Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common malignancy and the third leading cause of cancer death worldwide.Chronic infection with hepatitis B virus(HBV)and hepatitis C virus accounts for approximately75%-80%of HCC cases worldwide.In particular,chronic HBV infection is a predominant risk factor for HCC in Asia and Africa.Hepatic resection and radiofrequency ablation are increasingly used for the curative treatment of HCC,and good local control can be achieved.However,the high rate of recurrence is a major obstacle to improving prognosis.A high viral load of HBV DNA is the most important correctable risk factor for recurrence.Furthermore,interferon and/or nucleotide analogues may decrease HBV DNA.Therefore,these drugs may decrease recurrence.In this article,treatment strategies for HBV-related HCC are described in order to reduce recurrence and improve survival.     

The prognostic factor for outcome following second resection for intrahepatic recurrence of hepatocellular carcinoma with a hepatitis B virus infection background

Purpose Second resection has been proved to be a safe and effective treatment for patients with intrahepatic recurrent HCC after primary resection; however, preoperative prognostic factors for outcome following second resection in patients with a hepatitis B virus (HBV) infection background remains to be clarified.Methods Fifty-seven patients with intrahepatic recurrent an HCC and HBV infection background received second resection from 1997 to 2003 in our institute. All of them were negative for anti-hepatitis C virus (HCV) and positive regarding HBV profile. Patient and tumor factors were analyzed.Results At the time of preparing this paper, 31 had re-recurrence and 21patients had died. No postoperative mortality was noted. The 1-, 3-, and 5-year overall survival after second resection were 69.9%, 61.2%, and 30.6%, respectively. Univariate and multivariate analysis showed that vascular invasion and time to recurrence were the independent prognostic factors for overall survival following second resection. The 3- and 4-year overall survival after second resection were 57.7% and 46.6% in patients with the presence of any of two risk factors (n=46), and 100% and 100% in those with absence of both risk factors (n=11, P=0.008).Conclusions Vascular invasion and time to recurrence were the prognostic factors for overall survival following second resection of intrahepatic recurrent HCC.This study was jointly supported by a grant from the Shanghai Medical Center Project, the Promising Young Doctor of Shanghai grant from the Bureau of Public Health of Shanghai, and the Project 211 grant from Ministry of Education of China.     

Overexpression of metastasis-associated in colon cancer 1 predicts a poor outcome of hepatitis B virus-related hepatocellular carcinoma

AIM: To investigate the intratumoral expression of metastasis-associated in colon cancer 1 (MACC1) and c-Met and determine their clinical values associated with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).METHODS: A retrospective study admitted three hundred fifty-four patients with HBV-related HCC. The expression and distribution of MACC1 and c-Met were assessed by quantitative real-time polymerase chain reaction and immunohistochemistry staining. Prognostic factors influencing survival, metastasis and recurrence were assessed.RESULTS: Intratumoral MACC1 level was found to be associated with HCC disease progression. Both median tumor-free survival (TFS) and overall survival (OS) were significantly shorter in the postoperative HCC patients with high intratumoral MACC1 expression, as compared to those with low intratumoral MACC1 levels (TFS: 34 mo vs 48.0 mo, P < 0.001; OS: 40 mo vs 48 mo, P < 0.01). Multivariable analysis indicated that high MACC1 expression or co-expression with c-Met were independent predictors for HCC clinic outcome (P < 0.001).CONCLUSION: High intratumoral MACC1 expression can be associated with enhanced tumor progression and poor outcome of HBV-related HCC. MACC1 may serve as a prognostic biomarker for postoperative HCC.     

Resection of hepatitis B virus-related hepatocellular carcinoma: Evolving strategies and emerging therapies to improve outcome

The incidence of hepatocellular carcinoma (HCC) is increasing worldwide, largely due to hepatitis B virus (HBV), hepatitis C virus and liver cirrhosis. Chronic HBV infection is estimated to cause 55%-60% of the cases of HCC worldwide and over 70% in Asian countries. Liver resection is currently the mainstay of treatment due to the low surgical mortality, a wider treatment indication, and simplicity of post-treatment follow-up. There is an ever-increasing demand on surgeons to perform curative liver resection in HCC, with the hope of avoiding tumor recurrences. Hepatitis B-related-HCC has distinct clinicopathological features, which should be considered when treating the disease. The author presents a review of the recently evolving strategies and emerging therapies to improve HCC postresectional outcomes and focus on perioperative measures to improve patient outcome, with particular reference to the current status of adjuvant therapies in HCC patients after liver resection.     

