Role of antiviral therapy in reducing recurrence and improving survival in hepatitis B virus-associated hepatocellular carcinoma following curative resection (Review)

Zuo,Chaohui; Xia,Man; Wu,Qunfeng; Zhu,Haizhen; Liu,Jingshi; Liu,Chen

doi:10.3892/ol.2014.2727

Role of antiviral therapy in reducing recurrence and improving survival in hepatitis B virus-associated hepatocellular carcinoma following curative resection (Review)

Authors:
- Chaohui Zuo
- Man Xia
- Qunfeng Wu
- Haizhen Zhu
- Jingshi Liu
- Chen Liu
View Affiliations

Affiliations: Department of Gastroduodenal and Pancreatic Surgery, Translation Medicine Research Center of Liver Cancer, Hunan Province Tumor Hospital and Affiliated Tumor Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China, Department of Pathology, Immunology and Laboratory Medicine and Shands Cancer Center, University of Florida, Gainesville, FL 32610-0275, USA
Published online on: November 21, 2014 https://doi.org/10.3892/ol.2014.2727
Pages: 527-534
Copyright: © Zuo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hepatocellular carcinoma (HCC) is one of the major causes of cancer‑related mortality worldwide, with the majority of cases associated with persistent hepatitis B virus (HBV) or hepatitis C virus infection. In particular, chronic HBV infection is a predominant risk factor for the development of HCC in Asian and African populations. Hepatic resection, liver transplantion and radiofrequency ablation are increasingly used for the curative treatment of HCC, however, the survival rate of HCC patients who have undergone curative resection remains unsatisfactory due to the high recurrence rate. HCC is a complex disease that is typically resistant to the most commonly used types of chemotherapy and radiotherapy; therefore, the development of novel treatment strategies is required to improve the survival rate of this disease. A high viral load of HBV DNA is the most important correctable risk factor for HCC recurrence, for example nucleos(t)ide analogs improve the outcome following curative resection of HBV‑associated HCC, and interferon‑α exhibits antitumor activity against various types of cancer via direct inhibitory effects on tumor cells, anti‑angiogenesis, enhanced immunogenicity of tumors, immunomodulatory effects and liver dysfunction. In the present review, antiviral treatment for HBV‑associated HCC is described as a strategy to reduce recurrence and improve survival.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistitics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Ding J and Wang H: Multiple interactive factors in hepatocarcinogenesis. Cancer Lett. 346:17–23. 2014. View Article : Google Scholar : PubMed/NCBI
3	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar
4	Miamen AG, Dong H and Roberts LR: Immunotherapeutic approches to hepatocellular carcinoma treatment. Liver Cancer. 1:226–237. 2012. View Article : Google Scholar
5	Yuen MF, Hou JL and Chutaputti A; Asia Pacific Working Party on Prevention of Hepatocellular Carcinoma. Hepatocellular carcinoma in the Asia pacific region. J Gastroenterol Hepatol. 24:346–53. 2009. View Article : Google Scholar : PubMed/NCBI
6	Trepo C: A brief history of hepatitis milestones. Liver Int. 34(Suppl 1): 29–37. 2014. View Article : Google Scholar : PubMed/NCBI
7	Ishikawa T: Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma. World J Gastroenterol. 19:8861–8866. 2013. View Article : Google Scholar :
8	Malek NP, Schmidt S, Huber P, Manns MP and Greten TF: The diagnosis and treatment of hepatocellular carcinoma. Dtsch Arztebi Int. 111:101–106. 2014.
