HBV/HCV相关肝细胞癌根治后抗病毒治疗
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摘要
背景：在全世界范围内，肝细胞癌（Hepatocellular carcinoma，HCC）占恶性肿瘤发病率第五位，占恶性肿瘤相关死亡率第三位，且由于病毒性肝炎、肥胖等的流行，HCC发病率不断上升。而据预测，有一半HCC新增病例和死亡发生于中国，慢性乙型肝炎（Hepatitis B virus，HBV）和慢性丙型肝炎（Hepatitis C virus，HCV）是HCC的主要病因。现阶段，对于肿瘤早期、肝储备功能尚可的患者，手术切除或消融是主要的治愈手段，但根治性治疗后，5年复发率仍然达到70%，且目前尚无有效手段预防HCC复发。已有许多研究证明抗病毒治疗可预防HCC的发生，推测抗病毒治疗应能预防HCC根治后复发，延长生存，但现有的研究结果却未获得一致结论。
目的：1.评估HBV/HCV相关HCC根治后抗病毒治疗对复发和生存的影响；2.评估辅助抗病毒治疗的安全性；3.分层分析：辅助干扰素（Interferon，IFN）抗病毒治疗的有效性和安全性；辅助核苷（酸）类似物抗病毒治疗的有效性和安全性；HBV相关HCC根治后辅助抗病毒治疗的有效性和安全性；HCV相关HCC根治后辅助抗病毒治疗的有效性和安全性。
方法：我们系统检索了截止2012年12月19日以下四大电子数据库的所有文献：MEDLINE (PubMed)，EMBASE，Cochrane Library databases和Science Citation IndexExpanded。同时手工检索纳入文献和相关综述的参考文献，不限制语言和文献种类。只有比较HCC根治后辅助抗病毒治疗和安慰剂或无任何辅助治疗的随机对照实验（Randomized controlled trials，RCT）才纳入本研究。2名研究者独立筛选文献、提取数据和评估偏倚风险。对于生存数据（时间事件指标），选取风险比（Hazard ratio，HR）及其95%可信区间（Confidence interval，CI）作为效应指标；统计分析使用RevMan5.1和Stata11.0软件；所有研究均采用意向性治疗（Intention-to-treat，ITT）原则分析数据。
结果：9个RCT纳入本研究（其中3个低偏倚风险；6个偏倚风险不确定）；共纳入954名病人，经随机分组后，493名进入辅助抗病毒治疗组；461名进入对照组。所有纳入的研究均使用传统IFN行辅助抗病毒治疗，没有研究使用聚乙二醇干扰素或核苷（酸）类似物。与对照组相比，辅助IFN治疗组无复发生存（HR=0.81，95%CI=0.68～0.95；p=0.01）和总生存（HR=0.59，95%CI=0.46～0.76；p<0.0001）均明显改善。亚组分析显示：HCV相关HCC患者可从辅助IFN治疗中明显获益，而HBV相关HCC患者间则无统计学差异。由于中重度药物副作用，如白细胞减少、中性粒细胞减少、血小板减少、肝脏毒性等，28.3%的病人需要减量，8.2%的病人需要停药。
结论：我们的研究表明，HBV/HCV相关HCC根治后辅助IFN抗病毒治疗很可能使患者获益，尤其是对于HCV相关HCC患者。需要进行更多高质量的随机对照试验，研究更强有力的抗病毒药物，单独使用或联用，用于辅助治疗病毒相关性HCC，尤其是HBV相关HCC。未来的研究还需要更多关注患者生活质量和药物副作用等。
Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and thethird most frequent cause of cancer-related death worldwide. Due to the prevalence of theviral hepatitis, obesity, and so on, the incidence rates of HCC are increasing all over theworld. Half of these cases were estimated to occur in China. Hepatitis B virus (HBV) andhepatitis C virus (HCV) are the main cause of HCC. Nowadays, for patients with earlytumor stage and compensated liver function, surgical resection or ablation is the maincurative treatment choice. But approximately70%of patients suffered from recurrenceafter curative treatment within five years. Besides, there was not any effective strategy toprevent HCC recurrence. Antiviral regimens have been shown to improve the liverpathology and reduce the risk of HCC in patients with chronic viral hepatitis. It ishypothesized that adjuvant antiviral therapy following curative treatment of HCC wouldprevent recurrence and meanwhile improve survival. But available published work reportscontroversial results.
Aim:1. To evaluate the effect of adjuvant antiviral therapy on recurrence and survivalafter curative treatment of HBV/HCV-related HCC;2. To evaluate the safety of adjuvantantiviral therapy;3. Stratified analyses: adjuvant interferon (IFN) therapy versus placebo orno treatment, adjuvant nucleos(t)ide analogs (NA) therapy versus placebo or no treatment,subgroup of HBV-related HCC and subgroup of HCV-related HCC will be analyzed if thenecessary data is provided.
Methods: We conducted a systematic search using electronic databases (PubMed,EMBASE, Cochrane Library databases and Science Citation Index Expanded) for all thepublished studies without restriction of language or publication type (last date of searchingpublished work:19December,2012). Reference lists of all identified papers (includedstudies and relevant reviews) were checked for additional studies suitable for inclusion. Allrandomized controlled trials comparing adjuvant antiviral therapy versus placebo or notreatment were considered for this review. Two authors independently identified the trialsfor inclusion, extracted data and assessed the risk of bias. Results were expressed as HazardRatio (HR) for time-to-event outcomes with95%confidence intervals (CI). The statisticswere performed by RevMan version5.1and STATA version11.0. All studies wereanalyzed using the 'intention to treat' principle.
Results: We included nine trials (three of low risk of bias and six of unclear risk of bias)with954patients randomized:493to the adjuvant antiviral therapy group and461to thecontrol group. All the included studies used conventional IFN as adjuvant antiviral therapy;none of them used pegylated IFN or NA. There were significant improvements forrecurrence free survival (HR=0.81,95%CI=0.68~0.95; P=0.01) and overall survival(HR=0.59,95%CI=0.46~0.76; P <0.0001) in the adjuvant IFN group compared withthe control group. Subgroup analysis also showed a significant difference favoring IFNtherapy in HCV-related HCC patients, but for HBV-related patients, the difference failed toreach statistical significance between the two groups. A dose reduction was needed in28.3%of patients and discontinuation of IFN therapy happened in8.2%of patients due tomoderate to severe side-effects like leucocytopenia, neutropenia, thrombocytopenia andhepatic toxicity.
Conclusion: Our study suggested potential benefits of adjuvant IFN therapy followingcurative treatment of HBV/HCV-HCC, especially for HCV-related HCC. Further high-quality randomized controlled trials of more potent adjuvant antiviral regimens, eitherused alone or in combination, for virus-related HCC, especially HBV-related HCC, areneeded. Future trials should also focus on other clinically relevant aspects, such as qualityof life and adverse effects.
