Prognosis Of HBV-related Hepatocellular Carcinoma Research Articles

Genetic variants and Expression of Cytochrome p450 Oxidoreductase Predict Postoperative Survival in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma.

Our current study investigates the prognostic values of genetic variants and mRNA expression of cytochrome p450 oxidoreductase (POR) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). A total of 19 candidate single nucleotide polymorphisms (SNPs) located in the exons of POR were genotyped using Sanger sequencing from 476 HBV-related HCC patients who underwent hepatectomy between 2003 and 2013. The mRNA expression of POR in 212 patients with HBV-related HCC was obtained from GSE14520 dataset. Survival analysis was performed to investigate the association of POR variants and mRNA expression with overall survival (OS) and recurrence-free survival (RFS). Nomograms were used to predict the prognosis of HBV-related HCC patients. Gene set enrichment analysis (GSEA) was used to investigate the mechanism of POR in HBV-related HCC prognosis. The polymorphism POR-rs1057868 was significantly associated with HBV-related HCC OS (CT/TT vs. CC, hazard ratio [HR] = 0.69, 95% confidence interval [CI] = [0.54, 0.88], P = 0.003), but not significantly associated with RFS (CT/TT vs. CC, P = 0.378). POR mRNA expression was also significantly associated with HBV-related HCC OS (high vs. low, HR = 0.61, 95% CI = [0.38, 0.97], P = 0.036), but not significantly associated with the RFS (high vs. low, P = 0.201). Two nomograms were developed to predict the HBV-related HCC OS. Furthermore, GSEA suggests that multiple gene sets were significantly enriched in liver cancer survival and recurrence, as well as POR-related target therapy in the liver. In conclusion, our study suggests that POR-rs1057868 and mRNA expression may serve as a potential postoperative prognosis biomarker in HBV-related HCC.

Comprehensive investigation of key biomarkers and pathways in hepatitis B virus-related hepatocellular carcinoma.

Objective: Our study is aim to explore potential key biomarkers and pathways in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) using genome-wide expression profile dataset and methods.Methods: Dataset from the GSE14520 is used as the training cohort and The Cancer Genome Atlas dataset as the validation cohort. Differentially expressed genes (DEGs) screening were performed by the limma package. Gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), gene ontology, the Kyoto Encyclopedia of Genes and Genomes, and risk score model were used for pathway and genes identification.Results: GSEA revealed that several pathways and biological processes are associated with hepatocarcinogenesis, such as the cell cycle, DNA repair, and p53 pathway. A total of 160 DEGs were identified. The enriched functions and pathways of the DEGs included toxic substance decomposition and metabolism processes, and the P450 and p53 pathways. Eleven of the DEGs were identified as hub DEGs in the WGCNA. In survival analysis of hub DEGs, high expression of PRC1 and TOP2A were significantly associated with poor clinical outcome of HBV-related HCC, and shown a good performance in HBV-related HCC diagnosis. The prognostic signature consisting of PRC1 and TOP2A also doing well in the prediction of HBV-related HCC prognosis. The diagnostic and prognostic values of PRC1 and TOP2A was confirmed in TCGA HCC patients.Conclusions: Key biomarkers and pathways identified in the present study may enhance the comprehend of the molecular mechanisms underlying hepatocarcinogenesis. Additionally, mRNA expression of PRC1 and TOP2A may serve as potential diagnostic and prognostic biomarkers for HBV-related HCC.

Diagnostic and prognostic values of the mRNA expression of excision repair cross-complementation enzymes in hepatitis B virus-related hepatocellular carcinoma.

