Q, Guo J-S. Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol: WJG. 2015;21(13):3860–6. https://doi.org/10.3748/wjg.v21.i13.3860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295(1):65–73. https://doi.org/10.1001/jama.295.1.65.

    Article  CAS  PubMed  Google Scholar 

  88. Mommeja-Marin H, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a marker of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology. 2003;37(6):1309–19. https://doi.org/10.1053/jhep.2003.50208.

    Article  PubMed  Google Scholar 

  89. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology. 2009;49(5):1503–14. https://doi.org/10.1002/hep.22841.

    Article  CAS  PubMed  Google Scholar 

  90. Woo G, Tomlinson G, Nishikawa Y, Kowgier M, Sherman M, Wong DKH, et al. Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses. Gastroenterology. 2010;139(4):1218–29.e5. https://doi.org/10.1053/j.gastro.2010.06.042.

    Article  CAS  PubMed  Google Scholar 

  91. Wang Y-C, Yang S-S, Su C-W, Wang Y-J, Lee K-C, Huo T-I, et al. Predictors of response to pegylated interferon in chronic hepatitis B: a real-world hospital-based analysis. Sci Rep. 2016;6:29605. https://doi.org/10.1038/srep29605; https://www.nature.com/articles/srep29605#supplementary-information.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Fung J, Lai C-L, Seto W-K, Yuen M-F. Nucleoside/nucleotide analogues in the treatment of chronic hepatitis B. J Antimicrob Chemother. 2011;66(12):2715–25. https://doi.org/10.1093/jac/dkr388.

    Article  CAS  PubMed  Google Scholar 

  93. Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468–75. https://doi.org/10.1016/S0140-6736(12)61425-1.

    Article  CAS  PubMed  Google Scholar 

  94. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52(3):886–93. https://doi.org/10.1002/hep.23785.

    Article  CAS  PubMed  Google Scholar 

  95. Colonno RJ, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF, et al. Entecavir resistance is rare in nucleoside naive patients with hepatitis B. Hepatology. 2006;44(6):1656–65. https://doi.org/10.1002/hep.21422.

    Article  CAS  PubMed  Google Scholar 

  96. Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, Sezaki H, et al. Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology. 2013;58(1):98–107. https://doi.org/10.1002/hep.26180.

    Article  CAS  PubMed  Google Scholar 

  97. WHO. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. WHO Guidelines Approved by the Guidelines Review Committee. Geneva: WHO; 2015.

    Google Scholar 

  98. Arends P, Sonneveld MJ, Zoutendijk R, Carey I, Brown A, Fasano M, et al. Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: limited role for risk scores in Caucasians. Gut. 2015;64(8):1289–95. https://doi.org/10.1136/gutjnl-2014-307023.

    Article  CAS  PubMed  Google Scholar 

  99. Spearman CW, Afihene M, Ally R, Apica B, Awuku Y, Cunha L, et al. Hepatitis B in sub-Saharan Africa: strategies to achieve the 2030 elimination targets. Lancet Gastroenterol Hepatol. 2017;2(12):900–9. https://doi.org/10.1016/S2468-1253(17)30295-9.

    Article  PubMed  Google Scholar 

  100. Trepo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014;384(9959):2053–63. https://doi.org/10.1016/S0140-6736(14)60220-8.

    Article  CAS  PubMed  Google Scholar 

  101. Zoulim F, Durantel D. Antiviral therapies and prospects for a cure of chronic hepatitis B. Cold Spring Harb Perspect Med. 2015;5(4):pii: a021501. https://doi.org/10.1101/cshperspect.a021501.

    Article  CAS  Google Scholar 

  102. Rapti I, Hadziyannis S. Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues. World J Hepatol. 2015;7(8):1064–73. https://doi.org/10.4254/wjh.v7.i8.1064.

    Article  PubMed Central  PubMed  Google Scholar 

  103. Study of ARB-001467 in subjects with chronic HBV infection receiving nucleos(t)ide analogue therapy. https://ClinicalTrials.gov/show/NCT02631096.

  104. Study of ARO-HBV in normal adult volunteers and patients with hepatitis B virus (HBV). https://ClinicalTrials.gov/show/NCT03365947.

  105. Blank A, Markert C, Hohmann N, Carls A, Mikus G, Lehr T, et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol. 2016;65(3):483–9. https://doi.org/10.1016/j.jhep.2016.04.013.

    Article  CAS  PubMed  Google Scholar 

  106. A study of treatment with RO6864018 in virologically suppressed participants with chronic hepatitis B virus (HBV) infection. https://ClinicalTrials.gov/show/NCT02391805.