目的：1.评估HBV/HCV相关HCC根治后抗病毒治疗对复发和生存的影响；2.评估辅助抗病毒治疗的安全性；3.分层分析：辅助干扰素（Interferon，IFN）抗病毒治疗的有效性和安全性；辅助核苷（酸）类似物抗病毒治疗的有效性和安全性；HBV相关HCC根治后辅助抗病毒治疗的有效性和安全性；HCV相关HCC根治后辅助抗病毒治疗的有效性和安全性。
方法：我们系统检索了截止2012年12月19日以下四大电子数据库的所有文献：MEDLINE (PubMed)，EMBASE，Cochrane Library databases和Science Citation IndexExpanded。同时手工检索纳入文献和相关综述的参考文献，不限制语言和文献种类。只有比较HCC根治后辅助抗病毒治疗和安慰剂或无任何辅助治疗的随机对照实验（Randomized controlled trials，RCT）才纳入本研究。2名研究者独立筛选文献、提取数据和评估偏倚风险。对于生存数据（时间事件指标），选取风险比（Hazard ratio，HR）及其95%可信区间（Confidence interval，CI）作为效应指标；统计分析使用RevMan5.1和Stata11.0软件；所有研究均采用意向性治疗（Intention-to-treat，ITT）原则分析数据。
结果：9个RCT纳入本研究（其中3个低偏倚风险；6个偏倚风险不确定）；共纳入954名病人，经随机分组后，493名进入辅助抗病毒治疗组；461名进入对照组。所有纳入的研究均使用传统IFN行辅助抗病毒治疗，没有研究使用聚乙二醇干扰素或核苷（酸）类似物。与对照组相比，辅助IFN治疗组无复发生存（HR=0.81，95%CI=0.68～0.95；p=0.01）和总生存（HR=0.59，95%CI=0.46～0.76；p<0.0001）均明显改善。亚组分析显示：HCV相关HCC患者可从辅助IFN治疗中明显获益，而HBV相关HCC患者间则无统计学差异。由于中重度药物副作用，如白细胞减少、中性粒细胞减少、血小板减少、肝脏毒性等，28.3%的病人需要减量，8.2%的病人需要停药。
结论：我们的研究表明，HBV/HCV相关HCC根治后辅助IFN抗病毒治疗很可能使患者获益，尤其是对于HCV相关HCC患者。需要进行更多高质量的随机对照试验，研究更强有力的抗病毒药物，单独使用或联用，用于辅助治疗病毒相关性HCC，尤其是HBV相关HCC。未来的研究还需要更多关注患者生活质量和药物副作用等。
Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and thethird most frequent cause of cancer-related death worldwide. Due to the prevalence of theviral hepatitis, obesity, and so on, the incidence rates of HCC are increasing all over theworld. Half of these cases were estimated to occur in China. Hepatitis B virus (HBV) andhepatitis C virus (HCV) are the main cause of HCC. Nowadays, for patients with earlytumor stage and compensated liver function, surgical resection or ablation is the maincurative treatment choice. But approximately70%of patients suffered from recurrenceafter curative treatment within five years. Besides, there was not any effective strategy toprevent HCC recurrence. Antiviral regimens have been shown to improve the liverpathology and reduce the risk of HCC in patients with chronic viral hepatitis. It ishypothesized that adjuvant antiviral therapy following curative treatment of HCC wouldprevent recurrence and meanwhile improve survival. But available published work reportscontroversial results.
Aim:1. To evaluate the effect of adjuvant antiviral therapy on recurrence and survivalafter curative treatment of HBV/HCV-related HCC;2. To evaluate the safety of adjuvantantiviral therapy;3. Stratified analyses: adjuvant interferon (IFN) therapy versus placebo orno treatment, adjuvant nucleos(t)ide analogs (NA) therapy versus placebo or no treatment,subgroup of HBV-related HCC and subgroup of HCV-related HCC will be analyzed if thenecessary data is provided.
Methods: We conducted a systematic search using electronic databases (PubMed,EMBASE, Cochrane Library databases and Science Citation Index Expanded) for all thepublished studies without restriction of language or publication type (last date of searchingpublished work:19December,2012). Reference lists of all identified papers (includedstudies and relevant reviews) were checked for additional studies suitable for inclusion. Allrandomized controlled trials comparing adjuvant antiviral therapy versus placebo or notreatment were considered for this review. Two authors independently identified the trialsfor inclusion, extracted data and assessed the risk of bias. Results were expressed as HazardRatio (HR) for time-to-event outcomes with95%confidence intervals (CI). The statisticswere performed by RevMan version5.1and STATA version11.0. All studies wereanalyzed using the 'intention to treat' principle.
Results: We included nine trials (three of low risk of bias and six of unclear risk of bias)with954patients randomized:493to the adjuvant antiviral therapy group and461to thecontrol group. All the included studies used conventional IFN as adjuvant antiviral therapy;none of them used pegylated IFN or NA. There were significant improvements forrecurrence free survival (HR=0.81,95%CI=0.68~0.95; P=0.01) and overall survival(HR=0.59,95%CI=0.46~0.76; P <0.0001) in the adjuvant IFN group compared withthe control group. Subgroup analysis also showed a significant difference favoring IFNtherapy in HCV-related HCC patients, but for HBV-related patients, the difference failed toreach statistical significance between the two groups. A dose reduction was needed in28.3%of patients and discontinuation of IFN therapy happened in8.2%of patients due tomoderate to severe side-effects like leucocytopenia, neutropenia, thrombocytopenia andhepatic toxicity.
Conclusion: Our study suggested potential benefits of adjuvant IFN therapy followingcurative treatment of HBV/HCV-HCC, especially for HCV-related HCC. Further high-quality randomized controlled trials of more potent adjuvant antiviral regimens, eitherused alone or in combination, for virus-related HCC, especially HBV-related HCC, areneeded. Future trials should also focus on other clinically relevant aspects, such as qualityof life and adverse effects.
引文
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics.CA Cancer J Clin2011;61:69-90.
2. Yang WS, Va P, Bray F, Gao S, Gao J, Li HL, Xiang YB. The role of pre-existingdiabetes mellitus on hepatocellular carcinoma occurrence and prognosis: ameta-analysis of prospective cohort studies. PLoS One2011;6: e27326.
3. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence,mortality, and survival trends in the United States from1975to2005. J Clin Oncol2009;27:1485-91.
4. Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C. Trends in mortalityfrom hepatocellular carcinoma in Europe,1980-2004. Hepatology2008;48:137-45.
5. Parkin DM. The global health burden of infection-associated cancers in the year2002.Int J Cancer2006;118:3030-44.
6. Tsukuma H, Tanaka H, Ajiki W, Oshima A. Liver cancer and its prevention. AsianPac J Cancer Prev2005;6:244-50.
7. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F,Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment ofsmall hepatocellular carcinomas in patients with cirrhosis. N Engl J Med1996;334:693-9.
8. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology2005;42:1208-36.
9. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol2005;40:225-35.
10. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation forhepatocellular carcinoma. Semin Liver Dis2005;25:181-200.
11. Shiraha H, Yamamoto K, Namba M. Human hepatocyte carcinogenesis (Review). IntJ Oncol2013;42:1133-8.
12. Zemel R, Issachar A, Tur-Kaspa R. The role of oncogenic viruses in the pathogenesisof hepatocellular carcinoma. Clin Liver Dis2011;15:261-79, vii-x.
13. Fujita N, Sugimoto R, Ma N, Tanaka H, Iwasa M, Kobayashi Y, Kawanishi S,Watanabe S, Kaito M, Takei Y. Comparison of hepatic oxidative DNA damage inpatients with chronic hepatitis B and C. J Viral Hepat2008;15:498-507.
14. Lin SM, Lin CJ, Hsu CW, Tai DI, Sheen IS, Lin DY, Liaw YF. Prospectiverandomized controlled study of interferon-alpha in preventing hepatocellularcarcinoma recurrence after medical ablation therapy for primary tumors. Cancer2004;100:376-82.
15. Jeong SW, Jang JY, Chung RT. Hepatitis C virus and hepatocarcinogenesis. Clin MolHepatol2012;18:347-56.
16. Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, Capussotti L,Calise F, Pellicci R, Belli G, Tagger A, Colombo M, et al. Prevention ofhepatocellular carcinoma recurrence with alpha-interferon after liver resection inHCV cirrhosis. Hepatology2006;44:1543-54.
17. Miao RY, Zhao HT, Yang HY, Mao YL, Lu X, Zhao Y, Liu CN, Zhong SX, Sang XT,Huang JF. Postoperative adjuvant antiviral therapy for hepatitis B/C virus-relatedhepatocellular carcinoma: A meta-analysis. World Journal of Gastroenterology2010;16:2931-42.
18. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect ofinterferon therapy in patients with chronic hepatitis B virus infection. Hepatology1999;29:971-5.
19. Miyake Y, Kobashi H, Yamamoto K. Meta-analysis: the effect of interferon ondevelopment of hepatocellular carcinoma in patients with chronic hepatitis B virusinfection. J Gastroenterol2009;44:470-5.
20. Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitisB infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther2008;28:1067-77.
21. Yang YF, Zhao W, Zhong YD, Xia HM, Shen L, Zhang N. Interferon therapy inchronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: ameta-analysis. J Viral Hepat2009;16:265-71.
22. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM,Shue K, Keene ON, Dixon JS, Gray DF, et al. Lamivudine for patients with chronichepatitis B and advanced liver disease. N Engl J Med2004;351:1521-31.
23. Shamliyan TA, MacDonald R, Shaukat A, Taylor BC, Yuan JM, Johnson JR, TacklindJ, Rutks I, Kane RL, Wilt TJ. Antiviral therapy for adults with chronic hepatitis B: asystematic review for a National Institutes of Health Consensus DevelopmentConference. Ann Intern Med2009;150:111-24.
24. Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, Shiomi S,Seki S, Kobayashi K, Otani S. Randomised trial of effects of interferon-alpha onincidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis.Lancet1995;346:1051-5.
25. Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, Tsubota A, ChayamaK, Murashima N, Kumada H. Interferon beta prevents recurrence of hepatocellularcarcinoma after complete resection or ablation of the primary tumor-A prospectiverandomized study of hepatitis C virus-Related liver cancer. Hepatology2000;32:228-32.
26. Miyaguchi S, Watanabe T, Takahashi H, Nakamura M, Saito H, Ishii H. Interferontherapy for hepatocellular carcinoma patients with low HCV-RNA levels.Hepatogastroenterology2002;49:724-9.
27. Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, Koike Y, Yoshida H,Omata M. Interferon therapy after tumor ablation improves prognosis in patients withhepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med2003;138:299-306.
28. Nishiguchi S, Tamori A, Kubo S. Effect of long-term postoperative interferon therapyon intrahepatic recurrence and survival rate after resection of hepatitis C virus-relatedhepatocellular carcinoma. Intervirology2005;48:71-5.
29. Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ,Fan J, Zhou XD, Zhou J, et al. Postoperative interferon alpha treatment postponedrecurrence and improved overall survival in patients after curative resection ofHBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res ClinOncol2006;132:458-65.
30. Lo CM, Liu CL, Chan SC, Lam CM, Poon RTP, Ng IOL, Fan ST, Wong J. Arandomized, controlled trial of postoperative adjuvant interferon therapy afterresection of hepatocellular carcinoma. Annals of Surgery2007;245:831-42.
31. Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL,Lee WC, Chau GY, Chen YS, et al. Long-term results of a randomized,observation-controlled, phase III Trial of Adjuvant Interferon alfa-2b inhepatocellular carcinoma after curative resection. Annals of Surgery2012;255:8-17.
32. Zhong JH, Li H, Li LQ, You XM, Zhang Y, Zhao YN, Liu JY, Xiang BD, Wu GB.Adjuvant therapy options following curative treatment of hepatocellular carcinoma: Asystematic review of randomized trials. Ejso2012;38:286-95.
33. Zhang CH, Xu GL, Jia WD, Ge YS. Effects of interferon alpha treatment onrecurrence and survival after complete resection or ablation of hepatocellularcarcinoma: A meta-analysis of randomized controlled trials. International Journal ofCancer2009;124:2982-8.
34. Breitenstein S, Dimitroulis D, Petrowsky H, Puhan MA, Mullhaupt B, Clavien PA.Systematic review and meta-analysis of interferon after curative treatment ofhepatocellular carcinoma in patients with viral hepatitis. British Journal of Surgery2009;96:975-81.
35. Shen YC, Hsu C, Chen LT, Cheng CC, Hu FC, Cheng AL. Adjuvant interferontherapy after curative therapy for hepatocellular carcinoma (HCC): A meta-regressionapproach. Journal of Hepatology2010;52:889-94.
36. Miyake Y, Takaki A, Iwasaki Y, Yamamoto K. Meta-analysis: interferon-alphaprevents the recurrence after curative treatment of hepatitis C virus-relatedhepatocellular carcinoma. Journal of Viral Hepatitis2010;17:287-92.
37. Singal AK, Freeman Jr DH, Anand BS. Meta-analysis: Interferon improves outcomesfollowing ablation or resection of hepatocellular carcinoma. AlimentaryPharmacology and Therapeutics2010;32:851-8.
38. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, Porter AC,Tugwell P, Moher D, Bouter LM. Development of AMSTAR: a measurement tool toassess the methodological quality of systematic reviews. BMC Med Res Methodol2007;7:10.
39. Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, Wu MS, Lin JT. Association betweennucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinomarecurrence following liver resection. JAMA2012;308:1906-14.
40. Lee JW, Lee JI, Chung HJ, Kim YS, Lee DH. Effect of antiviral therapy on laterecurrence after curative resection of B-viral hepatocellular carcinoma (HCC).Journal of Hepatology2012;56: S398.
41. Jeong E, Lee JW, Lee JI, Kim YS, Jeong S, Haeng L. Antiviral therapy after curativeresection of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC)improves the outcome in patients with high serum HBV DNA level. Hepatology2011;54:1384A.
42. Hann HW, Bergin D, Coben R, Dimarino AJ. Prevention of new hepatocellularcarcinoma with concomitant antiviral therapy in chronic hepatitis B patients whoseinitial tumor was successfully ablated. International Journal of Cancer2011;128:740-3.
43. Chan ACY, Chok KSH, Yuen WK, Chan SC, Poon RTP, Lo CM, Fan ST. Impact ofantiviral therapy on the survival of patients after major hepatectomy for hepatitis Bvirus-related hepatocellular carcinoma. Archives of Surgery2011;146:675-81.
44. Inuzuka T. Nucleotide analogues may prolong survival time without recurrence andoverall survival time for HBV-related liver diseases after curative treatment ofhepatocellular carcinoma. Hepatology2010;52:525A.
45. Koda M, Nagahara T, Matono T, Sugihara T, Mandai M, Ueki M, Ohyama K, HoshoK, Okano J, Kishimoto Y, Kono M, Maruyama S, et al. Nucleotide analogs forpatients with HBV-related hepatocellular carcinoma increase the survival rate throughimproved liver function. Intern Med2009;48:11-7.
46. Chuma M, Hige S, Kamiyama T, Meguro T, Nagasaka A, Nakanishi K, Yamamoto Y,Nakanishi M, Kohara T, Sho T, Yamamoto K, Horimoto H, et al. The influence ofhepatitis B DNA level and antiviral therapy on recurrence after initial curativetreatment in patients with hepatocellular carcinoma. J Gastroenterol2009;44:991-9.
47. Yoshida H, Goto E, Sato T, Ohki T, Masuzaki R, Tateishi R, Goto T, Shiina S,Kawabe T, Omata M. Safety and efficacy of lamivudine after radiofrequency ablationin patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Int2008;2:89-94.
48. Kuzuya T, Katano Y, Kumada T, Toyoda H, Nakano I, Hirooka Y, Itoh A, Ishigami M,Hayashi K, Honda T, Goto H. Efficacy of antiviral therapy with lamivudine afterinitial treatment for hepatitis B virus-related hepatocellular carcinoma. JGastroenterol Hepatol2007;22:1929-35.
49. Kubo S, Tanaka H, Takemura S, Yamamoto S, Hai S, Ichikawa T, Kodai S, ShinkawaH, Sakaguchi H, Tamori A, Habu D, Nishiguchi S. Effects of lamivudine on outcomeafter liver resection for hepatocellular carcinoma in patients with active replication ofhepatitis B virus. Hepatol Res2007;37:94-100.
50. Zhong JH, Li le Q, Wu LC. Lamivudine with or without adefovir dipivoxil forpostoperative hepatocellular carcinoma. Cochrane Database Syst Rev2011:CD008713.
51. Higgins JPT, Green S,(editors). Cochrane Handbook for Systematic Reviews ofInterventions Version5.1.0[updated March2011]. The Cochrane Collaboration2011.
52. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods forincorporating summary time-to-event data into meta-analysis. Trials2007;8:16.
53. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematicreviews and meta-analyses: the PRISMA statement. Ann Intern Med2009;151:264-9,W64.
54. Jin YJ, Shim JH, Lee HC, Yoo DJ, Kim KM, Lim YS, Suh DJ. Suppressive effects ofentecavir on hepatitis B virus and hepatocellular carcinoma. J Gastroenterol Hepatol2011;26:1380-8.
55. Katagiri S, Tokushige K, Yamamoto M.[Postoperative interferon therapy afterresection of hepatitis C virus-related hepatocellular carcinoma]. Nihon ShokakibyoGakkai Zasshi2008;105:795-801.
56. Uenishi T, Nishiguchi S, Tamori A, Yamamoto T, Shuto T, Hirohashi K, Takemura S,Tanaka H, Kubo S. Influence of interferon therapy on outcome after surgery forhepatitis C virus-related hepatocellular carcinoma. Hepatol Res2006;36:195-200.
57. Chen LT, Chen MF, Lee LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL,Lee WC, Chau GY, Chen YS, et al. Randomized phase III study of adjuvantinterferon alfa-2b in hepatocellular carcinoma with curative resection. Hepatology2005Oct;42Suppl.1:237A-8A.