9	Lopez LJ and Marrero JA: Hepatocellular carcinoma. Curr Opin Gastroenterol. 20:248–253. 2004. View Article : Google Scholar
10	Shen Y, Lin ZZ, Hsu CH, Hsu C, Hsu C, Shao YY and Cheng AL: Clinical trials in hepatocellular carcinoma: an update. Liver Cance. 2:345–364. 2013. View Article : Google Scholar
11	Sasaki K, Matsuda M, Ohkura Y, Kawamura Y, Inoue M, Hashimoto M, Ikeda K, Kumada H and Watanabe G: In hepatocellular carcinomas, any proportion of poorly differentiated components is associated with poor prognosis after hepatectomy. World J Surg. 38:1147–1153. 2014. View Article : Google Scholar
12	Lin S, Hoffmann K and Schemmer P: Treatment of hepatocellular carcinoma: a systematic review. Liver Cancer. 1:144–158. 2012. View Article : Google Scholar
13	Singal AK, Guturu P, Hmoud B, Kuo YF, Salameh H and Wiesner RH: Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplanation. 95:755–760. 2013. View Article : Google Scholar
14	Jiang L, Yan L, Wen T, et al: Hepatitis B prophylaxis using lamivudine and individualized low-dose hepatitis B immunoglobulin in living donor liver transplantation. Transplant Proc. 45:2326–2330. 2013. View Article : Google Scholar : PubMed/NCBI
15	Vitale A, Volk M and Cillo U: Transplant benefit for patients with hepatocellular carcinoma. World J Gastroenterol. 19:9183–9188. 2013. View Article : Google Scholar
16	Fang Y, Chen W, Liang X, Li D, Lou H, Chen R, Wang K and Pan H: Comparison of long-term effectiveness and complications of radiofrequency ablation with hepatectomy for small hepatocellular carcinoma. J Gastroenterol Hepatol. 29:193–200. 2014. View Article : Google Scholar
17	Wang Y, Luo Q, Li Y, Deng S, Wei S and Li X: Radiofrequency ablation versus hepatic resection for small hepatocellular carcinomas: a meta-analysis of randomized and nonrandomized controlled trials. PloS One. 9:e844842014. View Article : Google Scholar : PubMed/NCBI
18	Cucchetti A, Piscaqlia F, Cescon M, Ercolani G and Pinna AD: Systematic review of surgical resection vs radiofrequency ablation for hepatocellular carcinoma. World J Gastroenterol. 19:4106–4188. 2013. View Article : Google Scholar : PubMed/NCBI
19	Yang T, Zhang J, Lu JH, Yang LQ, Yang GS, Wu MC and Yu WF: A new staging system for resectable hepatocellular carcinoma: comparison with six existing staging systems in a large Chinese cohort. J Cancer Res Clin Oncol. 137:739–750. 2011. View Article : Google Scholar
20	Maluccio M and Covey A: Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin. 62:394–399. 2012. View Article : Google Scholar : PubMed/NCBI
21	DuBray BJ Jr, Chapman WC and Anderson CD: Hepatocellular carcinoma: a review of the surgical approaches to management. Mo Med. 108:195–198. 2011.PubMed/NCBI
22	Salhab M and Canelo R: An overview of evidence-based management of hepatocellular carcinoma: a meta-analysis. J Cancer Res Ther. 7:463–475. 2011. View Article : Google Scholar
23	Young AL, Adair R, Prasad KR, Toogood GJ and Lodge JP: Hepatocellular carcinoma within a noncirrhotic, nonfibrotic, seronegative liver: surgical approaches and outcomes. J Am Coll Surg. 214:174–183. 2012. View Article : Google Scholar
24	Gluer AM, Cocco N, Laurence JM, Johnston ES, Hollands MJ, Pleass HC, Richardson AJ and Lam VW: Systematic review of actual 10-year survival following resection for hepatocellular carcinoma. HPB (Oxford). 14:285–290. 2012. View Article : Google Scholar