BackgroundThe current study aims at using the whole genome expression profile chips for systematically investigating the diagnostic and prognostic values of excision repair cross-complementation (ERCC) genes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).Materials and methodsWhole genome expression profile chips were obtained from the GSE14520. The receiver-operating characteristic (ROC) curve, survival analysis, and nomogram were used to investigate the diagnostic and prognostic values of ERCC genes. Investigation of the potential function of ERCC8 was carried out by gene set enrichment analysis (GSEA) and genome-wide coexpression analysis.ResultsROC analysis suggests that six ERCC genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, and ERCC8) were dysregulated and may have potential to distinguish between HBV-related HCC tumor and paracancerous tissues (area under the curve of ROC ranged from 0.623 to 0.744). Survival analysis demonstrated that high ERCC8 expression was associated with a significantly decreased risk of recurrence (adjusted P=0.021; HR=0.643; 95% CI=0.442–0.937) and death (adjusted P=0.049; HR=0.631; 95% CI=0.399–0.998) in HBV-related HCC. Then, we also developed two nomograms for the HBV-related HCC individualized prognosis predictions. GSEA suggests that the high expression of ERCC8 may have involvement in the energy metabolism biological processes. As the genome-wide coexpression analysis and functional assessment of ERCC8 suggest, those coexpressed genes were significantly enriched in multiple biological processes of DNA damage and repair.ConclusionThe present study indicates that six ERCC genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, and ERCC8) were dysregulated between HBV-related HCC tumor and paracancerous tissues and that the mRNA expression of ERCC8 may serve as a potential biomarker for the HBV-related HCC prognosis.

Highly elevated soluble Tim-3 levels correlate with increased hepatocellular carcinoma risk and poor survival of hepatocellular carcinoma patients in chronic hepatitis B virus infection.

Background and objectiveUpregulated T-cell immunoglobulin and mucin domain containing molecule-3 (Tim-3) in hepatitis B virus (HBV)-specific CD8+ T-cells contributes to CD8+ T-cell exhaustion during chronic HBV infection. The membrane-bound Tim-3 can be cleaved from the cell surface by sheddase, yielding soluble Tim-3 (sTim-3). This study investigated serum sTim-3 levels in patients with chronic HBV infection of various liver diseases.MethodsSerum sTim-3 levels were quantitatively determined in 288 patients with chronic HBV infection of various liver diseases. The sTim-3 levels were analyzed in relation to liver diseases including HBV-related hepatocellular carcinoma (HCC) and overall survival of HCC patients.ResultsSerum sTim-3 levels in the patients with chronic HBV infection were significantly elevated compared with healthy controls (P<0.001) and the levels from asymptomatic HBV carrier status, chronic hepatitis, liver cirrhosis to HCC were progressively increased. Serum sTim-3 levels were closely associated with the severity of liver function abnormalities. Importantly, serum sTim-3 levels were independently associated with HCC risk (OR, 4.310; 95% CI, 2.141–8.676, P<0.001) in comparison to non-HCC diseases in chronic HBV infection and significantly associated with the overall survival of HCC patients, with a level >3000 pg/mL being related to shorter overall survival than a level ≤3000 pg/mL (P=0.019).ConclusionSerum sTim-3 is involved in disease progression and HCC development in chronic HBV infection and its quantitative determination may be potentially used as a marker for monitoring the disease progression and predicting the HCC prognosis in chronic HBV infection.

Serum Iron Levels Decreased in Patients with HBV-Related Hepatocellular Carcinoma, as a Risk Factor for the Prognosis of HBV-Related HCC.