58. Cheng SQ, Wu MC, Chen H, Shen F, Yang JH, Cong WM, Zhao YX, Wang PJ.[Anti-viral therapy using lamivudine and thymosin is helpful to prevent recurrence inhepatocellular carcinoma with coexisting active hepatitis B]. Zhonghua Zhong Liu ZaZhi2005;27:114-6.
59. Mazzaferro V, Romito R, ColomboM, Capussotti L, Polastri R, Pellicci R, Calise F,Belli G, Mariani L, Camerini T, Bonino F, On behalf of The HITF. Prospectiverandomised trial on IFN-therapy for the secondary prevention of HCC recurrenceafter curative resection in HCV related cirrhosis. Preliminary report [EASL abstract].Journal of Hepatology2004;4034.
60. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Kinoshita H. Randomizedclinical trial of long-term outcome after resection of hepatitis C virus-relatedhepatocellular carcinoma by postoperative interferon therapy. Br J Surg2002;89:418-22.
61. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Yamazaki O, Shiomi S,Tamori A, Oka H, Igawa S, Kuroki T, Kinoshita H. Effects of long-term postoperativeinterferon-alpha therapy on intrahepatic recurrence after resection of hepatitis Cvirus-related hepatocellular carcinoma. A randomized, controlled trial. Ann InternMed2001;134:963-7.
62. Nishiguchi S, Kubo S, Tamori A, Shiomi S, Tanaka H, Shuto T, Yamazaki O,Hirohashi K, Oka H, Igawa S, Kuroki T, Kinoshita H. Randomized trial ofpostoperative long-term interferon-alpha on intrahepatic recurrence after resection ofhepatocellular carcinoma related to hepatitis C virus: a preliminary report [abtract].Journal of Gastroenterology and Hepatology2000;15Suppl: F9.
63. Nishiguchi S, Kubo S, Hirohashi K, Shuto T, Yamazaki O, Oka H. Effects ofpostoperative interferon-a on recurrence after curative resection in patients withhepatitis C virus-related hepatocellular carcinoma:A prospective randomized trial[abstract]. Hepatology1999;30:212a.
64. Nishiguchi S, Kubo S. Randomized trial of post-operative interferon therapy afterresection of hepatitis C virus-related hepatocellular carcinoma and long-termoutcomeed. Tokyo: Springer Japan,2004.209-18.
65. von Marschall Z, Scholz A, Cramer T, Schafer G, Schirner M, Oberg K, WiedenmannB, Hocker M, Rosewicz S. Effects of interferon alpha on vascular endothelial growthfactor gene transcription and tumor angiogenesis. J Natl Cancer Inst2003;95:437-48.
66. Dinney CP, Bielenberg DR, Perrotte P, Reich R, Eve BY, Bucana CD, Fidler IJ.Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth ofhuman bladder carcinoma in mice by systemic interferon-alpha administration.Cancer Res1998;58:808-14.
67. Wang L, Wu WZ, Sun HC, Wu XF, Qin LX, Liu YK, Liu KD, Tang ZY. Mechanismof interferon alpha on inhibition of metastasis and angiogenesis of hepatocellularcarcinoma after curative resection in nude mice. J Gastrointest Surg2003;7:587-94.
68. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S,Sugawara Y, Minagawa M, Takayama T, Kawasaki S, Makuuchi M. Risk factorscontributing to early and late phase intrahepatic recurrence of hepatocellularcarcinoma after hepatectomy. J Hepatol2003;38:200-7.
69. Poon RT, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Different risk factors andprognosis for early and late intrahepatic recurrence after resection of hepatocellularcarcinoma. Cancer2000;89:500-7.
70. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet2003;362:1907-17.
71. Bouchard MJ, Navas-Martin S. Hepatitis B and C virus hepatocarcinogenesis: lessonslearned and future challenges. Cancer Lett2011;305:123-43.
72. Gale M, Jr., Foy EM. Evasion of intracellular host defence by hepatitis C virus.Nature2005;436:939-45.
73. Foy E, Li K, Wang C, Sumpter R, Jr., Ikeda M, Lemon SM, Gale M, Jr. Regulation ofinterferon regulatory factor-3by the hepatitis C virus serine protease. Science2003;300:1145-8.
74. Liaw Y-F, Kao J-H, Piratvisuth T, Chan H, Chien R-N, Liu C-J, Gane E, Locarnini S,Lim S-G, Han K-H, Amarapurkar D, Cooksley G, et al. Asian-Pacific consensusstatement on the management of chronic hepatitis B: a2012update. HepatologyInternational2012;6:531-61.
75. Bian ZX, Shang HC. CONSORT2010statement: updated guidelines for reportingparallel group randomized trials. Ann Intern Med2011;154:290-1; author reply1-2.
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics.CA Cancer J Clin2011;61:69-90.
2. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F,Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment ofsmall hepatocellular carcinomas in patients with cirrhosis. N Engl J Med1996;334:693-9.
3. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology2005;42:1208-36.
4. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol2005;40:225-35.
5. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation forhepatocellular carcinoma. Semin Liver Dis2005;25:181-200.
6. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect ofinterferon therapy in patients with chronic hepatitis B virus infection. Hepatology1999;29:971-5.
7. Miyake Y, Kobashi H, Yamamoto K. Meta-analysis: the effect of interferon ondevelopment of hepatocellular carcinoma in patients with chronic hepatitis B virusinfection. J Gastroenterol2009;44:470-5.
8. Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitisB infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther2008;28:1067-77.
9. Yang YF, Zhao W, Zhong YD, Xia HM, Shen L, Zhang N. Interferon therapy inchronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: ameta-analysis. J Viral Hepat2009;16:265-71.
10. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM,Shue K, Keene ON, Dixon JS, Gray DF, et al. Lamivudine for patients with chronichepatitis B and advanced liver disease. N Engl J Med2004;351:1521-31.
11. Lo CM, Liu CL, Chan SC, Lam CM, Poon RTP, Ng IOL, Fan ST, Wong J. Arandomized, controlled trial of postoperative adjuvant interferon therapy afterresection of hepatocellular carcinoma. Annals of Surgery2007;245:831-42.
12. Li N, Lai ECH, Shi J, Guo WX, Xue J, Huang B, Lau WY, Wu MC, Cheng SQ. Acomparative study of antiviral therapy after resection of hepatocellular carcinoma inthe immune-active phase of hepatitis B virus infection. Annals of Surgical Oncology2010;17:179-85.
13. Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL,Lee WC, Chau GY, Chen YS, et al. Long-term results of a randomized,observation-controlled, phase III Trial of Adjuvant Interferon alfa-2b inhepatocellular carcinoma after curative resection. Annals of Surgery2012;255:8-17.
14. Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, Wu MS, Lin JT. Association betweennucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinomarecurrence following liver resection. JAMA2012;308:1906-14.
15. Lee D, Chung YH, Kim JA, Jin YJ, Lee SH, Shim JH, Lim YS, Lee HC, Lee YS, SuhDJ, Ryu SH, Park NH, et al. Adjuvant pegylated interferon therapy for metastatictumor antigen1positive hepatocellular carcinoma treated with curative surgicalresection. Hepatology2010;52:1157A.
16. Someya T, Ikeda K, Saitoh S, Kobayashi M, Hosaka T, Sezaki H, Akuta N, Suzuki F,Suzuki Y, Arase Y, Kumada H. Interferon lowers tumor recurrence rate after surgicalresection or ablation of hepatocellular carcinoma: a pilot study of patients withhepatitis B virus-related cirrhosis. J Gastroenterol2006;41:1206-13.
17. Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ,Fan J, Zhou XD, Zhou J, et al. Postoperative interferon alpha treatment postponedrecurrence and improved overall survival in patients after curative resection ofHBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res ClinOncol2006;132:458-65.
18. Qu LS, Jin F, Huang XW, Shen XZ. Interferon-alpha therapy after curative resectionprevents early recurrence and improves survival in patients with hepatitis Bvirus-related hepatocellular carcinoma. J Surg Oncol2010;102:796-801.
19. Kubo S, Tanaka H, Takemura S, Yamamoto S, Hai S, Ichikawa T, Kodai S, ShinkawaH, Sakaguchi H, Tamori A, Habu D, Nishiguchi S. Effects of lamivudine on outcomeafter liver resection for hepatocellular carcinoma in patients with active replication ofhepatitis B virus. Hepatol Res2007;37:94-100.