  107. A study evaluating the safety, pharmacokinetics, and pharmacodynamics of RO6864018 in male, healthy, Asian participants. https://ClinicalTrials.gov/show/NCT02015715.

  108. A study evaluating the safety, pharmacokinetics, and antiviral efficacy of SB 9200 in subjects infected with chronic HBV. https://ClinicalTrials.gov/show/NCT02751996.

  109. Dose-ranging study to assess the safety, PK and initial antiviral efficacy of NVR 3–778 in chronic HBV patients. https://ClinicalTrials.gov/show/NCT02401737.

  110. An efficacy, safety, and pharmacokinetics study of JNJ-56136379 in participants with chronic hepatitis B virus infection. https://ClinicalTrials.gov/show/NCT03361956.

  111. A study of orally administered JNJ-56136379 to evaluate safety, tolerability and pharmacokinetics after single ascending doses and one multiple dose regimen in healthy participants (part I), and after multiple dose regimens in participants with chronic hepatitis B (part II). https://ClinicalTrials.gov/show/NCT02662712.

  112. A study evaluating ABI-H0731 as adjunctive therapy in HBeAg-positive patients with chronic hepatitis B. https://ClinicalTrials.gov/show/NCT03576066.

  113. Safety, tolerability, pharmacokinetics and antiviral activity of IONIS-HBVRx in treatment-naïve patients with chronic HBV infection. https://ClinicalTrials.gov/show/NCT02981602.

  114. Testoni B, Durantel D, Zoulim F. Novel targets for hepatitis B virus therapy. Liver Int. 2017;37(Suppl 1):33–9. https://doi.org/10.1111/liv.13307.

    Article  CAS  PubMed  Google Scholar 

  115. Seeger C, Sohn JA. Targeting hepatitis B virus with CRISPR/Cas9. Mol Ther Nucleic Acids. 2014;3:e216. https://doi.org/10.1038/mtna.2014.68.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Kennedy EM, Kornepati AV, Cullen BR. Targeting hepatitis B virus cccDNA using CRISPR/Cas9. Antivir Res. 2015;123:188–92. https://doi.org/10.1016/j.antiviral.2015.10.004.

    Article  CAS  PubMed  Google Scholar 

  117. Lucifora J, Xia Y, Reisinger F, Zhang K, Stadler D, Cheng X, et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science. 2014;343(6176):1221–8. https://doi.org/10.1126/science.1243462.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  118. Decorsiere A, Mueller H, van Breugel PC, Abdul F, Gerossier L, Beran RK, et al. Hepatitis B virus X protein identifies the Smc5/6 complex as a host restriction factor. Nature. 2016;531(7594):386–9. https://doi.org/10.1038/nature17170.

    Article  CAS  PubMed  Google Scholar 

  119. Testino G, Leone S, Borro P. Alcohol and hepatocellular carcinoma: a review and a point of view. World J Gastroenterol: WJG. 2014;20(43):15943–54. https://doi.org/10.3748/wjg.v20.i43.15943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Morgan TR, Mandayam S, Jamal MM. Alcohol and hepatocellular carcinoma. Gastroenterology. 2004;127(5 Suppl 1):S87–96.

    Article  CAS  PubMed  Google Scholar 

  121. NIAAA. Alcohol facts and statistics. National Institute on Alcohol Abuse and Alcoholism. 2017. https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/alcohol-facts-and-statistics.

  122. Mann R. The epidemiology of alcoholic liver disease. National Institute on Alcohol Abuse and Alcoholism. 2004. https://pubs.niaaa.nih.gov/publications/arh27-3/209-219.htm.

  123. NIDA. Sex and gender differences in substance use. National Institute on Drug Abuse. 2016. https://www.drugabuse.gov/publications/research-reports/substance-use-in-women/sex-gender-differences-in-substance-use.

  124. Ramadori P, Cubero FJ, Liedtke C, Trautwein C, Nevzorova YA. Alcohol and hepatocellular carcinoma: adding fuel to the flame. Cancers. 2017;9(10):130. https://doi.org/10.3390/cancers9100130.

    Article  CAS  PubMed Central  Google Scholar 

  125. Lieber CS. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol (Fayetteville, NY). 2004;34(1):9–19. https://doi.org/10.1016/j.alcohol.2004.07.008.

    Article  CAS  Google Scholar 

  126. Purohit V, Rapaka R, Kwon OS, Song BJ. Roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma. Life Sci. 2013;92(1) https://doi.org/10.1016/j.lfs.2012.10.009.

  127. Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology. 2002;36(5):1206–13. https://doi.org/10.1053/jhep.2002.36780.