Background: Hepatocellular carcinoma (HCC) is common and the second leading causes of cancer-related deaths. HCC usually occurs on the basis of chronic liver diseases. At present, the study of iron metabolism in chronic liver diseases was limited to chronic HCV infection, nonalcoholic fatty liver disease, and alcoholic liver disease. This study aimed to investigate the effect of serum iron levels on the progression of chronic HBV infection and the relationship with the prognosis of HBV-related HCC.Methods: A respective study involving 277 healthy individuals as controls (HC), 295 patients with chronic hepatitis B (CHB), 224 patients with HBV-related liver cirrhosis (HBV-related LC), and 586 patients with HBV- related HCC were enrolled in this study. Hematological parameters, HBVDNA and liver biochemistry were analyzed. Child-Pugh grade and BCLC stage of the HBV-related HCC patients were calculated.Results: The serum iron levels were lowest in the HBV- related HCC group as compared with HC, CHB, and HBV-related LC groups (35.07 ± 6.97, 27.37 ± 10.26, 24.53 ± 10.36 vs. 17.90 ± 0.14, P < 0.001). Strikingly, serum iron levels were lowest in HBV- related HCC patients with tumor size more than 10 cm as compared with HBV- related HCC patients with tumor size smaller than 3, 3–5, and 5–10 cm by subgroup analysis (22.12 ± 0.94, 21.44 ± 1.41, 15.65 ± 0.98 vs. 13.36 ± 1.15, P < 0.001). Serum iron levels significantly decreased with worsening Child-Pugh grades and BCLC stages in HBV-related HCC group. In addition, serum iron levels was positively correlated with Retinol-Binding Protein, total bile acid, hemoglobin, and lymphocyte and negatively correlated with white blood cell (WBC) and platelet in HBV- related HCC group. ROC curve analysis showed serum iron levels at 15.1 μmol/L as the optimal cut-off point for determining the survival of HBV-related HCC. By the Cox regression model analysis, serum iron levels <15.1 μmol/l together with higher AFP levels, worse BCLC stages, and larger tumor size showed higher mortality of HBV-related HCC patients (hazard ratio = 2.280, 95% confidence interval, 1.815–2.865; P < 0.001).Conclusions: Serum iron levels affected the progression of chronic HBV infection. The prognosis of HBV- related HCC patients with serum iron levels <15.1 μmol/l together with higher AFP levels, worse BCLC stages, and larger tumor lesion were poor.

Hepatitis B virus core antigen mutations predict post-operative prognosis of patients with primary hepatocellular carcinoma.

The aim of this study was to explore the relationship between hepatitis B virus (HBV) core antigen (HBc) mutations and the post-operative prognosis of HBV-related hepatocellular carcinoma (HCC). In total, 98 patients suffering from HBV-related HCC and treated with surgery were enrolled, with a 48 month follow-up. The preCore/Core region of the HBV genome from tumour tissue (TT) and paired adjacent non-tumour tissue (ANTT) of these patients was sequenced, and a phylogenetic tree was reconstructed. The correlations between the viral features and evolutionary divergence of preCore/Core amino acid sequences from 67 paired TTs and ANTTs were analysed. Cox proportional hazard model analysis was applied for post-operative hazard risk evaluation. Phylogenetic analysis revealed that all of the sequences were ascribed to genotype C. The evolutionary divergence of amino acid sequences from matched TTs and ANTTs was significantly negatively correlated with serum and intrahepatic HBV DNA levels. Multivariate analysis showed that the HBc E77 mutation was associated with shorter overall survival, and HBc S87 and P156 mutations were independent risk factors for relapse. Furthermore, in contrast to with patients without the S87 mutation, no correlation was observed between serum HBV DNA and intrahepatic HBV DNA in HCC patients with the S87 mutation. Analysis of the intrahepatic sequence may advance our understanding of viral status; thus, it is useful for prognosis prediction for HBV-related HCC.

Hepatitis B Surface Antigen Promotes the Invasion of Hepatitis B Virus-Related Hepatocellular Carcinoma Cells by Upregulation of Toll-Like Receptor 2.