20. Kuzuya T, Katano Y, Kumada T, Toyoda H, Nakano I, Hirooka Y, Itoh A, Ishigami M,Hayashi K, Honda T, Goto H. Efficacy of antiviral therapy with lamivudine afterinitial treatment for hepatitis B virus-related hepatocellular carcinoma. JGastroenterol Hepatol2007;22:1929-35.
21. Yoshida H, Goto E, Sato T, Ohki T, Masuzaki R, Tateishi R, Goto T, Shiina S,Kawabe T, Omata M. Safety and efficacy of lamivudine after radiofrequency ablationin patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Int2008;2:89-94.
22. Chuma M, Hige S, Kamiyama T, Meguro T, Nagasaka A, Nakanishi K, Yamamoto Y,Nakanishi M, Kohara T, Sho T, Yamamoto K, Horimoto H, et al. The influence ofhepatitis B DNA level and antiviral therapy on recurrence after initial curativetreatment in patients with hepatocellular carcinoma. J Gastroenterol2009;44:991-9.
23. Koda M, Nagahara T, Matono T, Sugihara T, Mandai M, Ueki M, Ohyama K, HoshoK, Okano J, Kishimoto Y, Kono M, Maruyama S, et al. Nucleotide analogs forpatients with HBV-related hepatocellular carcinoma increase the survival rate throughimproved liver function. Intern Med2009;48:11-7.
24. Inuzuka T. Nucleotide analogues may prolong survival time without recurrence andoverall survival time for HBV-related liver diseases after curative treatment ofhepatocellular carcinoma. Hepatology2010;52:525A.
25. Chan ACY, Chok KSH, Yuen WK, Chan SC, Poon RTP, Lo CM, Fan ST. Impact ofantiviral therapy on the survival of patients after major hepatectomy for hepatitis Bvirus-related hepatocellular carcinoma. Archives of Surgery2011;146:675-81.
26. Hann HW, Bergin D, Coben R, Dimarino AJ. Prevention of new hepatocellularcarcinoma with concomitant antiviral therapy in chronic hepatitis B patients whoseinitial tumor was successfully ablated. International Journal of Cancer2011;128:740-3.
27. Jeong E, Lee JW, Lee JI, Kim YS, Jeong S, Haeng L. Antiviral therapy after curativeresection of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC)improves the outcome in patients with high serum HBV DNA level. Hepatology2011;54:1384A.
28. Lee JW, Lee JI, Chung HJ, Kim YS, Lee DH. Effect of antiviral therapy on laterecurrence after curative resection of B-viral hepatocellular carcinoma (HCC).Journal of Hepatology2012;56: S398.
29. Yeung P, Wong DK, Lai CL, Fung J, Seto WK, Yuen MF. Association of hepatitis Bvirus pre-S deletions with the development of hepatocellular carcinoma in chronichepatitis B. J Infect Dis2011;203:646-54.
30. Yuen MF, Tanaka Y, Shinkai N, Poon RT, But DY, Fong DY, Fung J, Wong DK, YuenJC, Mizokami M, Lai CL. Risk for hepatocellular carcinoma with respect to hepatitisB virus genotypes B/C, specific mutations of enhancer II/core promoter/precoreregions and HBV DNA levels. Gut2008;57:98-102.
31. Zhang H, Zhai Y, Hu Z, Wu C, Qian J, Jia W, Ma F, Huang W, Yu L, Yue W, Wang Z,Li P, et al. Genome-wide association study identifies1p36.22as a new susceptibilitylocus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet2010;42:755-8.
32. Chan KY, Wong CM, Kwan JS, Lee JM, Cheung KW, Yuen MF, Lai CL, Poon RT,Sham PC, Ng IO. Genome-wide association study of hepatocellular carcinoma inSouthern Chinese patients with chronic hepatitis B virus infection. PLoS One2011;6:e28798.
33. Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence ofhepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)idetherapy: a systematic review. J Hepatol2010;53:348-56.
34. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W,Goodman Z, Chi YC, Zhang H, et al. Long-term entecavir therapy results in thereversal of fibrosis/cirrhosis and continued histological improvement in patients withchronic hepatitis B. Hepatology2010;52:886-93.
35. Lai CL, Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinomawith antiviral therapy. Hepatology2013;57:399-408.
36. KASL Clinical Practice Guidelines: Management of chronic hepatitis B. Clin MolHepatol2012;18:109-62.
37. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection.J Hepatol2012;57:167-85.
38. An HJ, Jang JW, Kwon JH, You CR, Kim JD, Bae SH, Choi JY, Yoon SK, Lee KH,Kim DG. Effect of hepatitis B viral status on cancer recurrence and long-termprognosis after surgical resection in patients with hepatocellular carcinoma.Hepatology International2010;4:310.
39. Shim JH, Lee HC, Choi JG, Lee D, Kim KM, Lim YS, Chung YH, Lee YS, Suh DJ.Clinical implication of hepatitis B viral load in hepatitis B E antigen-negative chronichepatitis B patients with hepatocellular carcinoma treated with curative resection.Journal of Hepatology2011;54: S301.
40. Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, Huo TI, Sheen IJ. Differentialroles of tumor, hepatic inflammation and hepatitis B virus in early and latehepatocellular carcinoma recurrences. Journal of Hepatology2009;50: S304.
41. Wang L, Wu WZ, Sun HC, Wu XF, Qin LX, Liu YK, Liu KD, Tang ZY. Mechanismof interferon alpha on inhibition of metastasis and angiogenesis of hepatocellularcarcinoma after curative resection in nude mice. J Gastrointest Surg2003;7:587-94.
42. Huang G, Lai ECH, Lau WY, Zhou WP, Shen F, Pan ZY, Fu SY, Wu MC.Posthepatectomy HBV reactivation in hepatitis B-Related hepatocellular carcinomainfluences postoperative survival in patients with preoperative low HBV-DNA levels.Annals of Surgery2013;257:490-505.
2. Yang WS, Va P, Bray F, Gao S, Gao J, Li HL, Xiang YB. The role of pre-existingdiabetes mellitus on hepatocellular carcinoma occurrence and prognosis: ameta-analysis of prospective cohort studies. PLoS One2011;6: e27326.
3. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence,mortality, and survival trends in the United States from1975to2005. J Clin Oncol2009;27:1485-91.
4. Bosetti C, Levi F, Boffetta P, Lucchini F, Negri E, La Vecchia C. Trends in mortalityfrom hepatocellular carcinoma in Europe,1980-2004. Hepatology2008;48:137-45.
5. Parkin DM. The global health burden of infection-associated cancers in the year2002.Int J Cancer2006;118:3030-44.
6. Tsukuma H, Tanaka H, Ajiki W, Oshima A. Liver cancer and its prevention. AsianPac J Cancer Prev2005;6:244-50.
7. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F,Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment ofsmall hepatocellular carcinomas in patients with cirrhosis. N Engl J Med1996;334:693-9.
8. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology2005;42:1208-36.
9. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol2005;40:225-35.
10. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation forhepatocellular carcinoma. Semin Liver Dis2005;25:181-200.
11. Shiraha H, Yamamoto K, Namba M. Human hepatocyte carcinogenesis (Review). IntJ Oncol2013;42:1133-8.
12. Zemel R, Issachar A, Tur-Kaspa R. The role of oncogenic viruses in the pathogenesisof hepatocellular carcinoma. Clin Liver Dis2011;15:261-79, vii-x.
13. Fujita N, Sugimoto R, Ma N, Tanaka H, Iwasa M, Kobayashi Y, Kawanishi S,Watanabe S, Kaito M, Takei Y. Comparison of hepatic oxidative DNA damage inpatients with chronic hepatitis B and C. J Viral Hepat2008;15:498-507.
14. Lin SM, Lin CJ, Hsu CW, Tai DI, Sheen IS, Lin DY, Liaw YF. Prospectiverandomized controlled study of interferon-alpha in preventing hepatocellularcarcinoma recurrence after medical ablation therapy for primary tumors. Cancer2004;100:376-82.
15. Jeong SW, Jang JY, Chung RT. Hepatitis C virus and hepatocarcinogenesis. Clin MolHepatol2012;18:347-56.
16. Mazzaferro V, Romito R, Schiavo M, Mariani L, Camerini T, Bhoori S, Capussotti L,Calise F, Pellicci R, Belli G, Tagger A, Colombo M, et al. Prevention ofhepatocellular carcinoma recurrence with alpha-interferon after liver resection inHCV cirrhosis. Hepatology2006;44:1543-54.