Human liver tissue metabolic profiling research on hepatitis B virus-related hepatocellular carcinoma

AIM: To select characteristic endogenous metabolites in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients and to identify their molecular mechanism and potential clinical value. METHODS: An ultra performance liquid chromatography and linear trap quadrupole-Orbitrap XL-mass spectrometry platform was used to analyze endogenous metabolites in the homogenate of central tumor tissue, adjacent tissue and distant tissue obtained from 10 HBV-related HCC patients. After pretreatment with Mzmine software, including peak detection, alignment and normalization, the acquired data were treated with Simca-P+software to establish multivariate statistical analysis based on a pattern recognition technique and characteristic metabolites highly correlated with changing trends in metabolic profiling were selected and further identified. RESULTS: Based on data acquired using Mzmine software, a principal component analysis model (R2X = 66.9%, Q2 = 21.7%) with 6 principal components and an orthogonal partial least squares discriminant analy-sis model (R2X = 76.5%, R2Y = 93.7%, Q2 = 68.7%) with 2 predicted principal components and 5 orthogonal principal components were established in the three tissue groups. Forty-nine ions were selected, 33 ions passed the 2 related samples nonparametric test (P < 0.05) and 14 of these were further identified as characteristic metabolites that showed significant differences in levels between the central tumor tissue group and distant tumor tissue group, including 9 metabolites (L -phenylalanine, glycerophosphocholine, lysophosphatidylcholines, lysophosphatidylethanolamines and chenodeoxycholic acid glycine conjugate) which had been reported as serum metabolite biomarkers for HCC diagnosis in previous research, and 5 metabolites (betasitosterol, quinaldic acid, arachidyl carnitine, tetradecanal, and oleamide) which had not been reported before. CONCLUSION: Characteristic metabolites and metabolic pathways highly related to HCC pathogenesis and progression are identified through     

Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma

ABM: Recent studies suggested that cyclooxygenase-2 (COX-2) enhances tumor angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Although COX-2 expression has been demonstrated in hepatocellular carcinoma (HCC), the significance of COX-2 in progression of HCC remains unclear. This study evaluated the clinico-pathological correlation of COX-2 level and its relationship with VEGF level in HCC. METHODS: Fresh tumor tissues were obtained from 100 patients who underwent resection of HCC. COX-2 protein expression was examined by immunohistochemistry, and quantitatively by an enzyme immunometric assay (EIA) of tumor cytosolic COX-2 levels. Tumor cytosolic VEGF levels were measured by an ELISA. RESULTS: Immunostaining showed expression of COX-2 in tumor cells. Tumor cytosolic COX-2 levels correlated with VEGF levels (r = 0.469,P<0.001). Correlation with clinicopathological features showed significantly higher tumor cytosolic COX-2 levels in the presence of multiple tumors (P = 0.027), venous invasion (P = 0.030), microsatellite lesions (P=0.037) and advanced tumor stage (P = 0.008). Higher tumor cytosolic COX-2 levels were associated with worse patient survival. CONCLUSION: This study shows that elevated tumor COX-2 levels correlate with elevated VEGF levels and invasiveness in HCC, suggesting that COX-2 plays a significant role in the progression of HCC.     

Dermatomyositis associated with hepatocellular carcinoma in an elderly female patient with hepatitis C virus-related liver cirrhosis

A 79-year-old female patient with hepatitis C virus-related liver cirrhosis was diagnosed as having hepatocellular carcinoma (HCC) with a diameter of 2.0 cm. She refused therapy for HCC. Nine months after the diagnosis, she developed dermatomyositis when the HCC enlarged to a diameter of 6.0 cm. She underwent therapy for dermatomyositis, and then transcatheter arterial chemoembolization for HCC. Although the manifestations of dermatomyositis improved and entire tumor necrosis was achieved, she died of pneumonia 2 mo after the treatment of HCC. HCC and/or chronic hepatitis C virus infection might be involved in the pathogenesis of dermatomyositis.     