Hepatitis B virus (HBV) infection is one of the major risk factors leading to the development of hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) plays a pivotal role in HBV-related HCC pathogenesis, and Toll-like receptor (TLR) 2 is also considered to mediate tumor progression. However, the interaction between HBsAg and TLR2 in HCC progression remains unclear. Thus, the aim of the study was to explore the effect of HBsAg-TLR2 pathway on growth and invasion of HBV-related HCC cells and examine the potential mechanisms been involved. The expression of TLR2 was measured in two different HCC cell lines (HepG2 and HepG2.2.15) with or without recombinant HBsAg by real-time reverse polymerase chain reaction and Western blot. Cellular proliferation, invasion, cytokine productions, and downstream signaling pathways were also measured in TLR2-silencing HepG2.2.15 cells in response to HBsAg stimulation. The mRNA and protein levels of TLR2 were significantly elevated in HepG2.2.15 cells than those in HepG2 cells. HBsAg simulation increased proinflammatory cytokine production and invasion of HepG2.2.15 cells, while this process was inhibited by TLR2 silence. However, TLR2 siRNA transfection alone did not affect the bioactivities of tumor cells. Moreover, HBsAg increased expression of MyD88 and phosphorylation of NF-κB p50 and p38MAPK. Downregulation of TLR2 inhibited HBsAg-induced MyD88 and p-NF-κB, but not p-p38MAPK in HepG2.2.15 cells. In conclusion, HBsAg stimulation promotes the invasion of HBV-related HCC cells. TLR2/MyD88/NF-κB signaling pathway may be involved in this procession by upregulation of cytokine production. The interaction between TLR2 and HBsAg may contribute to the poor prognosis of HBV-related HCC.

Association between Recipient IL-15 Genetic Variant and the Prognosis of HBV-Related Hepatocellular Carcinoma after Liver Transplantation.

Objective To investigate the association of donor and recipient IL-15 genetic variants with HCC recurrence and prognosis after LT. Methods A total of 112 liver transplant patients with HBV-related HCC were enrolled. IL-15 rs10519613 and rs13122930 were genotyped in donors and recipients. Results Recipient IL-15 rs10519613 polymorphism was found to be significantly related to HCC recurrence after LT. In multivariate analysis, tumor thrombus, UCSF criteria, and recipient IL-15 rs10519613 genotypes were independent predictive factors of HCC recurrence after LT. Kaplan-Meier survival analysis demonstrated that patients with recipient IL-15 rs10519613 CA/AA genotypes had a decreased disease-free survival and overall survival than those with the CC genotype. Recipient IL-15 rs10519613 genetic variant could improve survival prediction when combined with the UCSF criteria. Furthermore, Cox proportional hazard regression analysis revealed that tumor size (p = 0.012, p = 0.623), tumor thrombus (p = 0.011, p = 0.015), UCSF criteria (p = 0.471, p = 0.013), and recipient IL-15 rs10519613 genotype (p = 0.039, p = 0.008) were independent factors of predicting DFS and OS. Conclusions Recipient IL-15 rs10519613 polymorphism was associated with HCC recurrence after LT and might be a potential genetic marker for the clinical outcome of HCC patients treated with LT.

Correction: Activation of IL6/IGFIR Confers Poor Prognosis of HBV-Related Hepatocellular Carcinoma through Induction of OCT4/NANOG Expression.

Correction: Activation of IL6/IGFIR Confers Poor Prognosis of HBV-Related Hepatocellular Carcinoma through Induction of OCT4/NANOG Expression.

Genetic polymorphisms of immune checkpoint proteins PD-1 and TIM-3 are associated with survival of patients with hepatitis B virus-related hepatocellular carcinoma.

Programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule 3 (TIM-3) are involved in hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study examined the associations of PD1 and TIM3 polymorphisms with the overall survival (OS) of a prospective cohort of 258 HBV-related HCC patients. Results showed that PD1 +8669 G allele-containing genotypes or TIM3 −1516 genotype GG were significantly associated with longer OS (P < 0.001 and P = 0.001, respectively). In multivariate analysis, PD1 +8669 G allele-containing genotypes and TIM3 −1516 genotype GG were independently associated with longer OS (hazard ratio (HR), 1.835; 95% confidence interval (CI), 1.342–2.509; P < 0.001 and HR, 2.070; 95%CI, 1.428–3.002; P < 0.001, respectively). PD1 +8669 G allele-containing genotypes were significantly associated with longer OS in patients receiving surgical (resection or radiofrequency) treatment, transcatheter arterial chemoembolization (TACE) or supportive and symptomatic treatment. TIM3 −1516 genotype GG was significantly associated with longer OS in TACE patients. In multivariate analysis, PD1 +8669 G allele-containing genotypes were independently associated with longer OS in each treatment population. TIM3 −1516 genotype GG was independently associated with longer OS in patients receiving surgical treatment or TACE. These findings suggest that PD1 +8669 A/G and TIM3 −1516 G/T polymorphisms may affect the prognosis of HBV-related HCC and may be new predictors of prognosis for HCC patients.