    Article  CAS  PubMed  Google Scholar 

  128. Perlemuter G, Letteron P, Carnot F, Zavala F, Pessayre D, Nalpas B, et al. Alcohol and hepatitis C virus core protein additively increase lipid peroxidation and synergistically trigger hepatic cytokine expression in a transgenic mouse model. J Hepatol. 2003;39(6):1020–7.

    Article  CAS  PubMed  Google Scholar 

  129. Addolorato G, Mirijello A, Barrio P, Gual A. Treatment of alcohol use disorders in patients with alcoholic liver disease. J Hepatol. 2016;65(3):618–30. https://doi.org/10.1016/j.jhep.2016.04.029.

    Article  PubMed  Google Scholar 

  130. Petrick JL, Campbell PT, Koshiol J, Thistle JE, Andreotti G, Beane-Freeman LE, et al. Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: the liver cancer pooling project. Br J Cancer. 2018;118(7):1005–12. https://doi.org/10.1038/s41416-018-0007-z.

    Article  PubMed Central  PubMed  Google Scholar 

  131. Shih WL, Chang HC, Liaw YF, Lin SM, Lee SD, Chen PJ, et al. Influences of tobacco and alcohol use on hepatocellular carcinoma survival. Int J Cancer. 2012;131(11):2612–21. https://doi.org/10.1002/ijc.27508.

    Article  CAS  PubMed  Google Scholar 

  132. Heckley GA, Jarl J, Asamoah BO, G-Gerdtham U. How the risk of liver cancer changes after alcohol cessation: a review and meta-analysis of the current literature. BMC Cancer. 2011;11:446. https://doi.org/10.1186/1471-2407-11-446.

    Article  PubMed Central  PubMed  Google Scholar 

  133. Fleming MF, Mundt MP, French MT, Manwell LB, Stauffacher EA, Barry KL. Brief physician advice for problem drinkers: long-term efficacy and benefit-cost analysis. Alcohol Clin Exp Res. 2002;26(1):36–43.

    Article  PubMed  Google Scholar 

  134. Moyer A, Finney JW, Swearingen CE, Vergun P. Brief interventions for alcohol problems: a meta-analytic review of controlled investigations in treatment-seeking and non-treatment-seeking populations. Addiction. 2002;97(3):279–92.

    Article  PubMed  Google Scholar 

  135. Kaner EF, Beyer F, Dickinson HO, Pienaar E, Campbell F, Schlesinger C, et al. Effectiveness of brief alcohol interventions in primary care populations. Cochrane Database Syst Rev. 2007;2:CD004148. https://doi.org/10.1002/14651858.CD004148.pub3.

    Article  Google Scholar 

  136. Kaner EF, Beyer FR, Muirhead C, Campbell F, Pienaar ED, Bertholet N, et al. Effectiveness of brief alcohol interventions in primary care populations. Cochrane Database Syst Rev. 2018;(2):CD004148. https://doi.org/10.1002/14651858.CD004148.pub4.

  137. Bendtsen P, Anderson P, Wojnar M, Newbury-Birch D, Mussener U, Colom J, et al. Professional’s attitudes do not influence screening and brief interventions rates for hazardous and harmful drinkers: results from ODHIN study. Alcohol Alcohol. 2015;50(4):430–7. https://doi.org/10.1093/alcalc/agv020.

    Article  PubMed  Google Scholar 

  138. Owens L, Rose A, Thompson A, Pirmohamed M, Gilmore I, Richardson P. P1112: baclofen: maintenance of abstinence in alcohol dependent patients attending liver clinic. J Hepatol. 2015;62:S767. https://doi.org/10.1016/S0168-8278(15)31309-X.

    Article  Google Scholar 

  139. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet. 2007;370(9603):1915–22. https://doi.org/10.1016/S0140-6736(07)61814-5.

    Article  CAS  PubMed  Google Scholar 

  140. Wang T, Huang W, Chen F. Baclofen, a GABAB receptor agonist, inhibits human hepatocellular carcinoma cell growth in vitro and in vivo. Life Sci. 2008;82(9–10):536–41. https://doi.org/10.1016/j.lfs.2007.12.014.

    Article  CAS  PubMed  Google Scholar 

  141. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. https://doi.org/10.1002/hep.28431.

    Article  PubMed  Google Scholar 

  142. Baffy G. Hepatocellular carcinoma in non-alcoholic fatty liver disease: epidemiology, pathogenesis, and prevention. J Clin Transl Hepatol. 2013;1(2):131–7. https://doi.org/10.14218/jcth.2013.00005.