Dermatomyositis associated with hepatitis B virus-related hepatocellular carcinoma

Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) with typical cutaneous manifestations. It has been proposed that DM may be caused by autoimmune responses to viral infections, and previous studies have also shown that an association between DM and malignancy. However, chronic hepatitis B virus (HBV) infection associated with DM and hepatocellular carcinoma (HCC) is rarely encountered. The authors report a case of DM and HCC in a patient with a HBV infection. A 58-year-old man presented erythematous skin rashes on a sun-exposed area of 2 year’s duration, and recent proximal muscle weakness. His medical history revealed that he had a chronic HBV infection. A diagnosis of DM relies on proximal muscle weakness, elevated muscle enzymes, myopathic changes (demonstrated by electromyography), muscle biopsy evidence of myositis, and its characteristic cutaneous findings. A Liver mass in the left lobe visualized by abdominal computed tomography was confirmed histologically as HCC. This case suggests that DM associated with HCC might be caused by a HBV infection.     

Clinical features of hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer death,and chronic hepatitis B is a serious worldwide problem.The epidemiology of HCC is distinctive.Hepatitis B virus (HBV) plays a major role in hepatocarcinogenesis.Prevention of HBV-related HCC is a key issue in current hepatology.This paper describes the prevention and clinical features of HBVrelated HCC,along with a short review of the disease.     

Prediction and prophylaxis of hepatocellular carcinoma occurrence and postoperative recurrence in chronic hepatitis B virus-infected subjects

Hepatocellular carcinoma (HCC) is one of the most common and highly fatal malignancies worldwide. Chronic infection with hepatitis B virus (HBV) is a major cause of HCC. High HBV replication rate and related non-resolving inflammation are the major risk factors of HCC occurrence and postoperative recurrence. Early prophylactic options are effective in reducing HCC occurrence and improving survival. Therefore, it is important to identify HBV-infected patients who are at a higher risk of developing HCC and HBV-HCC patients who are more likely to relapse after surgery, thus providing them with more precise prophylactic strategies. Several prediction models of HCC occurrence have been constructed, with satisfactory predictive accuracy and discriminatory ability. However, there is a lack of consensus for their clinical implementation. Several staging systems have been proposed for HCC prognosis. However, the accuracy of these staging systems based on demographic characteristics and clinical measurements needs to be further improved, possibly by systematically incorporating viral and inflammatory factors. Since antiviral treatments are effective in promoting liver function reserve, reducing HCC occurrence and prolonging postoperative survival in some HBV-infected subjects, it is very important to identify subgroups of HBV-infected patients who would most benefit from antiviral treatment.     

Prevention of cancer recurrence after treatment for hepatitis C virus-related hepatocellular carcinoma by interferon therapy

The outcome of treatment for hepatitis C virus-related hepatocellular carcinoma is still unsatisfactory because of the high rate of recurrence of cancer, including intrahepatic metastasis and multicentric carcinogenesis after treatment. The rate of recurrence, especially that of multicentric carcinogenesis, is affected by persistent active hepatitis and hepatic fibrosis caused by chronic hepatitis C. Interferon therapy improves the outcome after treatment of hepatocellular carcinoma by decreasing recurrence and preserving or improving liver function when treatment is successful. Radical treatment by anatomic resection and interferon therapy can markedly improve the outcome in patients with hepatitis C virus-related hepatocellular carcinoma.     