17. Miao RY, Zhao HT, Yang HY, Mao YL, Lu X, Zhao Y, Liu CN, Zhong SX, Sang XT,Huang JF. Postoperative adjuvant antiviral therapy for hepatitis B/C virus-relatedhepatocellular carcinoma: A meta-analysis. World Journal of Gastroenterology2010;16:2931-42.
18. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect ofinterferon therapy in patients with chronic hepatitis B virus infection. Hepatology1999;29:971-5.
19. Miyake Y, Kobashi H, Yamamoto K. Meta-analysis: the effect of interferon ondevelopment of hepatocellular carcinoma in patients with chronic hepatitis B virusinfection. J Gastroenterol2009;44:470-5.
20. Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitisB infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther2008;28:1067-77.
21. Yang YF, Zhao W, Zhong YD, Xia HM, Shen L, Zhang N. Interferon therapy inchronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: ameta-analysis. J Viral Hepat2009;16:265-71.
22. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM,Shue K, Keene ON, Dixon JS, Gray DF, et al. Lamivudine for patients with chronichepatitis B and advanced liver disease. N Engl J Med2004;351:1521-31.
23. Shamliyan TA, MacDonald R, Shaukat A, Taylor BC, Yuan JM, Johnson JR, TacklindJ, Rutks I, Kane RL, Wilt TJ. Antiviral therapy for adults with chronic hepatitis B: asystematic review for a National Institutes of Health Consensus DevelopmentConference. Ann Intern Med2009;150:111-24.
24. Nishiguchi S, Kuroki T, Nakatani S, Morimoto H, Takeda T, Nakajima S, Shiomi S,Seki S, Kobayashi K, Otani S. Randomised trial of effects of interferon-alpha onincidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis.Lancet1995;346:1051-5.
25. Ikeda K, Arase Y, Saitoh S, Kobayashi M, Suzuki Y, Suzuki F, Tsubota A, ChayamaK, Murashima N, Kumada H. Interferon beta prevents recurrence of hepatocellularcarcinoma after complete resection or ablation of the primary tumor-A prospectiverandomized study of hepatitis C virus-Related liver cancer. Hepatology2000;32:228-32.
26. Miyaguchi S, Watanabe T, Takahashi H, Nakamura M, Saito H, Ishii H. Interferontherapy for hepatocellular carcinoma patients with low HCV-RNA levels.Hepatogastroenterology2002;49:724-9.
27. Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, Koike Y, Yoshida H,Omata M. Interferon therapy after tumor ablation improves prognosis in patients withhepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med2003;138:299-306.
28. Nishiguchi S, Tamori A, Kubo S. Effect of long-term postoperative interferon therapyon intrahepatic recurrence and survival rate after resection of hepatitis C virus-relatedhepatocellular carcinoma. Intervirology2005;48:71-5.
29. Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ,Fan J, Zhou XD, Zhou J, et al. Postoperative interferon alpha treatment postponedrecurrence and improved overall survival in patients after curative resection ofHBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res ClinOncol2006;132:458-65.
30. Lo CM, Liu CL, Chan SC, Lam CM, Poon RTP, Ng IOL, Fan ST, Wong J. Arandomized, controlled trial of postoperative adjuvant interferon therapy afterresection of hepatocellular carcinoma. Annals of Surgery2007;245:831-42.
31. Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL,Lee WC, Chau GY, Chen YS, et al. Long-term results of a randomized,observation-controlled, phase III Trial of Adjuvant Interferon alfa-2b inhepatocellular carcinoma after curative resection. Annals of Surgery2012;255:8-17.
32. Zhong JH, Li H, Li LQ, You XM, Zhang Y, Zhao YN, Liu JY, Xiang BD, Wu GB.Adjuvant therapy options following curative treatment of hepatocellular carcinoma: Asystematic review of randomized trials. Ejso2012;38:286-95.
33. Zhang CH, Xu GL, Jia WD, Ge YS. Effects of interferon alpha treatment onrecurrence and survival after complete resection or ablation of hepatocellularcarcinoma: A meta-analysis of randomized controlled trials. International Journal ofCancer2009;124:2982-8.
34. Breitenstein S, Dimitroulis D, Petrowsky H, Puhan MA, Mullhaupt B, Clavien PA.Systematic review and meta-analysis of interferon after curative treatment ofhepatocellular carcinoma in patients with viral hepatitis. British Journal of Surgery2009;96:975-81.
35. Shen YC, Hsu C, Chen LT, Cheng CC, Hu FC, Cheng AL. Adjuvant interferontherapy after curative therapy for hepatocellular carcinoma (HCC): A meta-regressionapproach. Journal of Hepatology2010;52:889-94.
36. Miyake Y, Takaki A, Iwasaki Y, Yamamoto K. Meta-analysis: interferon-alphaprevents the recurrence after curative treatment of hepatitis C virus-relatedhepatocellular carcinoma. Journal of Viral Hepatitis2010;17:287-92.
37. Singal AK, Freeman Jr DH, Anand BS. Meta-analysis: Interferon improves outcomesfollowing ablation or resection of hepatocellular carcinoma. AlimentaryPharmacology and Therapeutics2010;32:851-8.
38. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, Porter AC,Tugwell P, Moher D, Bouter LM. Development of AMSTAR: a measurement tool toassess the methodological quality of systematic reviews. BMC Med Res Methodol2007;7:10.
39. Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, Wu MS, Lin JT. Association betweennucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinomarecurrence following liver resection. JAMA2012;308:1906-14.
40. Lee JW, Lee JI, Chung HJ, Kim YS, Lee DH. Effect of antiviral therapy on laterecurrence after curative resection of B-viral hepatocellular carcinoma (HCC).Journal of Hepatology2012;56: S398.
41. Jeong E, Lee JW, Lee JI, Kim YS, Jeong S, Haeng L. Antiviral therapy after curativeresection of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC)improves the outcome in patients with high serum HBV DNA level. Hepatology2011;54:1384A.
42. Hann HW, Bergin D, Coben R, Dimarino AJ. Prevention of new hepatocellularcarcinoma with concomitant antiviral therapy in chronic hepatitis B patients whoseinitial tumor was successfully ablated. International Journal of Cancer2011;128:740-3.
43. Chan ACY, Chok KSH, Yuen WK, Chan SC, Poon RTP, Lo CM, Fan ST. Impact ofantiviral therapy on the survival of patients after major hepatectomy for hepatitis Bvirus-related hepatocellular carcinoma. Archives of Surgery2011;146:675-81.
44. Inuzuka T. Nucleotide analogues may prolong survival time without recurrence andoverall survival time for HBV-related liver diseases after curative treatment ofhepatocellular carcinoma. Hepatology2010;52:525A.
45. Koda M, Nagahara T, Matono T, Sugihara T, Mandai M, Ueki M, Ohyama K, HoshoK, Okano J, Kishimoto Y, Kono M, Maruyama S, et al. Nucleotide analogs forpatients with HBV-related hepatocellular carcinoma increase the survival rate throughimproved liver function. Intern Med2009;48:11-7.
46. Chuma M, Hige S, Kamiyama T, Meguro T, Nagasaka A, Nakanishi K, Yamamoto Y,Nakanishi M, Kohara T, Sho T, Yamamoto K, Horimoto H, et al. The influence ofhepatitis B DNA level and antiviral therapy on recurrence after initial curativetreatment in patients with hepatocellular carcinoma. J Gastroenterol2009;44:991-9.
47. Yoshida H, Goto E, Sato T, Ohki T, Masuzaki R, Tateishi R, Goto T, Shiina S,Kawabe T, Omata M. Safety and efficacy of lamivudine after radiofrequency ablationin patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Int2008;2:89-94.
48. Kuzuya T, Katano Y, Kumada T, Toyoda H, Nakano I, Hirooka Y, Itoh A, Ishigami M,Hayashi K, Honda T, Goto H. Efficacy of antiviral therapy with lamivudine afterinitial treatment for hepatitis B virus-related hepatocellular carcinoma. JGastroenterol Hepatol2007;22:1929-35.
49. Kubo S, Tanaka H, Takemura S, Yamamoto S, Hai S, Ichikawa T, Kodai S, ShinkawaH, Sakaguchi H, Tamori A, Habu D, Nishiguchi S. Effects of lamivudine on outcomeafter liver resection for hepatocellular carcinoma in patients with active replication ofhepatitis B virus. Hepatol Res2007;37:94-100.