    Article  PubMed Central  PubMed  Google Scholar 

  143. Ong JP, Younossi ZM. Epidemiology and natural history of NAFLD and NASH. Clin Liver Dis. 2007;11(1):1–16, vii. https://doi.org/10.1016/j.cld.2007.02.009.

    Article  PubMed  Google Scholar 

  144. Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56(6):1384–91. https://doi.org/10.1016/j.jhep.2011.10.027.

    Article  PubMed  Google Scholar 

  145. Janus O, Zobair MY, Vishnu R, Lyn PL, Terry G, James M, et al. Cryptogenic cirrhosis and posttransplantation nonalcoholic fatty liver disease. Liver Transpl. 2001;7(9):797–801. https://doi.org/10.1053/jlts.2001.24644.

    Article  Google Scholar 

  146. Eduardo F, Estela Á, Nora D, Graciela L, Cristina L. Natural history of nonalcoholic steathepatitis: a longitudinal study of repeat liver biopsies. Hepatology. 2004;40(4):820–6. https://doi.org/10.1002/hep.1840400411.

    Article  Google Scholar 

  147. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129(1):113–21.

    Article  PubMed  Google Scholar 

  148. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10(12):1342–59.e2. https://doi.org/10.1016/j.cgh.2012.10.001.

    Article  PubMed Central  PubMed  Google Scholar 

  149. Bugianesi E, Leone N, Vanni E, Marchesini G, Brunello F, Carucci P, et al. Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology. 2002;123(1):134–40.

    Article  PubMed  Google Scholar 

  150. Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860. https://doi.org/10.1038/nature05485.

    Article  CAS  PubMed  Google Scholar 

  151. Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007;67(6):2497–507. https://doi.org/10.1158/0008-5472.Can-06-3075.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  152. Sara A, Ilaria P, Cristiana B, Maurizio P, Sebastiano C, Erica N, et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 2005;42(6):1339–48. https://doi.org/10.1002/hep.20965.

    Article  CAS  Google Scholar 

  153. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 2012;33(4):547–94. https://doi.org/10.1210/er.2011-1015.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  154. Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G, Groyer A. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem Pharmacol. 2004;68(6):1003–15. https://doi.org/10.1016/j.bcp.2004.05.029.

    Article  CAS  PubMed  Google Scholar 

  155. Che L, Pilo MG, Cigliano A, Latte G, Simile MM, Ribback S, et al. Oncogene dependent requirement of fatty acid synthase in hepatocellular carcinoma. Cell Cycle. 2017;16(6):499–507. https://doi.org/10.1080/15384101.2017.1282586.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  156. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7(10):763–77. https://doi.org/10.1038/nrc2222.

    Article  CAS  PubMed  Google Scholar 

  157. Yamashita T, Honda M, Takatori H, Nishino R, Minato H, Takamura H, et al. Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma. J Hepatol. 2009;50(1):100–10. https://doi.org/10.1016/j.jhep.2008.07.036.

    Article  CAS  PubMed  Google Scholar 

  158. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis. 2007;11(1):191–207, x–xi. https://doi.org/10.1016/j.cld.2007.02.006.

    Article  CAS  PubMed  Google Scholar 

  159. Yang S, Zhu H, Li Y, Lin H, Gabrielson K, Trush MA, et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch Biochem Biophys. 2000;378(2):259–68. https://doi.org/10.1006/abbi.2000.1829.

    Article  CAS  PubMed  Google Scholar 

  160. Hu W, Feng Z, Eveleigh J, Iyer G, Pan J, Amin S, et al. The major lipid peroxidation product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis. 2002;23(11):1781–9.

    Article  CAS  PubMed  Google Scholar 

  161. Xu Z, Chen L, Leung L, Yen TS, Lee C, Chan JY. Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc Natl Acad Sci U S A. 2005;102(11):4120–5. https://doi.org/10.1073/pnas.0500660102.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  162. Stickel F, Hellerbrand C. Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications. Gut. 2010;59(10):1303–7. https://doi.org/10.1136/gut.2009.199661.

    Article  CAS  PubMed  Google Scholar 

  163. Fabio M, Cristiana B. Adipokines in liver diseases. Hepatology. 2009;50(3):957–69. https://doi.org/10.1002/hep.23046.

    Article  CAS  Google Scholar 

  164. He G, Karin M. NF-kappaB and STAT3—key players in liver inflammation and cancer. Cell Res. 2011;21(1):159–68. https://doi.org/10.1038/cr.2010.183.

    Article  CAS  PubMed  Google Scholar 

  165. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51(5):1820–32. https://doi.org/10.1002/hep.23594.

    Article  PubMed  Google Scholar 

  166. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367–78.e5. https://doi.org/10.1053/j.gastro.2015.04.005.