Long noncoding RNAs in hepatitis B virus-related hepatocellular carcinoma

AIM: To study the expression of long noncoding RNAs (lncRNAs) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).METHODS: The lncRNA profiles between HBV-related HCC tissues and corresponding normal liver tissues were generated using microarray analysis. Datasets were analyzed using multiple algorithms to depict alterations in gene expression on the basis of gene ontology (GO), pathway analysis, and lncRNA levels.RESULTS: The microarray revealed that 1772 lncRNAs and 2508 mRNAs were differently expressed. The pathway analysis demonstrated that the cell cycle, cytokine-cytokine receptor interaction, chemokine signaling pathway, and phosphoinositide 3-kinase-protein kinase B signaling pathway may play important roles in HCC. Several GO terms, such as cell cycle, DNA replication, immune response, and signal transduction, were enriched in gene lists, suggesting a potential correlation with HBV-related HCC. The upregulated large intergenic noncoding RNA ULK4P2 was physically combined with enhancer of zeste homolog 2. Therefore, the lncRNAs may participate in regulating HBV-related HCC.CONCLUSION: lncRNAs play important roles in HCC, future studies should verify whether large intergenic noncoding ULK4P2 functions by combining with enhancer of zeste homolog 2 in HCC.     

小肝细胞癌术后早期复发的危险因素分析

目的 探讨小肝细胞癌（sHCC）患者术后早期复发的危险因素。方法 收集2004至2006年上海东方肝胆外科医院手术切除肿瘤的sHCC患者75例。选取20项临床和病理学参数,以2年为早期复发的时限,应用COX风险比例模型进行单因素和多因素分析,筛选影响早期复发的独立危险因素。结果 本组75例sHCC患者经手术切除肿瘤后,1～5 a累积肿瘤复发率分别为10.7%、46.7%、76.0%、86.7%和92.0%;经COX风险比例模型分析,发现术前AFP＞400 μg/L（HR=2.477,95% CI=1.100～5.576,P=0.029）和肿瘤分布超过半肝（HR=5.801,95% CI=1.831～18.379,P=0.003）是sHCC患者术后早期复发的独立危险因素。结论 对于术前AFP＞400 μg/L和肿瘤分布超过半肝的sHCC患者,应加强术后随访,及早发现复发肿瘤并给予积极的治疗,以改善患者预后。     

Antiviral therapies for hepatitis B virus-related hepatocellular carcinoma

Chronic hepatitis B virus(HBV) infection is a critical risk factor for the carcinogenesis and progression of hepatocellular carcinoma(HCC). It promotes HCC development by inducing liver fibrogenesis, genetic and epigenetic alterations, and the expression of active viral-coded proteins. Effective antiviral treatments inhibit the replication of HBV, reduce serum viral load and accelerate hepatitis B e antigen serum conversion. Timely initiation of antiviral treatment is not only essential for preventing the incidence of HCC in chronic hepatitis B patients, but also important for reducing HBV reactivation, improving liver function, reducing or delaying HCC recurrence, and prolonging overall survival of HBV-related HCC patients after curative and palliative therapies. The selection of antiviral drugs, monitoring of indicators such as HBV DNA and hepatitis B surface antigen, and timely rescue treatment when necessary, are essential in antiviral therapies for HBVrelated HCC.     

Effects of adenovirus-mediated human cyclooxygenase-2 antisense RNA on the growth of hepatocellular carcinoma

AIM: To investigate the relation between the expression of cyclooxygenase-2 (COX-2) and liver cancer, to construct the recombinant adenovirus encoding human COX-2 antisense RNA, and to explore its effects on liver cancer cell proliferation. METHODS: We studied the expression of COX-2 in 34 cases of hepatocellular carcinoma (HCC) and SMMC7402 and SMMC7721 by immunohistochemical technique. Recombinant adenovirus Ad-AShcox-2 was constructed and transfected into human HCC cell lines SMMC7402 and SMMC7721, and its effects on COX-2 expression, cell apoptosis and cell cycle were analyzed by flow cytometry. Cell proliferation was determined by colony-forming efficiency. RESULTS: We observed COX-2 expression in 82.4% of HCC and SMMC7402 cells, but no COX-2 expression in SMMC7721 cells. In addition, recombinant adenovirus encoding antisense COX-2 fragment Ad-AShcox-2 was obtained with the titer of 1.06×1012PFU/mL. Ad-AShcox-2 could reduce the expression of COX-2 and enhance the percentage of cells in G1/G0 phase in SMMC7402 cell line. The difference of apoptotic index between the Ad-AShcox-2 group and control group was statistically significant (tcontrol group=32.62 and tAd-Lacz = 10.93, P<0.001) in SMMC7402 but not in SMMC7721. Similarly, colony-forming rates of SMMC7402 and SMMC7721 cell lines, after the transfer of Ad-AShcox-2, were (2.7±0.94)% and (33.6±4.24)%, respectively. CONCLUSION: Reduction in the expression of COX-2 can inhibit COX-2 expressing HCC cells.     