50. Zhong JH, Li le Q, Wu LC. Lamivudine with or without adefovir dipivoxil forpostoperative hepatocellular carcinoma. Cochrane Database Syst Rev2011:CD008713.
51. Higgins JPT, Green S,(editors). Cochrane Handbook for Systematic Reviews ofInterventions Version5.1.0[updated March2011]. The Cochrane Collaboration2011.
52. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods forincorporating summary time-to-event data into meta-analysis. Trials2007;8:16.
53. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematicreviews and meta-analyses: the PRISMA statement. Ann Intern Med2009;151:264-9,W64.
54. Jin YJ, Shim JH, Lee HC, Yoo DJ, Kim KM, Lim YS, Suh DJ. Suppressive effects ofentecavir on hepatitis B virus and hepatocellular carcinoma. J Gastroenterol Hepatol2011;26:1380-8.
55. Katagiri S, Tokushige K, Yamamoto M.[Postoperative interferon therapy afterresection of hepatitis C virus-related hepatocellular carcinoma]. Nihon ShokakibyoGakkai Zasshi2008;105:795-801.
56. Uenishi T, Nishiguchi S, Tamori A, Yamamoto T, Shuto T, Hirohashi K, Takemura S,Tanaka H, Kubo S. Influence of interferon therapy on outcome after surgery forhepatitis C virus-related hepatocellular carcinoma. Hepatol Res2006;36:195-200.
57. Chen LT, Chen MF, Lee LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL,Lee WC, Chau GY, Chen YS, et al. Randomized phase III study of adjuvantinterferon alfa-2b in hepatocellular carcinoma with curative resection. Hepatology2005Oct;42Suppl.1:237A-8A.
58. Cheng SQ, Wu MC, Chen H, Shen F, Yang JH, Cong WM, Zhao YX, Wang PJ.[Anti-viral therapy using lamivudine and thymosin is helpful to prevent recurrence inhepatocellular carcinoma with coexisting active hepatitis B]. Zhonghua Zhong Liu ZaZhi2005;27:114-6.
59. Mazzaferro V, Romito R, ColomboM, Capussotti L, Polastri R, Pellicci R, Calise F,Belli G, Mariani L, Camerini T, Bonino F, On behalf of The HITF. Prospectiverandomised trial on IFN-therapy for the secondary prevention of HCC recurrenceafter curative resection in HCV related cirrhosis. Preliminary report [EASL abstract].Journal of Hepatology2004;4034.
60. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Kinoshita H. Randomizedclinical trial of long-term outcome after resection of hepatitis C virus-relatedhepatocellular carcinoma by postoperative interferon therapy. Br J Surg2002;89:418-22.
61. Kubo S, Nishiguchi S, Hirohashi K, Tanaka H, Shuto T, Yamazaki O, Shiomi S,Tamori A, Oka H, Igawa S, Kuroki T, Kinoshita H. Effects of long-term postoperativeinterferon-alpha therapy on intrahepatic recurrence after resection of hepatitis Cvirus-related hepatocellular carcinoma. A randomized, controlled trial. Ann InternMed2001;134:963-7.
62. Nishiguchi S, Kubo S, Tamori A, Shiomi S, Tanaka H, Shuto T, Yamazaki O,Hirohashi K, Oka H, Igawa S, Kuroki T, Kinoshita H. Randomized trial ofpostoperative long-term interferon-alpha on intrahepatic recurrence after resection ofhepatocellular carcinoma related to hepatitis C virus: a preliminary report [abtract].Journal of Gastroenterology and Hepatology2000;15Suppl: F9.
63. Nishiguchi S, Kubo S, Hirohashi K, Shuto T, Yamazaki O, Oka H. Effects ofpostoperative interferon-a on recurrence after curative resection in patients withhepatitis C virus-related hepatocellular carcinoma:A prospective randomized trial[abstract]. Hepatology1999;30:212a.
64. Nishiguchi S, Kubo S. Randomized trial of post-operative interferon therapy afterresection of hepatitis C virus-related hepatocellular carcinoma and long-termoutcomeed. Tokyo: Springer Japan,2004.209-18.
65. von Marschall Z, Scholz A, Cramer T, Schafer G, Schirner M, Oberg K, WiedenmannB, Hocker M, Rosewicz S. Effects of interferon alpha on vascular endothelial growthfactor gene transcription and tumor angiogenesis. J Natl Cancer Inst2003;95:437-48.
66. Dinney CP, Bielenberg DR, Perrotte P, Reich R, Eve BY, Bucana CD, Fidler IJ.Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth ofhuman bladder carcinoma in mice by systemic interferon-alpha administration.Cancer Res1998;58:808-14.
67. Wang L, Wu WZ, Sun HC, Wu XF, Qin LX, Liu YK, Liu KD, Tang ZY. Mechanismof interferon alpha on inhibition of metastasis and angiogenesis of hepatocellularcarcinoma after curative resection in nude mice. J Gastrointest Surg2003;7:587-94.
68. Imamura H, Matsuyama Y, Tanaka E, Ohkubo T, Hasegawa K, Miyagawa S,Sugawara Y, Minagawa M, Takayama T, Kawasaki S, Makuuchi M. Risk factorscontributing to early and late phase intrahepatic recurrence of hepatocellularcarcinoma after hepatectomy. J Hepatol2003;38:200-7.
69. Poon RT, Fan ST, Ng IO, Lo CM, Liu CL, Wong J. Different risk factors andprognosis for early and late intrahepatic recurrence after resection of hepatocellularcarcinoma. Cancer2000;89:500-7.
70. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet2003;362:1907-17.
71. Bouchard MJ, Navas-Martin S. Hepatitis B and C virus hepatocarcinogenesis: lessonslearned and future challenges. Cancer Lett2011;305:123-43.
72. Gale M, Jr., Foy EM. Evasion of intracellular host defence by hepatitis C virus.Nature2005;436:939-45.
73. Foy E, Li K, Wang C, Sumpter R, Jr., Ikeda M, Lemon SM, Gale M, Jr. Regulation ofinterferon regulatory factor-3by the hepatitis C virus serine protease. Science2003;300:1145-8.
74. Liaw Y-F, Kao J-H, Piratvisuth T, Chan H, Chien R-N, Liu C-J, Gane E, Locarnini S,Lim S-G, Han K-H, Amarapurkar D, Cooksley G, et al. Asian-Pacific consensusstatement on the management of chronic hepatitis B: a2012update. HepatologyInternational2012;6:531-61.
75. Bian ZX, Shang HC. CONSORT2010statement: updated guidelines for reportingparallel group randomized trials. Ann Intern Med2011;154:290-1; author reply1-2.
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics.CA Cancer J Clin2011;61:69-90.
2. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, Montalto F,Ammatuna M, Morabito A, Gennari L. Liver transplantation for the treatment ofsmall hepatocellular carcinomas in patients with cirrhosis. N Engl J Med1996;334:693-9.
3. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology2005;42:1208-36.
4. Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol2005;40:225-35.
5. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation forhepatocellular carcinoma. Semin Liver Dis2005;25:181-200.
6. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect ofinterferon therapy in patients with chronic hepatitis B virus infection. Hepatology1999;29:971-5.
7. Miyake Y, Kobashi H, Yamamoto K. Meta-analysis: the effect of interferon ondevelopment of hepatocellular carcinoma in patients with chronic hepatitis B virusinfection. J Gastroenterol2009;44:470-5.
8. Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis: Treatment of hepatitisB infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther2008;28:1067-77.
9. Yang YF, Zhao W, Zhong YD, Xia HM, Shen L, Zhang N. Interferon therapy inchronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: ameta-analysis. J Viral Hepat2009;16:265-71.
10. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM,Shue K, Keene ON, Dixon JS, Gray DF, et al. Lamivudine for patients with chronichepatitis B and advanced liver disease. N Engl J Med2004;351:1521-31.
11. Lo CM, Liu CL, Chan SC, Lam CM, Poon RTP, Ng IOL, Fan ST, Wong J. Arandomized, controlled trial of postoperative adjuvant interferon therapy afterresection of hepatocellular carcinoma. Annals of Surgery2007;245:831-42.
12. Li N, Lai ECH, Shi J, Guo WX, Xue J, Huang B, Lau WY, Wu MC, Cheng SQ. Acomparative study of antiviral therapy after resection of hepatocellular carcinoma inthe immune-active phase of hepatitis B virus infection. Annals of Surgical Oncology2010;17:179-85.