    Article  PubMed  Google Scholar 

  167. Vilar-Gomez E, Calzadilla-Bertot L, Friedman SL, Gra-Oramas B, Gonzalez-Fabian L, Villa-Jimenez O, et al. Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2017;45(2):332–44. https://doi.org/10.1111/apt.13860.

    Article  CAS  PubMed  Google Scholar 

  168. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57. https://doi.org/10.1002/hep.29367.

    Article  PubMed  Google Scholar 

  169. Sung KC, Ryu S, Lee JY, Kim JY, Wild SH, Byrne CD. Effect of exercise on the development of new fatty liver and the resolution of existing fatty liver. J Hepatol. 2016;65(4):791–7. https://doi.org/10.1016/j.jhep.2016.05.026.

    Article  CAS  PubMed  Google Scholar 

  170. Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2008;6(12):1396–402. https://doi.org/10.1016/j.cgh.2008.08.012.

    Article  PubMed  Google Scholar 

  171. Lassailly G, Caiazzo R, Buob D, Pigeyre M, Verkindt H, Labreuche J, et al. Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients. Gastroenterology. 2015;149(2):379–88; quiz e15–6. https://doi.org/10.1053/j.gastro.2015.04.014.

    Article  PubMed  Google Scholar 

  172. Mathurin P, Hollebecque A, Arnalsteen L, Buob D, Leteurtre E, Caiazzo R, et al. Prospective study of the long-term effects of bariatric surgery on liver injury in patients without advanced disease. Gastroenterology. 2009;137(2):532–40. https://doi.org/10.1053/j.gastro.2009.04.052.

    Article  CAS  PubMed  Google Scholar 

  173. Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med. 2012;366(17):1577–85. https://doi.org/10.1056/NEJMoa1200111.

    Article  CAS  PubMed  Google Scholar 

  174. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, et al. Bariatric surgery versus intensive medical therapy for diabetes—3-year outcomes. N Engl J Med. 2014;370(21):2002–13. https://doi.org/10.1056/NEJMoa1401329.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  175. Schauer PR, Kashyap SR, Wolski K, Brethauer SA, Kirwan JP, Pothier CE, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366(17):1567–76. https://doi.org/10.1056/NEJMoa1200225.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  176. Chavez-Tapia NC, Tellez-Avila FI, Barrientos-Gutierrez T, Mendez-Sanchez N, Lizardi-Cervera J, Uribe M. Bariatric surgery for non-alcoholic steatohepatitis in obese patients. Cochrane Database Syst Rev. 2010;(1):CD007340. https://doi.org/10.1002/14651858.CD007340.pub2.

  177. Kral JG, Thung SN, Biron S, Hould FS, Lebel S, Marceau S, et al. Effects of surgical treatment of the metabolic syndrome on liver fibrosis and cirrhosis. Surgery. 2004;135(1):48–58. https://doi.org/10.1016/j.surg.2003.10.003.

    Article  PubMed  Google Scholar 

  178. Klein S, Mittendorfer B, Eagon JC, Patterson B, Grant L, Feirt N, et al. Gastric bypass surgery improves metabolic and hepatic abnormalities associated with nonalcoholic fatty liver disease. Gastroenterology. 2006;130(6):1564–72. https://doi.org/10.1053/j.gastro.2006.01.042.

    Article  CAS  PubMed  Google Scholar 

  179. Dallal RM, Mattar SG, Lord JL, Watson AR, Cottam DR, Eid GM, et al. Results of laparoscopic gastric bypass in patients with cirrhosis. Obes Surg. 2004;14(1):47–53. https://doi.org/10.1381/096089204772787284.

    Article  PubMed  Google Scholar 

  180. Shimizu H, Phuong V, Maia M, Kroh M, Chand B, Schauer PR, et al. Bariatric surgery in patients with liver cirrhosis. Surg Obes Relat Dis. 2013;9(1):1–6. https://doi.org/10.1016/j.soard.2012.07.021.

    Article  PubMed  Google Scholar 

  181. Jan A, Narwaria M, Mahawar KK. A systematic review of bariatric surgery in patients with liver cirrhosis. Obes Surg. 2015;25(8):1518–26. https://doi.org/10.1007/s11695-015-1727-2.

    Article  PubMed  Google Scholar 

  182. Mosko JD, Nguyen GC. Increased perioperative mortality following bariatric surgery among patients with cirrhosis. Clin Gastroenterol Hepatol. 2011;9(10):897–901. https://doi.org/10.1016/j.cgh.2011.07.007.