Management of hepatitis B virus infection during treatment for hepatitis B virus-related hepatocellular carcinoma

Although liver resection is considered the most effective treatment for hepatocellular carcinoma (HCC), treatment outcomes are unsatisfactory because of the high rate of HCC recurrence. Since we reported hepatitis B e-antigen positivity and high serum hepatitis B virus (HBV) DNA concentrations are strong risk factors for HCC recurrence after curative resection of HBV-related HCC in the early 2000s, many investigators have demonstrated the effects of viral status on HCC recurrence and post-treatment outcomes. These findings suggest controlling viral status is important to prevent HCC recurrence and improve survival after curative treatment for HBV-related HCC. Antiviral therapy after curative treatment aims to improve prognosis by preventing HCC recurrence and maintaining liver function. Therapy with interferon and nucleos(t)ide analogs may be useful for preventing HCC recurrence and improving overall survival in patients who have undergone curative resection for HBV-related HCC. In addition, reactivation of viral replication can occur after liver resection for HBV-related HCC. Antiviral therapy can be recommended for patients to prevent HBV reactivation. Nevertheless, further studies are required to establish treatment guidelines for patients with HBV-related HCC.     

Cyclooxygenase-2 expression is associated with initiation of hepatocellular carcinoma,while prostaglandin receptor-1 expression predicts survival

AIM to determine whether cyclooxygenase-2(COX-2) and prostaglandin E1 receptor(EP1) contribute to disease and whether they help predict prognosis.METHODS We retrospectively reviewed the records of 116 patients with hepatocellular carcinoma(HCC) who underwent surgery between 2008 and 2011 at our hospital. Expression of COX-2 and EP1 receptor was examined by immunohistochemistry of formalin-fixed, paraffinembedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined.RESULTS Factors associated with poor overall survival(OS) were alpha-fetoprotein 400 ng/m L, tumor size ≥ 5 cm, and high EP1 receptor expression, but not high COX-2 expression. Disease-free survival was not significantly different between patients with low or high levels of COX-2 or EP1. COX-2 immunoreactivity was significantly higher in well-differentiated HCC tissues(Edmondson grade Ⅰ-Ⅱ) than in poorly differentiated tissues(Edmondson grade Ⅲ-Ⅳ)(P = 0.003). EP1 receptor immunoreactivity was significantly higher in poorly differentiated tissue than in well-differentiated tissue(P = 0.001).CONCLUSION COX-2 expression appears to be linked to early HCC events(initiation), while EP1 receptor expression may participate in tumor progression and predict survival.     

Surgical approach for hepatitis C virus-related hepatocellular carcinoma

Hepatitis C is a strong prognostic factor for patients with hepatocellular carcinoma(HCC). Although liver resection and liver transplantation offer the chance of a cure for HCC,adequate management of co-existing infection with hepatitis C virus(HCV) is important to enable better long-term outcomes after surgery for HCV-related HCC. For patients undergoing liver resection,perioperative anti-viral treatment is recommended,since a decreased HCV viral load itself is reportedly associated with a lower tumor recurrence rate and a longer overall survival. For patients undergoing transplanatations for HCC complicated by end-stage liver disease,the post-transplant management of HCV infection is also necessary to prevent progressive graft injury caused by active hepatitis under the immunosuppressive condition that is needed after liver transplantation. Although only a few lines of solid evidence are available for postoperative antiviral treatment because of the limited indication and frequent adverse events caused by conventional high-dose combination interferon therapy,new direct acting anti-viral agents would enable interferon-free anti-viral treatment with a higher virologic response and minimal side effects.     