25	Rahbari NN, Wente MN, Schemmer P, Diener MK, Hoffmann K, Motschall E, Schmidt J, Weitz J and Büchler MW: Systematic review and meta-analysis of the effect of portal triad clamping on outcome after hepatic resection. Br J Surg. 95:424–432. 2008. View Article : Google Scholar : PubMed/NCBI
26	Liao X, Chen L, Fu W and Zhou J: Heparin-binding epidermal growth factor-like growth factor protects rat intestine after portal triad clamping. Growth Factors. 31:74–80. 2013. View Article : Google Scholar : PubMed/NCBI
27	Wang PF, Li CH, Chen YW, Zhang AQ, Cai SW and Dong JH: Preserving hepatic artery flow during portal triad blood inflow occlusion improves remnant liver regeneration in rats after partial hepatectomy. J Surg Res. 181:329–336. 2013. View Article : Google Scholar
28	Rammohan A, Sathyanesan J, Ramaswami S, Lakshmanan A, Senthil-Kumar P, Srinivasan UP, Ramasamy R and Ravichandran P: Embolization of liver tumors: Past, present and future. World J Radiol. 4:405–412. 2012. View Article : Google Scholar : PubMed/NCBI
29	Choi JY: Treatment algorithm for intermediate and advanced stage hepatocellular carcinoma: Korea. Oncology. 81(Suppl 1): 141–147. 2011. View Article : Google Scholar
30	Fan ST, Mau Lo C, Poon RT, et al: Continuous improvement of survival outcomes of resection of hepatocellular carcinoma: a 20-year experience. Ann Surg. 253:745–758. 2011. View Article : Google Scholar : PubMed/NCBI
31	Xi T, Lai EC, Min AR, Shi LH, Wu D, Xue F, Wang K, Yan Z, Xia Y, Shen F, et al: Adjuvant transatheter arterial chemoembolization after curative resection of hepatocellular carcinoma: a non-randomized comparative study. Hepatogastroenterology. 59:1198–1203. 2012.PubMed/NCBI
32	Shirable K, Wakiyama S, Gion T, Motomura K, Koyanagi T, Sakamoto S and Nagaie T: Clinicopathological risk factors linked to recurrence pattern after curative hepatic resection for hepatocellular carcinoma - results of 152 resected cases. Hepatogastroenterology. 54:2084–2087. 2007.
33	Ho CM, Wu CY, Lee PH, Lai HS, Ho MC, Wu YM and Hu RH: Analysis of the risk factors of untransplantable recurrence after primary curative resection for patients with hepatocellular carcinoma. Ann Surg Oncol. 20:2526–2533. 2013. View Article : Google Scholar : PubMed/NCBI
34	Severi T, van Malenstein H, Verslype C and van Pelt JF: Tumor initiation and progression in hepatocellular carcinoma: risk factors, classification, and therapeutic targets. Acta Pharmacol Sin. 31:1409–1420. 2010. View Article : Google Scholar : PubMed/NCBI
35	Wang H and Chen L: Tumor microenvironment and hepatocellular carcinoma metastasis. J Gastroenterol Hepatol. 28(Suppl 1): 43–48. 2013. View Article : Google Scholar
36	Xu J, Xu HY, Zhang Q, Song F, Jiang JL, Yang XM, Mi L, Wen N, Tian R, Wang L, et al: HAb18G/CD147 functions in invasion and metastasis of hepatocellular carcinoma. Mol Cancer Res. 5:605–614. 2007. View Article : Google Scholar : PubMed/NCBI
37	Zhong B, Huang MP, Yin GQ and Gao X: Effects of costimulation on intrahepatic immunopathogenesis in patients with chronic HBV infection. Inflamm Res. 63:217–229. 2014. View Article : Google Scholar :
38	Wong GL, Chan HL, Tse YK, Lo AO and Wong VW: On-treatment alpha-fetoprotein is a specific tumor marker for hepatocellular carcinoma in patients with chronic hepatitis B receiving entecavir. Hepatology. 59:986–995. 2014. View Article : Google Scholar
39	Abu-Amara M and Feld JJ: Does antiviral therapy for chronic hepatitis B reduce the risk of hepatocellular carcinoma? Semin Liver Dis. 33:157–166. 2013. View Article : Google Scholar : PubMed/NCBI