    Article  PubMed  Google Scholar 

  183. Rizvon MK, Chou CL. Surgery in the patient with liver disease. Med Clin North Am. 2003;87(1):211–27.

    Article  PubMed  Google Scholar 

  184. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Anti-diabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol. 2013;108:881. https://doi.org/10.1038/ajg.2013.5.

    Article  CAS  PubMed  Google Scholar 

  185. Zhou Y-Y, Zhu G-Q, Liu T, Zheng J-N, Cheng Z, Zou T-T, et al. Systematic review with network meta-analysis: antidiabetic medication and risk of hepatocellular carcinoma. Sci Rep. 2016;6:33743. https://doi.org/10.1038/srep33743.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  186. Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti G. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia. 2010;53(9):1838–45. https://doi.org/10.1007/s00125-010-1804-y.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  187. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39(1):188–96. https://doi.org/10.1002/hep.20012.

    Article  CAS  PubMed  Google Scholar 

  188. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355(22):2297–307. https://doi.org/10.1056/NEJMoa060326.

    Article  CAS  PubMed  Google Scholar 

  189. Aithal GP, Thomas JA, Kaye PV, Lawson A, Ryder SD, Spendlove I, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176–84. https://doi.org/10.1053/j.gastro.2008.06.047.

    Article  CAS  PubMed  Google Scholar 

  190. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–85. https://doi.org/10.1056/NEJMoa0907929.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  191. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165(5):305–15. https://doi.org/10.7326/m15-1774.

    Article  PubMed  Google Scholar 

  192. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370(9593):1129–36. https://doi.org/10.1016/s0140-6736(07)61514-1.

    Article  CAS  PubMed  Google Scholar 

  193. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA. 2007;298(10):1180–8. https://doi.org/10.1001/jama.298.10.1180.

    Article  CAS  PubMed  Google Scholar 

  194. Lutchman G, Modi A, Kleiner DE, Promrat K, Heller T, Ghany M, et al. The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis. Hepatology. 2007;46(2):424–9. https://doi.org/10.1002/hep.21661.

    Article  CAS  PubMed  Google Scholar 

  195. Demierre M-F, Higgins PDR, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nat Rev Cancer. 2005;5:930. https://doi.org/10.1038/nrc1751.

    Article  CAS  PubMed  Google Scholar 

  196. Mullen PJ, Yu R, Longo J, Archer MC, Penn LZ. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer. 2016;16:718. https://doi.org/10.1038/nrc.2016.76.

    Article  CAS  PubMed  Google Scholar 

  197. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology. 2013;144(2):323–32. https://doi.org/10.1053/j.gastro.2012.10.005.

    Article  CAS  PubMed  Google Scholar 

  198. Kim G, Jang SY, Nam CM, Kang ES. Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study. J Hepatol. 2018;68(3):476–84. https://doi.org/10.1016/j.jhep.2017.10.018.

    Article  CAS  PubMed  Google Scholar 

  199. Cholesterol Treatment Trialists Collaboration, Emberson JR, Kearney PM, Blackwell L, Newman C, Reith C, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7(1):e29849. https://doi.org/10.1371/journal.pone.0029849.

    Article  CAS  Google Scholar 

  200. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–65. https://doi.org/10.1016/S0140-6736(14)61933-4.

    Article  CAS  PubMed  Google Scholar 

  201. Mudaliar S, Henry RR, Sanyal AJ, Morrow L, Marschall HU, Kipnes M, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology. 2013;145(3):574–82.e1. https://doi.org/10.1053/j.gastro.2013.05.042.

    Article  CAS  PubMed  Google Scholar 

  202. Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147–59.e5.

    Article  CAS  PubMed  Google Scholar 

  203. Zimmermann HW, Seidler S, Nattermann J, Gassler N, Hellerbrand C, Zernecke A, et al. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PLoS One. 2010;5(6):e11049. https://doi.org/10.1371/journal.pone.0011049.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  204. Kazankov K, Barrera F, Moller HJ, Rosso C, Bugianesi E, David E, et al. The macrophage activation marker sCD163 is associated with morphological disease stages in patients with non-alcoholic fatty liver disease. Liver Int. 2016;36(10):1549–57. https://doi.org/10.1111/liv.13150.

    Article  CAS  PubMed  Google Scholar 

  205. Friedman SL, Ratziu V, Harrison SA, Abdelmalek MF, Aithal GP, Caballeria J, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018;67(5):1754–67. https://doi.org/10.1002/hep.29477.

    Article  CAS  PubMed  Google Scholar 

  206. Brenner C, Galluzzi L, Kepp O, Kroemer G. Decoding cell death signals in liver inflammation. J Hepatol. 2013;59(3):583–94. https://doi.org/10.1016/j.jhep.2013.03.033.