慢性乙型肝炎、乙肝肝硬化、乙肝肝癌患者Th1/Th2型细胞因子水平变化研究

目的分析慢性乙型肝炎(CHB)、乙肝肝硬化(LC)、乙肝肝癌(HCC)患者血清中Th1/Th2型细胞因子水平变化,为慢性乙型肝炎至肝癌的发生发展过程中的免疫变化研究提供线索,并为患者的临床治疗研究提供免疫学指标。方法选取2010年2月-2011年11月于首都医科大学附属北京佑安医院就诊的40例CHB患者、40例LC患者、53例HCC患者,用Luminex技术检测血清中Th1类细胞因子[白细胞介素(interleukin,IL)-12、干扰素(interferon,IFN)-γ和肿瘤坏死因子(tumor necrosis factor,TNF)-α]水平及Th2类细胞因子(IL-4、IL-6和IL-10)水平,并将25例健康志愿者作为正常对照组进行比较。结果除TNF-α外,CHB组、LC组和HCC组Th1类IL-12、IFN-γ和Th2类IL-4、IL-6、IL-10细胞因子水平均低于正常对照组;CHB组中大部分Th1类和Th2类细胞因子都高于LC组和HCC组;HCC组中TNF-α细胞因子水平要高于CHB组、LC组。结论 CHB、LC和HCC患者体内Th1/Th2细胞因子分泌水平受到抑制,Th1/Th2平衡发生漂移,对HBV病毒的清除作用受到抑制。TNF-α在肝癌发生过程中发挥着重要作用。     

Postoperative outcomes and recurrence patterns of intermediate-stage hepatocellular carcinoma dictated by the sum of tumor size and number

BACKGROUNDThe selection criteria for Barcelona Clinic Liver Cancer (BCLC) intermediate-stage hepatocellular carcinoma (HCC) patients who would truly benefit from liver resection (LR) remain undefined.AIMTo identify BCLC-B HCC patients more suitable for LR.METHODSWe included patients undergoing curative LR for BCLC stage A or B multi-nodular HCC (MNHCC) and stratified BCLC-B patients by the sum of tumor size and number (N + S). Overall survival (OS), recurrence-free survival (RFS), recur-rence-to-death survival (RTDS), recurrence patterns, and treatments after recurrence in BCLC-B patients in each subgroup were compared with those in BCLC-A patients.RESULTSIn total, 143 patients who underwent curative LR for MNHCC with BCLC-A (n = 25) or BCLC-B (n = 118) were retrospectively analyzed. According to the N + S, patients with BCLC-B HCC were divided into two subgroups: BCLC-B1 (N + S ≤ 10, n = 83) and BCLC-B2 (N + S > 10, n = 35). Compared with BCLC-B2 patients, those with BCLC-B1 had a better OS (5-year OS rate: 67.4% vs 33.6%; P < 0.001), which was comparable to that in BCLC-A patients (5-year OS rate: 67.4% vs 74.1%; P = 0.250), and a better RFS (median RFS: 19 mo vs 7 mo; P < 0.001), which was worse than that in BCLC-A patients (median RFS: 19 mo vs 48 mo; P = 0.022). Further analysis of patients who developed recurrence showed that both BCLC-B1 and BCLC-A patients had better RTDS (median RTDS: Not reached vs 49 mo; P = 0.599), while the RTDS in BCLC-B2 patients was worse (median RTDS: 16 mo vs not reached, P < 0.001; 16 mo vs 49 mo, P = 0.042). The recurrence patterns were similar between BCLC-B1 and BCLC-A patients, but BCLC-B2 patients had a shorter recurrence time and a higher proportion of patients had recurrence with macrovascular invasion and/or extrahepatic metastasis, both of which were independent risk factors for RTDS.CONCLUSIONBCLC-B HCC patients undergoing hepatectomy with N + S ≤ 10 had mild recurrence patterns and excellent OS similar to those in BCLC-A MNHCC patients, and LR should be considered in these patients.