40	Brechot C, Kremsdorf D, Soussan P, Pineau P, Dejean A, Paterlini-Brechot P and Tiollais P: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC): molecular mechanisms and novel paradigms. Pathol Biol (Paris). 58:278–287. 2010. View Article : Google Scholar
41	Kew MC: Hepatocellular carcinoma in African blacks: Recent progress in etiology and pathogenesis. World J Hepatol. 2:65–73. 2010.PubMed/NCBI
42	Chen L, Zhang Q, Chang W, Du Y, Zhang H and Cao G: Viral and host inflammation-related factors that can predict the prognosis of hepatocellular carcinoma. Eur J Cancer. 48:1977–1987. 2012. View Article : Google Scholar : PubMed/NCBI
43	Chan HL and Sung JJ: Hepatocellular carcinoma and hepatitis B virus. Semin Liver Dis. 26:153–161. 2006. View Article : Google Scholar : PubMed/NCBI
44	Wu CF, Yu MW, Lin CL, Liu CJ, Shih WL, Tsai KS and Chen CJ: Long-term tracking of hepatitis B viral load and the relationship with risk for hepatocellular carcinoma in men. Carcinogenesis. 29:106–112. 2008. View Article : Google Scholar
45	Sun Y, Chen TY, Lu PX, Wang JB, Wu Y, Zhang QN, Qian GS and Tu H: Relationship between serum hepatitis B virus DNA load and hepatocellular carcinoma in Qidong, China: a cohort follow-up study of 14 years. Zhonghua Yi Xue Za Zhi. 92:1874–1877. 2012.(In Chinese). PubMed/NCBI
46	Pan W, Cheng G, Xing H, Shi J, Lu C, Wei J, Li L, Zhou C, Yuan Q, Zhou L and Yang M: Leukocyte telomere length-related rs621559 and rs398652 genetic variants influence risk of HBV-related hepatocellular carcinoma. PLoS One. 9:e1108632014. View Article : Google Scholar : PubMed/NCBI
47	Ke Y, Wang L, Li LQ and Zhong JH: Nucleos(t)ide analogues to treat hepatitis B virus-related hepatocellular carcinoma after radical resection. World J Hepatol. 6:653–659. 2014. View Article : Google Scholar
48	Sohn W, Paik YH, Kim JM, Kwon CH, Joh JW, Gwak GY, Choi MG, Lee JH, Koh KC, Paik SW and Yoo BC: HBV DNA and HBsAg levels as risk predictors of early and late recurrence after curative resection of HBV-related hepatocellular carcinoma. Ann Surg Oncol. 21:2429–2435. 2014. View Article : Google Scholar : PubMed/NCBI
49	Xia F, Lai EC, Lau WY, Ma K, Li X, Bie P and Qian C: High serum hyaluronic acid and HBV viral load are main prognostic factors of local recurrence after complete radiofrequency ablation of hepatitis B-related small hepatocellular carcinoma. Ann Surg Oncol. 19:1284–1291. 2012. View Article : Google Scholar
50	An HJ, Jang JW, Bae SH, Choi JY, Cho SH, Yoon SK, Han JY, Lee KH, Kim DG and Jung ES: Sustained low hepatitis B viral load predicts good outcome after curative resection in patients with hepatocellular carcinoma. J Gastroenterol Hepatol. 25:1876–1882. 2010. View Article : Google Scholar : PubMed/NCBI
51	Deng Y, Du Y, Zhang Q, Han X and Cao G: Human cytidine deaminases facilitate hepatitis B virus evolution and link inflammation and hepatocellular carcinoma. Cancer Lett. 343:161–171. 2014. View Article : Google Scholar
52	McMahon BJ: Chronic hepatitis B virus infection. Med Clin North Am. 98:39–54. 2014. View Article : Google Scholar
53	Su CH, Lin Y and Cai L: Genetic factors, viral infection, other factors and liver cancer: an update on current progress. Asian Pac J Cancer Prev. 14:4953–4960. 2013. View Article : Google Scholar : PubMed/NCBI
54	Shi L, Feng Y, Lin H, Ma R and Cai X: Role of estrogen in hepatocellular carcinoma: is inflammation the key? J Transl Med. 12:932014. View Article : Google Scholar : PubMed/NCBI
55	Höner Zu, Siederdissen C and Cornberg M: The role of HBsAg levels in the current management of chronic HBV infection. Ann Gastroenterol. 27:105–112. 2014.