ATXN7 Gene Variants and Expression Predict Post-Operative Clinical Outcomes in Hepatitis B Virus-Related Hepatocellular Carcinoma

Background/Aims: Hepatocellular carcinoma (HCC) is a lethal disease with nearly equal morbidity and mortality. Thus, the discovery and application of more useful predictive biomarkers for improving therapeutic effects and prediction of clinical outcomes is of crucial significance. Methods: A total of 475 HBV-related HCC patients were enrolled. Ataxin 7 (ATXN7) single nucleotide polymorphisms (SNPs) were genotyped by Sanger DNA sequencing after PCR amplification. The associations between ATXN7 SNPs and mRNA expression with the prognosis of HBV-related HCC were analyzed. Results: In all, rs3774729 was significantly associated with overall survival (OS) of HBV-related HCC (P = 0.013, HR = 0.66, 95% CI: 0.48-0.94). And patients with the AA genotype and a high level of serum alpha fetoprotein (AFP) had significantly worse OS when compared to patients with AG/GG genotypes and a low level of AFP (adjusted P = 0.007, adjusted HR = 1.83, 95% CI = 1.18-2.82). Furthermore, low expression of ATXN7 was significantly associated with poor recurrence-free survival (RFS) and OS (P = 0.007, HR = 2.38, 95% CI = 1.27-4.45 and P = 0.025, HR = 1.75, 95% CI = 1.18-2.62). Conclusion: ATXN7 may be a potential predictor of post-operative prognosis of HBV-related HCC.

Evaluation of Antiviral Therapy Performed after Curative Therapy in Patients with HBV-Related Hepatocellular Carcinoma: An Updated Meta-Analysis.

Background. The long-term prognosis after curative therapy for hepatitis B virus- (HBV-) related hepatocellular carcinoma (HCC) remains unsatisfactory due to the high incidence of recurrence. The effect of treatment with nucleotide analogues (NAs) in patients with HBV-related HCC after curative therapy remains unclear. Objective. To assess the impact of using NAs after curative therapy. Method. A computerized literature search was performed; eligible studies were identified from databases. The pooled risk ratios (RRs) and 95% CIs were calculated using Review Manager 5.3. Result. The meta-analysis included a total of 15 studies with 8060 patients. The one-year and three-year recurrence (one-year recurrence: RR 0.41 [95% CI 0.28 to 0.61]; P < 0.00001; three-year recurrence: RR 0.63 [95% CI 0.43 to 0.94]; P = 0.001) and the one-, three-, and five-year overall survival (OS) and disease-free survival (DFS) were significantly better in the treatment group. Conclusion. NAs can reduce the recurrence and improve the prognosis of HBV-related HCC after curative therapy.