    Article  CAS  PubMed  Google Scholar 

  207. Budas G, Karnik S, Jonnson T, Shafizadeh T, Watkins S, Breckenridge D, et al. Reduction of liver steatosis and fibrosis with an ASK1 inhibitor in a murine model of nash is accompanied by improvements in cholesterol, bile acid and lipid metabolism. J Hepatol. 2016;64(2):S170. https://doi.org/10.1016/S0168-8278(16)01686-X.

    Article  Google Scholar 

  208. Sumida Y, Yoneda M. Current and future pharmacological therapies for NAFLD/NASH. J Gastroenterol. 2018;53(3):362–76. https://doi.org/10.1007/s00535-017-1415-1.

    Article  CAS  PubMed  Google Scholar 

  209. Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology (Baltimore, Md). 2018;67(2):549–59. https://doi.org/10.1002/hep.29514.

    Article  CAS  Google Scholar 

  210. Komuves LG, Feren A, Jones AL, Fodor E. Expression of epidermal growth factor and its receptor in cirrhotic liver disease. J Histochem Cytochem. 2000;48(6):821–30. https://doi.org/10.1177/002215540004800610.

    Article  CAS  PubMed  Google Scholar 

  211. Fuchs BC, Hoshida Y, Fujii T, Wei L, Yamada S, Lauwers GY, et al. Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology. 2014;59(4):1577–90. https://doi.org/10.1002/hep.26898.

    Article  CAS  PubMed  Google Scholar 

  212. Schiffer E, Housset C, Cacheux W, Wendum D, Desbois-Mouthon C, Rey C, et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology. 2005;41(2):307–14. https://doi.org/10.1002/hep.20538.

    Article  CAS  PubMed  Google Scholar 

  213. Tonjes RR, Lohler J, O’Sullivan JF, Kay GF, Schmidt GH, Dalemans W, et al. Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice. Oncogene. 1995;10(4):765–8.

    CAS  PubMed  Google Scholar 

  214. Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, Chung RT, et al. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA. 2008;299(1):53–60. https://doi.org/10.1001/jama.2007.65.

    Article  CAS  PubMed  Google Scholar 

  215. Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359(19):1995–2004. https://doi.org/10.1056/NEJMoa0804525.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  216. Hoshida Y, Villanueva A, Sangiovanni A, Sole M, Hur C, Andersson KL, et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology. 2013;144(5):1024–30. https://doi.org/10.1053/j.gastro.2013.01.021.

    Article  CAS  PubMed  Google Scholar 

  217. Jiang G, Yu K, Shao L, Yu X, Hu C, Qian P, et al. Association between epidermal growth factor gene +61A/G polymorphism and the risk of hepatocellular carcinoma: a meta-analysis based on 16 studies. BMC Cancer. 2015;15:314. https://doi.org/10.1186/s12885-015-1318-6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  218. Lanaya H, Natarajan A, Komposch K, Li L, Amberg N, Chen L, et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat Cell Biol. 2014;16(10):972–7. https://doi.org/10.1038/ncb3031.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  219. Simon TG, Ma Y, Ludvigsson JF, Chong DQ, Giovannucci EL, Fuchs CS, et al. Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol. 2018;4(12):1683–90.

    Article  PubMed  PubMed Central  Google Scholar 

  220. Malehmir M, et al. Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer. Nat Med. 2019;25(4):641–55.

    Article  CAS  PubMed  Google Scholar 

  221. Hanazaki K, Kajikawa S, Shimozawa N, Mihara M, Shimada K, Hiraguri M, et al. Survival and recurrence after hepatic resection of 386 consecutive patients with hepatocellular carcinoma. J Am Coll Surg. 2000;191(4):381–8.

    Article  CAS  PubMed  Google Scholar 

  222. Zimmerman MA, Ghobrial R, Tong MJ, et al. Recurrence of hepatocellular carcinoma following liver transplantation: a review of preoperative and postoperative prognostic indicators. Arch Surg. 2008;143(2):182–8. https://doi.org/10.1001/archsurg.2007.39.

    Article  PubMed  Google Scholar 

  223. Haruhiko Y, Yasushi S, Masatoshi K, Shuichiro S, Toshihiko M, Masamichi K, et al. Effect of vitamin K2 on the recurrence of hepatocellular carcinoma. Hepatology. 2011;54(2):532–40. https://doi.org/10.1002/hep.24430.

    Article  CAS  Google Scholar 

  224. Okita K, Izumi N, Matsui O, Tanaka K, Kaneko S, Moriwaki H, et al. Peretinoin after curative therapy of hepatitis C-related hepatocellular carcinoma: a randomized double-blind placebo-controlled study. J Gastroenterol. 2015;50(2):191–202. https://doi.org/10.1007/s00535-014-0956-9.