56	Khaliq S, Latief N and Jahan S: Role of different regions of the hepatitis C virus genome in the therapeutic response to interferon-based treatment. Arch Virol. 159:1–15. 2014. View Article : Google Scholar
57	Qashqari H, Al-Mars A, Chaudhary A, Abuzenadah A, Damanhouri G, Alqahtani M, Mahmoud M, El Sayed Zaki M, Fatima K and Qadr I: Understanding the molecular mechanism(s) of hepatitis C virus (HCV) induced interferon resistance. Infect Genet Evol. 19:113–119. 2013. View Article : Google Scholar : PubMed/NCBI
58	Herzer K, Hofmann TG, Teufel A, Schimaski CC, Moehler M, Kanzler S, Schulze-Bergkamen H and Galle PR: IFN-α-induced apoptosis in hepatocellular carcinoma involves promyelocytic leukemia protein and TRAIL independently of p53. Cancer Res. 69:855–862. 2009. View Article : Google Scholar : PubMed/NCBI
59	Lamm D, Brausi M, O’Donnell MA and Witjes A: Interferon alfa in the treatment paradigm for non-muscle-invasive bladder cancer. Urol Oncol. 32:35.e21–35.e30. 2014. View Article : Google Scholar
60	Yang YF, Zhao W, Zhong YD, Yang YJ, Shen L, Zhang N and Huang P: Comparison of the efficacy of thymosin alpha-1 and interferon alpha in the treatment of chronic hepatitis B: a meta-analysis. Antiviral Res. 77:136–141. 2008. View Article : Google Scholar
61	Schweizer M, Mätzener P, Pfaffen G, Stalder H and Peterhans E: ‘Self’ and ‘nonself’ manipulation of interferon defense during persistent infection: bovine viral diarrhea virus resists alpha/beta interferon without blocking antiviral activity against unrelated viruses replicating in its host cells. J Virol. 80:6926–6935. 2006. View Article : Google Scholar : PubMed/NCBI
62	Wilden H, Schirrmacher V and Fournier P: Important role of interferon regulatory factor (IRF)-3 in the interferon response of mouse macrophages upon infection by Newcastle disease virus. Int J Oncol. 39:493–504. 2011.PubMed/NCBI
63	Liu Y, Lou G, Wu W, Shi Y, Zheng M and Chen Z: Interferon-α sensitizes HBx-expressing hepatocarcinoma cells to chemotherapeutic drugs through inhibition of HBx-mediated NF-κB activation. Virol J. 10:1682013. View Article : Google Scholar
64	Cabrera R, Ararat M, Cao M, Xu Y, Wasserfall C, Atkinson MA, Liu C and Nelson DR: Hepatocellular carcinoma immunopathogenesis: clinical evidence for global T cell defects and an immunomodulatory role for soluble CD25 (sCD25). Dig Dis Sci. 55:484–495. 2010. View Article : Google Scholar
65	Hou ZH, Han QJ, Zhang C, Tian ZG and Zhang J: miR146a impairs the IFN-induced anti-HBV immune response by downregulating STAT1 in hepatocytes. Liver Int. 34:58–68. 2014. View Article : Google Scholar
66	Alcantara FF, Tang H and McLachlan A: Functional characterization of the interferon regulatory element in the enhancer 1 region of the hepatitis B virus genome. Nucleic Acids Res. 30:2068–2075. 2002. View Article : Google Scholar : PubMed/NCBI
67	Belloni L, Allweiss L, Guerrieri F, Pediconi N, Volz T, Pollicino T, Petersen J, Raimondo G, Dandri M and Levrero M: IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome. J Clin Invest. 122:529–537. 2012. View Article : Google Scholar : PubMed/NCBI
68	Yang D, Zuo C, Wang X, Meng X, Xue B, Liu N, Yu R, Qin Y, Gao Y, Wang Q, et al: Complete replication of hepatitis B virus and hepatitis C virus in a newly developed hepatoma cell line. Proc Natl Acade Sci USA. 111:E1264–E1273. 2014. View Article : Google Scholar
69	Sung JJ, Tsoi KK, Wong VW, Li KC and Chan HL: Meta-analysis: Treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther. 28:1067–1077. 2008. View Article : Google Scholar : PubMed/NCBI