The transcription factor c-JUN/AP-1 promotes HBV-related liver tumorigenesis in mice

Hepatocellular carcinoma (HCC) develops as a consequence of chronic inflammatory liver diseases such as chronic hepatitis B virus (HBV) infection. The transcription factor c-Jun/activator protein 1 (AP-1) is strongly expressed in response to inflammatory stimuli, promotes hepatocyte survival during acute hepatitis and acts as an oncogene during chemically induced liver carcinogenesis in mice. Here, we therefore aimed to characterize the functions of c-Jun during HBV-related liver tumorigenesis. To this end, transgenic mice expressing all HBV envelope proteins (HBV(+)), an established model of HBV-related HCC, were crossed with knockout mice lacking c-Jun specifically in hepatocytes and tumorigenesis was analyzed. Hepatic expression of c-Jun was strongly induced at several time points during tumorigenesis in HBV(+) mice, whereas expression of other AP-1 components remained unchanged. Importantly, formation of premalignant foci and tumors was strongly reduced in HBV(+) mice lacking c-Jun. This phenotype correlated with impaired hepatocyte proliferation and increased expression of the cell cycle inhibitor p21, whereas hepatocyte survival was not affected. Progression and prognosis of HBV-related HCC correlates with the expression of the cytokine osteopontin (Opn), an established AP-1 target gene. Opn expression was strongly reduced in HBV(+) livers and primary mouse hepatocytes lacking c-Jun, demonstrating that c-Jun regulates hepatic Opn expression in a cell-autonomous manner. These findings indicate that c-Jun has important functions during HBV-associated tumorigenesis by promoting hepatocyte proliferation as well as progression of dysplasia. Therefore, targeting c-Jun may be a useful strategy to prevent hepatitis-associated tumorigenesis.

Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression.

To unravel the role of interleukin (IL)-6 and insulin-like growth factor (IGF)-I receptor (IGFIR) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC). Serum levels of IL6 were detected using ELISA assays (n = 120). The effects of IL6/IGFI on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGFI receptor (p-IGFIR) in tissues were detected by Western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGFIR expression levels in tissues (n = 191) were analyzed by real-time qRT-PCR and was correlated with early tumor recurrence using the Kaplan-Meier survival analysis. A high positive correlation between the expression levels of OCT4/NANOG and IGFIR/p-IGFIR in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGFIR was mostly confined to hepatitis B virus (HBV)-related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL6 were significantly correlated with high OCT4/NANOG expression. IL6 stimulated an autocrine IGFI/IGFIR expression STAT3 dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGFIR activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL6-induced stemness-related properties both in vitro and in vivo. The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL6-induced IGF/IGFIR activation, particularly in HBV-HCC.

Antiviral therapy decreases recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection: a meta-analysis.

The long-term outcome after curative resection of hepatocellular carcinoma (HCC) remains unsatisfactory because of the high incidence of recurrence. The present study was intended to assess the impact of hepatitis B virus (HBV) DNA level and nucleos(t)ide analog therapy on posthepatectomy recurrence of HBV-related HCC. Eligible studies were identified through a computerized literature search. The pooled relative risk ratio (RR) with 95 % confidence interval (CI) was calculated using Review Manager 5.1 Software. Twenty studies with a total of 8,204 participants were included for this meta-analysis. Pooled analysis showed that high viral load was significantly associated with risk of recurrence (RR: 1.85, 95 % CI: 1.41-2.42; P < 0.001), poorer disease-free survival (DFS) (RR: 1.96, 95 % CI: 1.62-2.38; P < 0.001), and poorer overall survival (OS) (RR: 1.47, 95 % CI: 1.22-1.77; P < 0.001) of HBV-related HCC after surgical resection. Nucleos(t)ide analog therapy significantly decreased the recurrence risk (RR: 0.69, 95 % CI: 0.59-0.80; P < 0.001) and improved both DFS (RR: 0.70, 95 % CI: 0.58-0.83; P < 0.001) and OS (RR: 0.46, 95 % CI: 0.32-0.68; P < 0.001). High DNA level is associated with posthepatectomy recurrence of HBV-related HCC. Nucleos(t)ide analog therapy improves the prognosis of HBV-related HCC after resection.