13. Chen LT, Chen MF, Li LA, Lee PH, Jeng LB, Lin DY, Wu CC, Mok KT, Chen CL,Lee WC, Chau GY, Chen YS, et al. Long-term results of a randomized,observation-controlled, phase III Trial of Adjuvant Interferon alfa-2b inhepatocellular carcinoma after curative resection. Annals of Surgery2012;255:8-17.
14. Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, Wu MS, Lin JT. Association betweennucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinomarecurrence following liver resection. JAMA2012;308:1906-14.
15. Lee D, Chung YH, Kim JA, Jin YJ, Lee SH, Shim JH, Lim YS, Lee HC, Lee YS, SuhDJ, Ryu SH, Park NH, et al. Adjuvant pegylated interferon therapy for metastatictumor antigen1positive hepatocellular carcinoma treated with curative surgicalresection. Hepatology2010;52:1157A.
16. Someya T, Ikeda K, Saitoh S, Kobayashi M, Hosaka T, Sezaki H, Akuta N, Suzuki F,Suzuki Y, Arase Y, Kumada H. Interferon lowers tumor recurrence rate after surgicalresection or ablation of hepatocellular carcinoma: a pilot study of patients withhepatitis B virus-related cirrhosis. J Gastroenterol2006;41:1206-13.
17. Sun HC, Tang ZY, Wang L, Qin LX, Ma ZC, Ye QH, Zhang BH, Qian YB, Wu ZQ,Fan J, Zhou XD, Zhou J, et al. Postoperative interferon alpha treatment postponedrecurrence and improved overall survival in patients after curative resection ofHBV-related hepatocellular carcinoma: a randomized clinical trial. J Cancer Res ClinOncol2006;132:458-65.
18. Qu LS, Jin F, Huang XW, Shen XZ. Interferon-alpha therapy after curative resectionprevents early recurrence and improves survival in patients with hepatitis Bvirus-related hepatocellular carcinoma. J Surg Oncol2010;102:796-801.
19. Kubo S, Tanaka H, Takemura S, Yamamoto S, Hai S, Ichikawa T, Kodai S, ShinkawaH, Sakaguchi H, Tamori A, Habu D, Nishiguchi S. Effects of lamivudine on outcomeafter liver resection for hepatocellular carcinoma in patients with active replication ofhepatitis B virus. Hepatol Res2007;37:94-100.
20. Kuzuya T, Katano Y, Kumada T, Toyoda H, Nakano I, Hirooka Y, Itoh A, Ishigami M,Hayashi K, Honda T, Goto H. Efficacy of antiviral therapy with lamivudine afterinitial treatment for hepatitis B virus-related hepatocellular carcinoma. JGastroenterol Hepatol2007;22:1929-35.
21. Yoshida H, Goto E, Sato T, Ohki T, Masuzaki R, Tateishi R, Goto T, Shiina S,Kawabe T, Omata M. Safety and efficacy of lamivudine after radiofrequency ablationin patients with hepatitis B virus-related hepatocellular carcinoma. Hepatol Int2008;2:89-94.
22. Chuma M, Hige S, Kamiyama T, Meguro T, Nagasaka A, Nakanishi K, Yamamoto Y,Nakanishi M, Kohara T, Sho T, Yamamoto K, Horimoto H, et al. The influence ofhepatitis B DNA level and antiviral therapy on recurrence after initial curativetreatment in patients with hepatocellular carcinoma. J Gastroenterol2009;44:991-9.
23. Koda M, Nagahara T, Matono T, Sugihara T, Mandai M, Ueki M, Ohyama K, HoshoK, Okano J, Kishimoto Y, Kono M, Maruyama S, et al. Nucleotide analogs forpatients with HBV-related hepatocellular carcinoma increase the survival rate throughimproved liver function. Intern Med2009;48:11-7.
24. Inuzuka T. Nucleotide analogues may prolong survival time without recurrence andoverall survival time for HBV-related liver diseases after curative treatment ofhepatocellular carcinoma. Hepatology2010;52:525A.
25. Chan ACY, Chok KSH, Yuen WK, Chan SC, Poon RTP, Lo CM, Fan ST. Impact ofantiviral therapy on the survival of patients after major hepatectomy for hepatitis Bvirus-related hepatocellular carcinoma. Archives of Surgery2011;146:675-81.
26. Hann HW, Bergin D, Coben R, Dimarino AJ. Prevention of new hepatocellularcarcinoma with concomitant antiviral therapy in chronic hepatitis B patients whoseinitial tumor was successfully ablated. International Journal of Cancer2011;128:740-3.
27. Jeong E, Lee JW, Lee JI, Kim YS, Jeong S, Haeng L. Antiviral therapy after curativeresection of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC)improves the outcome in patients with high serum HBV DNA level. Hepatology2011;54:1384A.
28. Lee JW, Lee JI, Chung HJ, Kim YS, Lee DH. Effect of antiviral therapy on laterecurrence after curative resection of B-viral hepatocellular carcinoma (HCC).Journal of Hepatology2012;56: S398.
29. Yeung P, Wong DK, Lai CL, Fung J, Seto WK, Yuen MF. Association of hepatitis Bvirus pre-S deletions with the development of hepatocellular carcinoma in chronichepatitis B. J Infect Dis2011;203:646-54.
30. Yuen MF, Tanaka Y, Shinkai N, Poon RT, But DY, Fong DY, Fung J, Wong DK, YuenJC, Mizokami M, Lai CL. Risk for hepatocellular carcinoma with respect to hepatitisB virus genotypes B/C, specific mutations of enhancer II/core promoter/precoreregions and HBV DNA levels. Gut2008;57:98-102.
31. Zhang H, Zhai Y, Hu Z, Wu C, Qian J, Jia W, Ma F, Huang W, Yu L, Yue W, Wang Z,Li P, et al. Genome-wide association study identifies1p36.22as a new susceptibilitylocus for hepatocellular carcinoma in chronic hepatitis B virus carriers. Nat Genet2010;42:755-8.
32. Chan KY, Wong CM, Kwan JS, Lee JM, Cheung KW, Yuen MF, Lai CL, Poon RT,Sham PC, Ng IO. Genome-wide association study of hepatocellular carcinoma inSouthern Chinese patients with chronic hepatitis B virus infection. PLoS One2011;6:e28798.
33. Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence ofhepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)idetherapy: a systematic review. J Hepatol2010;53:348-56.
34. Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, Safadi R, Lee SS, Halota W,Goodman Z, Chi YC, Zhang H, et al. Long-term entecavir therapy results in thereversal of fibrosis/cirrhosis and continued histological improvement in patients withchronic hepatitis B. Hepatology2010;52:886-93.
35. Lai CL, Yuen MF. Prevention of hepatitis B virus-related hepatocellular carcinomawith antiviral therapy. Hepatology2013;57:399-408.
36. KASL Clinical Practice Guidelines: Management of chronic hepatitis B. Clin MolHepatol2012;18:109-62.
37. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection.J Hepatol2012;57:167-85.
38. An HJ, Jang JW, Kwon JH, You CR, Kim JD, Bae SH, Choi JY, Yoon SK, Lee KH,Kim DG. Effect of hepatitis B viral status on cancer recurrence and long-termprognosis after surgical resection in patients with hepatocellular carcinoma.Hepatology International2010;4:310.
39. Shim JH, Lee HC, Choi JG, Lee D, Kim KM, Lim YS, Chung YH, Lee YS, Suh DJ.Clinical implication of hepatitis B viral load in hepatitis B E antigen-negative chronichepatitis B patients with hepatocellular carcinoma treated with curative resection.Journal of Hepatology2011;54: S301.
40. Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, Huo TI, Sheen IJ. Differentialroles of tumor, hepatic inflammation and hepatitis B virus in early and latehepatocellular carcinoma recurrences. Journal of Hepatology2009;50: S304.
41. Wang L, Wu WZ, Sun HC, Wu XF, Qin LX, Liu YK, Liu KD, Tang ZY. Mechanismof interferon alpha on inhibition of metastasis and angiogenesis of hepatocellularcarcinoma after curative resection in nude mice. J Gastrointest Surg2003;7:587-94.
42. Huang G, Lai ECH, Lau WY, Zhou WP, Shen F, Pan ZY, Fu SY, Wu MC.Posthepatectomy HBV reactivation in hepatitis B-Related hepatocellular carcinomainfluences postoperative survival in patients with preoperative low HBV-DNA levels.Annals of Surgery2013;257:490-505.
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