70	Xiaobin F, Shuguo Z, Jian Z, Yudong Q, Lijian L, Kuansheng M, Xiaowu L, Feng X, Dong Y, Shuguang W, et al: Effect of the pringle maneuver on tumor recurrence of hepatocellular carcinoma after curative resection (EPTRH): a randomized, prospective, controlled multicenter trial. BMC Cancer. 12:3402012. View Article : Google Scholar : PubMed/NCBI
71	Torzilli G, Donadon M and Cimino M: Are tumor exposure and anatomical resection antithetical during surgery for hepatocellular carcinoma? A critical review. Liver Cancer. 1:177–182. 2012. View Article : Google Scholar
72	Chen JA, Shi M, Li JQ and Qian CN: Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration. Hepatol Int. 4:537–547. 2010. View Article : Google Scholar : PubMed/NCBI
73	Zhung L, Zeng X, Yang Z and Meng Z: Effect and safety of interferon for hepatocellular carcinoma: a systematic review and meta-analysis. PloS One. 8:e613612013. View Article : Google Scholar
74	Qu LS, Jin F, Huang XW and Shen XZ: Interferon-α therapy after curative resection prevents early recurrence and improves survival in patients with hepatitic B virus-related hepatocellular carcinoma. J Surg Oncol. 102:796–801. 2010. View Article : Google Scholar : PubMed/NCBI
75	Qu LS, Jin F, Huang XW and Shen XZ: High hepatitis B viral load predicts recurrence of small hepatocellular carcinoma after curative resection. J Gastrointest Surg. 14:1111–1120. 2010. View Article : Google Scholar : PubMed/NCBI
76	Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ, Fan J, et al: Postoperative interferon α treatment postponed recurrence and improved overall survival in patients after curative resection of HBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res Clin Oncol. 132:458–465. 2006. View Article : Google Scholar : PubMed/NCBI
77	Wang J, He XD, Yao N, Liang WJ and Zhang YC: A meta-analysis of adjuvant therapy after potentially curative treatment for hepatocellular carcinoma. Can J Gastroenterol. 27:351–363. 2013.PubMed/NCBI
78	Tan ZM and Sun BC: Effects of antiviral therapy on preventing liver tumorigenesis and hepatocellular carcinoma recurrence. World J Gastroenterol. 19:8895–8901. 2013. View Article : Google Scholar :
79	Sun P, Yang X, He RQ, Hu QG, Song ZF, Xiong J and Zheng QC: Antiviral therapy after curative treatment of hepatitis B/C virus-related hepatocellular carcinoma: A systematic review of randomized trials. Hepatol Res. 44:259–269. 2014. View Article : Google Scholar
80	Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL, Lee WC, et al; Disease Committee of Adjuvant Therapy for Postoperative Hepatocellular Carcinoma, Taiwan Cooperative Oncology Group, National Health Research Institutes, Zhunan, Taiwan. Long-term results of a randomized, observation controlled, phase III trial of adjuvant interferon Alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg. 255:8–17. 2012. View Article : Google Scholar
81	Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H, Sasaki S, Imaki S, Imai K, Shibue T, et al: Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence. Nature. 424:516–523. 2003. View Article : Google Scholar : PubMed/NCBI
82	Slack FJ and Weidhaas JB: MicroRNA in cancer prognosis. N Eng J Med. 359:2720–2722. 2008. View Article : Google Scholar
83	Lujambio A and Lowe SW: The microcosmos of cancer. Nature. 482:347–355. 2012. View Article : Google Scholar : PubMed/NCBI
84	Kong YW, Ferland-McCollough D, Jackson TJ and Bushell M: microRNAs in cancer management. Lancet Oncol. 13:e249–e258. 2012. View Article : Google Scholar : PubMed/NCBI
85	Ji J, Shi J, Budhu A, Yu Z, Forgues M, Roessler S, Ambs S, Chen Y, Meltzer PS, Croce CM, et al: MicroRNA expression, survival, and response to interferon in liver cancer. N Eng J Med. 361:1437–1447. 2009. View Article : Google Scholar