A Genetic Variant in the Promoter Region of miR-106b-25 Cluster Predict Clinical Outcome of HBV-Related Hepatocellular Carcinoma in Chinese

Background MiR-106b-25 cluster, hosted in intron 13 of MCM7, may play integral roles in diverse processes including immune response, tumorigenesis and progression. A single nucleotide polymorphism (SNP), rs999885, is located in the promoter region of MCM7. Our previous study showed that the A to G base change of rs999885 may provide an increased risk for HCC in HBV persistent carriers by altering the expression of the miR-106b-25 cluster. However, it is unknown whether rs999885 is associated with prognosis of intermediate or advanced HBV-related hepatocellular carcinoma (HCC) patients.MethodsThe SNP, rs999885, was genotyped by using the TaqMan allelic discrimination Assay in 414 intermediate or advanced HCC patients. Log-rank test and Cox proportional hazard models were used for survival analysis.ResultsThe variant genotypes of rs999885 were associated with a significantly decreased risk of death for intermediate or advanced HCC [additive model: adjusted hazard ratio (HR) = 0.76,95% confidence intervals (CI) = 0.59–0.97]. Further stepwise regression analysis suggested that rs999885 was an independently protective factor for the prognosis of HCC in the final model (additive model: adjusted HR = 0.72, 95% CI = 0.56–0.91, P = 0.007).ConclusionsThese findings indicate that the A to G base change of rs999885 may provide a protective effect on the prognosis of intermediate or advanced HCC in Chinese.

Does Anti-HBV Therapy Benefit the Prognosis of HBV-Related Hepatocellular Carcinoma Following Hepatectomy?

The Hepatitis B virus (HBV) is an important etiological factor for hepatocarcinogenesis, because HBV DNA load and HBV reactivation are major risks that influence the long-term survival of hepatocellular carcinoma (HCC) patients who underwent hepatectomy and, thus, may cause postoperative liver function deterioration, tumor recurrence, and reduce patient's overall survival. However, anti-HBV therapy can suppress HBV replication, improve the remnant liver function, render patients better able to tolerate HCC treatments, and may even improve their prognosis. In this paper, an anti-HBV therapy that benefits the prognosis of HBV-related HCC following hepatectomy is reviewed.

CK19 can be used to predict the early recurrence and prognosis of HBV-related hepatocellular carcinoma patients with low AFP serum concentration after R0 radical hepatectomy

To investigate the expression of CK19 in HBV-related hepatocellular carcinoma (HCC) tissues in patients with low serum AFP concentration and the relationship between them and the recurrence and prognosis of HCC after R0 radical hepatectomy. The expressions of CK19 and Ki67 in HCC tissues of 235 cases were examined using tissue microarray and two-step methods of PV-6000 immunohistochemistry. The expression of CK19 mRNA in 20 frozen HCC specimens was examined by RT-PCR. The correlation between gene expressions and tumor recurrence and prognosis was analyzed. Among the 235 HBV-related HCC patients after R0 radical hepatectomy, the median disease-free survival (DFS) was 31.2 months in the patients with serum AFP < 400 µg/L and 13.8 months in the patients with serum AFP ≥ 400 µg/L (P = 0.041), the overall survival (OS) was 84.0 and 58.6 months in the two subgroups (P = 0.125), and the tumor recurrence within one year was in 43 cases (27%) and 37 cases (49.3%), respectively, (P = 0.001). The DFS was 11.6 months in the CK19-positive cases and 27.0 months in the CK19-negative cases (P > 0.05). The OS was significantly lower in the CK19-positive cases than that in the CK19-negative cases (P = 0.023). Both DFS and OS in the CK19-positive cases with AFP < 400 µg/L were significantly lower than those in the CK19-negative cases with AFP < 400 µg/L (both P < 0.05). The CK19 expression was significantly correlated with histological differentiation (P = 0.023), number of tumor foci (P = 0.044), vascular tumor embolism (P = 0.005), regional lymph node metastasis (P = 0.023), and 1-year recurrence (P = 0.006). Among the patients with AFP < 400 µg/L, the 1-year recurrence was 53% in the CK19-positive cases and 23% in the CK19-negative cases (P < 0.001), the median DFS was 11.3 months in CK19-positive cases and 34.0 months in CK19-negative cases (P = 0.010), and the median OS was 19.5 months in the CK19-positive cases, significantly lower than 84.0 months in the CK19-negative cases (P = 0.001). Cox regression analysis showed that CK19-positive expression was an independent factor affecting early HCC recurrence and prognosis. In HBV-related HCC patients after radical hepatectomy with AFP < 400 µg/L, positive expression of CK19 indicates a higher proliferation and invasiveness of HCC, and is an important factor of early recurrence and poor prognosis.