    Article  CAS  PubMed  Google Scholar 

  225. Lu L-C, Cheng A-L, Poon RTP. Recent advances in the prevention of hepatocellular carcinoma recurrence. Semin Liver Dis. 2014;34(04):427–34. https://doi.org/10.1055/s-0034-1394141.

    Article  PubMed  Google Scholar 

  226. Zhuang L, Zeng X, Yang Z, Meng Z. Effect and safety of interferon for hepatocellular carcinoma: a systematic review and meta-analysis. PLoS One. 2013;8(9):e61361. https://doi.org/10.1371/journal.pone.0061361.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  227. Lohitesh K, Chowdhury R, Mukherjee S. Resistance a major hindrance to chemotherapy in hepatocellular carcinoma: an insight. Cancer Cell Int. 2018;18:44. https://doi.org/10.1186/s12935-018-0538-7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  228. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–109. https://doi.org/10.1158/0008-5472.Can-04-1443.

    Article  CAS  PubMed  Google Scholar 

  229. Bruix J, Takayama T, Mazzaferro V, Chau G-Y, Yang J, Kudo M, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015;16(13):1344–54. https://doi.org/10.1016/S1470-2045(15)00198-9.

    Article  CAS  PubMed  Google Scholar 

  230. Wada Y, Nakashima O, Kutami R, Yamamoto O, Kojiro M. Clinicopathological study on hepatocellular carcinoma with lymphocytic infiltration. Hepatology. 1998;27(2):407–14. https://doi.org/10.1002/hep.510270214.

    Article  CAS  PubMed  Google Scholar 

  231. Flecken T, Schmidt N, Hild S, Gostick E, Drognitz O, Zeiser R, et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology. 2014;59(4):1415–26. https://doi.org/10.1002/hep.26731.

    Article  CAS  PubMed  Google Scholar 

  232. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492–502. https://doi.org/10.1016/S0140-6736(17)31046-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–52. https://doi.org/10.1016/S1470-2045(18)30351-6.

    Article  PubMed  Google Scholar 

  234. Takayama T, Makuuchi M, Sekine T, Terui S, Shiraiwa H, Kosuge T, et al. Distribution and therapeutic effect of intraarterially transferred tumor-infiltrating lymphocytes in hepatic malignancies. A preliminary report. Cancer. 1991;68(11):2391–6.

    Article  CAS  PubMed  Google Scholar 

  235. Takayama T, Sekine T, Kondo Y, Kakizoe T, Makuuchi M. Adjuvant adoptive immunotherapy against hepatocellular carcinoma. Hepatology. 1998;28(5):1436–7. https://doi.org/10.1002/hep.510280539.

    Article  CAS  PubMed  Google Scholar 

  236. Konomi Y, Sekine T, Takayama T, Fuji M, Tanaka T. Cytotoxic activity of CD4+ T cells against autologous tumor cells. Jpn J Cancer Res. 1995;86(9):854–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Lee JH, Lee J-H, Lim Y-S, Yeon JE, Song T-J, Yu SJ, et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology. 2015;148(7):1383–91.e6. https://doi.org/10.1053/j.gastro.2015.02.055.

    Article  CAS  PubMed  Google Scholar 

  238. Lee JH, Lee JH, Lim YS, Yeon JE, Song TJ, Yu S, et al. GS-008 – sustained efficacy of adjuvant immunotherapy with cytokineinduced killer cells for hepatocellular carcinoma: an extended 5-year follow-up. J Hepatol. 2018;68:S37–S8. https://doi.org/10.1016/S0168-8278(18)30291-5.

    Article  Google Scholar 

  239. Xie Y, Xiang Y, Sheng J, Zhang D, Yao X, Yang Y, et al. Immunotherapy for hepatocellular carcinoma: current advances and future expectations. J Immunol Res. 2018;2018:8. https://doi.org/10.1155/2018/8740976.

    Article  CAS  Google Scholar 

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  1. Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Derek J. Erstad, Shen Li, Kenneth K. Tanabe & Bryan C. Fuchs

  2. Tufts University School of Medicine, Boston, MA, USA

    Allen A. Razavi

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    Yujin Hoshida

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Erstad, D.J., Razavi, A.A., Li, S., Tanabe, K.K., Fuchs, B.C. (2019). Prevention Strategies for Hepatocellular Carcinoma. In: Hoshida, Y. (eds) Hepatocellular Carcinoma. Molecular and Translational Medicine. Humana, Cham. https://doi.org/10.1007/978-3-030-21540-8_13

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