86	Ji J, Yu Z, Yu Z, Forgues M, Uenishi T, Kubo S, Wakasa K, Zhou J, Fan J, Tang ZY, et al: Development of a miR-26 companion diagnostic test for adjuvant interferon-alpha therapy in hepatocellular carcinoma. Int J Biol Sci. 9:303–312. 2013. View Article : Google Scholar : PubMed/NCBI
87	Hou J, Zhou Y, Zheng Y, Fan J, Zhou W, Ng IO, Sun H, Qin L, Qiu S, Lee JM, et al: Hepatic RIG-I predicts survival and interferon-α therapeutic response in hepatocellular carcinoma. Cancer Cell. 25:49–63. 2014. View Article : Google Scholar
88	Zhao Y, Cai G, Zhou L, Liu L, Qi X, Bai M, Li Y, Fan D and Han G: Transarterial chemoembolization in hepatocellular carcinoma with vascular invasion or extrahepatic metastasis: A systematic review. Asia Pac J Clin. 9:357–364. 2013. View Article : Google Scholar
89	Lencioni R: Chemoembolization for hepatocellular carcinoma. Semin Oncol. 39:503–509. 2012. View Article : Google Scholar : PubMed/NCBI
90	Chen S, Chen J, Xi W, Xu W and Yin G: Clinical therapeutic effect and biological monitoring of p53 gene in advanced hepatocellular carcinoma. Am J Clin Oncol. 37:24–29. 2014. View Article : Google Scholar : PubMed/NCBI
91	Zhong JH and Li LQ: Postoperative adjuvant transarterial chemoembolization for participants with hepatocellular carcinoma: A meta-analysis. Hepatol Res. 40:943–953. 2010. View Article : Google Scholar : PubMed/NCBI
92	Matsuda M, Omata F, Fuwa S, Saida Y, Suzuki S, Uemura M, Ishii N, Iizuka Y, Fukuda K and Fujita Y: Prognosis of patients with hepatocellular carcinoma treated solely with transcatheter arterial chemoembolization: risk factors for one-year recurrence and two-year mortality (preliminary data). Intern Med. 52:847–853. 2013. View Article : Google Scholar : PubMed/NCBI
93	Breunig IM, Shaya FT, Hanna N, Seal B, Chirikov VV and Daniel Mullins C: Transarterial chemoembolization treatment: association between multiple treatments, cumulative expenditures, and survival. Value Health. 16:760–768. 2013. View Article : Google Scholar : PubMed/NCBI
94	Nagano H, Sakon M, Eguchi H, Kondo M, Yamamoto T, Ota H, Nakamura M, Wada H, Damdinsuren B, Marubashi S, et al: Hepatic resection followed by IFN-α and 5-FU for advanced hepatocellular carcinoma with tumor thrombus in the major portal branch. Hepatogastroenterology. 54:172–179. 2007.PubMed/NCBI
95	Choi JW, Park JY, Ahn SH, Yoon KT, Ko HK, Lee do Y, Lee JT, Kim KS, Choi JS, Han KH, et al: Efficacy and safety of transarterial chemoembolization in recurrent hepatocellular carcinoma after curative surgical resection. Am J Surg Oncol. 32:564–569. 2009. View Article : Google Scholar
96	Li KW, Li X, Wen TF and Lu WS: The effect of postoperative TACE on prognosis of HCC: an update. Hepatogastroenterology. 60:248–251. 2013.PubMed/NCBI
97	Tanaka K, Yabushita Y, Nakagawa K, Kumamoto T, Matsuo K, Taguri M and Endo I: Debulking surgery followed by intraarterial 5-fluorouracil chemotherapy plus subcutaneous interferon alfa for massive hepatocellular carcinoma with multiple intrahepatic metastases: a pilot study. Eur J Surg Oncol. 39:1364–1370. 2013. View Article : Google Scholar : PubMed/NCBI
98	Kumamoto T, Tanaka K, Matsuo K, Takeda K, Nojiri K, Mori K, Taniguchi K, Matsuyama R, Ueda M, Akiyama H, et al: Adjuvant hepatic arterial infusion chemotherapy with 5-Fluorouracil and interferon after curative resection of hepatocellular carcinoma: a preliminary report. Anticancer Res. 33:5585–5590. 2013.PubMed/NCBI
99	Yan Q, Ni J, Zhang GL, Yao X, Yuan WB, Zhou L and Zheng SS: Efficacy of postoperative antiviral combined transcatheter arterial chemoembolization therapy in prevention of hepatitis B-related hepatocellular carcinoma recurrence. Chin Med J (Engl). 126:855–859. 2013.