Impact of Antiviral Therapy on the Survival of Patients After Major Hepatectomy for Hepatitis B Virus–Related Hepatocellular Carcinoma

To assess whether commencement of antiviral therapy after hepatectomy improves the prognosis of hepatocellular carcinoma (HCC) in preoperatively antiviral-naive patients with chronic hepatitis B virus (HBV) infection. Retrospective analysis of a prospectively collected database. University teaching hospital. Disease-free and overall survival rates. One hundred thirty-six patients received major hepatectomy for HBV-related HCC from September 1, 2003, through December 31, 2007. Among them, 42 patients received antiviral therapy (treatment group) after hepatectomy, whereas 94 did not (control group). Patient demographics, preoperative liver function, tumor characteristics, and liver function at the time of tumor recurrence were comparable between the 2 groups. Disease-free and overall survival rates were significantly prolonged in the treatment group. The 1-, 3-, and 5-year overall survival rates in the treatment group were 88.1%, 79.1%, and 71.2%, respectively; in the control group, 76.5%, 47.5%, and 43.5%, respectively (P = .005). The 1-, 3-, and 5-year disease-free survival rates in the treatment group were 66.5%, 51.4%, and 51.4%, respectively; in the control group, 48.9%, 33.8%, and 33.8%, respectively (P = .05). Subgroup analysis stratified against tumor stage and major vascular invasion showed that posthepatectomy antiviral treatment conferred a significant survival benefit in stages I and II tumors or HCCs without major venous invasion. Antiviral therapy improves the prognosis of HBV-related HCC. It should be considered after hepatectomy for HBV-related HCC, especially in early-stage tumors.

Factors predicting occurrence and prognosis of hepatitis-B-virus-related hepatocellular carcinoma

Primary liver cancer is an important cause of cancer death, and hepatocellular carcinoma (HCC) accounts for 70%-85% of total liver cancer worldwide. Chronic hepatitis B virus (HBV) infection contributes to > 75% of HCC cases. High serum viral load is the most reliable indicator of viral replication in predicting development of HCC. HBV genotype C is closely associated with HCC in cirrhotic patients aged > 50 years, whereas genotype B is associated with development of HCC in non-cirrhotic young patients and postoperative relapse of HCC. Different HBV subgenotypes have distinct patterns of mutations, which are clearly associated with increased risk of HCC. Mutations accumulate during chronic HBV infection and predict occurrence of HCC. Chronic inflammation leads to increased frequency of viral mutation via cellular cytidine deaminase induction. Mutations are negatively selected by host immunity, whereas some immuno-escaped HBV mutants are active in hepatocarcinogenesis. Inflammatory pathways contribute to the inflammation-necrosis-regeneration process, ultimately HCC. Their hallmark molecules can predict malignancy in HBV-infected subjects. Continuing inflammation is involved in hepatocarcinogenesis and closely related to recurrence and metastasis. HBV load, genotype C, viral mutations and expression of inflammatory molecules in HBV-related HCC tissues are significantly associated with poor prognosis. Imbalance between intratumoral CD8(+) T cells and regulatory T cells or Th1 and Th2 cytokines in peritumoral tissues can predict prognosis of HBV-related HCC. These factors are important for developing active prevention and surveillance of HBV-infected subjects who are more likely to develop HCC, or for tailoring suitable treatment to improve survival or postpone postoperative recurrence of HCC.