100	Xie B, Wang DH and Spechcer SJ: Sorafenib for treatment of hepatocellular carcinoma: a systematic review. Dig Dis Sci. 57:1122–1129. 2012. View Article : Google Scholar : PubMed/NCBI
101	Zhu AX: Development of sorafenib and other molecularly targeted agents in hepatocellular carcinoma. Cancer. 112:250–259. 2008. View Article : Google Scholar
102	Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilkie S, Wilhelm S and Lynch M: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66:11851–11858. 2006. View Article : Google Scholar : PubMed/NCBI
103	Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
104	Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, et al: 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. 10:25–34. 2009. View Article : Google Scholar
105	Pawlik TM, Reyes DK, Cosgrove D, Kamel IR, Bhagat N and Geschwind JF: Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. J Clin Oncol. 29:3960–3967. 2011. View Article : Google Scholar : PubMed/NCBI
106	Wang SN, Chuang SC and Lee KT: Efficacy of sorafenib as adjuvant therapy to prevent early recurrence of hepatocellular carcinoma after curative surgery: A pilot study. Heptatol Res. 44:523–531. 2014. View Article : Google Scholar
107	Kim R, Menon N and Aucejo F: Safe use of sorafenib in a patient undergoing salvage liver transplantation for recurrent hepatocellular carcinoma after hepatic resection. Med Oncol. 28:1044–1047. 2011. View Article : Google Scholar
108	Kudo M: Adjuvant therapy after curative treatment for hepatocellular carcinoma. Oncology. 81(Suppl 1): 50–55. 2011. View Article : Google Scholar
109	Kusano H, Ogasawara S, Akiba J, Nakayama M, Ueda K and Yano H: Antiproliferative effects of sorafenib and pegylated IFN-α2b on human liver cancer cells in vitro and in vivo. Int J Oncol. 42:1897–1903. 2013.PubMed/NCBI
110	Wang L, Jia D, Duan F, Sun Z, Liu X, Zhou L, Sun L, Ren S, Ruan Y and Gu J: Combined anti-tumor effects of IFN-α and sorafenib on hepatocellular carcinoma in vitro and in vivo. Biochem Biophy Res Commun. 422:687–692. 2012. View Article : Google Scholar
111	Huang G, Lai EC, Lau WY, Zhou WP, Shen F, Pan ZY, Fu SY and Wu MC: Posthepatectomy HBV reactivation in hepatitis B-related hepatocellular carcinoma influences postoperative survival in patients with preoperative low HBV-DNA levels. Ann Surg. 257:490–505. 2012. View Article : Google Scholar : PubMed/NCBI
112	Su CW, Chiou YW, Tsai YH, Teng RD, Chau GY, Lei HJ, Hung HH, Huo TI and Wu JC: The influence of hepatitis B viral load and pre-s deletion mutations on post-operative recurrence of hepatocellular carcinoma and the tertiary preventive effects by anti-viral therapy. PloS One. 8:e664572013. View Article : Google Scholar : PubMed/NCBI
113	Albert A, Brunetto MR, Colombo M and Craxì A: Recent progress and new trends in the treatment of hepatitis B. J Med Virol. 67:458–462. 2002. View Article : Google Scholar
114	Takkenberg RB, Weegink CJ, Zaaijer HL and Reesink HW: New developments in antiviral therapy for chronic hepatitis B. Vox Sang. 98:481–494. 2010. View Article : Google Scholar