Jeong A. Kim

Long-term additional lamivudine therapy enhances durability of lamivudine-induced HBeAg loss: a prospective study

BACKGROUNDS/AIMS In the treatment of chronic hepatitis B (CHB) with lamivudine, adequate duration of the therapy remains to be determined. In this prospective study, the authors intended to investigate whether long-term additional administration of lamivudine might enhance the durability of lamivudine-induced HBeAg seroconversion. METHODS Eighty-five CHB patients who achieved HBeAg seroconversion by lamivudine received additional lamivudine therapy for at least 24 months at a dose of 100 mg per day. Among them, 61 patients whose serum HBeAg and HBV-DNA (solution hybridization assay) had been negative persistently for >24 months discontinued lamivudine therapy and followed-up for >12 months. We calculated the cumulative reappearance rate of serum HBV-DNA and HBeAg and also evaluated the predictive factors for post-treatment virologic relapse. RESULTS The cumulative reappearance rates of serum HBV-DNA following cessation of lamivudine therapy at 6 months, 1 year and 2 years were 15%, 21%, and 31%, respectively. The cumulative reappearance rates of serum HBeAg at 6 months, 1 year and 2 years were 11%, 13% and 16%, respectively. Old age and presence of precore mutant were two independent predictive factors for viral relapse. CONCLUSION These results suggested that long-term additional administration of lamivudine might enhance the durability of lamivudine-induced HBeAg seroconversion.

Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma.

Primary liver cancer is the third most common cause of cancer‐related death worldwide, with a rising incidence in Western countries. Little is known about the genetic etiology of this disease. To identify genetic factors associated with hepatocellular carcinoma (HCC) and liver cirrhosis (LC), we conducted a comprehensive, genome‐wide variation analysis in a population of unrelated Asian individuals. Copy number variation (CNV) and single nucleotide polymorphisms (SNPs) were assayed in peripheral blood with the high‐density Affymetrix SNP6.0 microarray platform. We used a two‐stage discovery and replication design to control for overfitting and to validate observed results. We identified a strong association with CNV at the T‐cell receptor gamma and alpha loci (P < 1 × 10−15) in HCC cases when contrasted with controls. This variation appears to be somatic in origin, reflecting differences between T‐cell receptor processing in lymphocytes from individuals with liver disease and healthy individuals that is not attributable to chronic hepatitis virus infection. Analysis of constitutional variation identified three susceptibility loci including the class II MHC complex, whose protein products present antigen to T‐cell receptors and mediate immune surveillance. Statistical analysis of biologic networks identified variation in the “antigen presentation and processing” pathway as being highly significantly associated with HCC (P = 1 × 10−11). SNP analysis identified two variants whose allele frequencies differ significantly between HCC and LC. One of these (P = 1.74 × 10−12) lies in the PTEN homolog TPTE2. Conclusion: Combined analysis of CNV, individual SNPs, and pathways suggest that HCC susceptibility is mediated by germline factors affecting the immune response and differences in T‐cell receptor processing. (HEPATOLOGY 2010)

Metastatic tumor antigen 1 is closely associated with frequent postoperative recurrence and poor survival in patients with hepatocellular carcinoma

Metastatic tumor antigen 1 (MTA1) is known to play a role in angiogenic processes as a stabilizer of hypoxia‐inducible factor 1‐α (HIF1‐α). In this study, we examined whether overexpression of MTA1 affects the recurrence of hepatocellular carcinoma (HCC) after surgical resection and the survival of the patients. A total of 506 HCC patients who underwent hepatic resection were included in the study. They were followed up for a median of 43 months (range, 1‐96 months) after hepatectomy. MTA1 expression levels were determined by the proportion of immunopositive cells (none, all negative; +, <50%; ++, >50%). The relationships between MTA1 expression and the HCC histological features, the appearance of recurrent HCC after surgical resection, and the survival of the patients were examined. Eighty‐eight cases (17%) of the HCCs were positive for MTA1, although the surrounding liver tissues were all negative for MTA1; 62 cases were + and 26 cases were ++. Increased MTA1 expression levels in HCC were correlated with larger tumors (P = 0.04), perinodal extension (P = 0.03), and microvascular invasion (P = 0.008). Histological differentiation had marginal significance (P = 0.056). However, there was no association between MTA1 expression and age, sex, Child‐Pugh class, and capsule invasion of HCC. Interestingly, MTA1 expression levels were significantly greater in hepatitis B virus (HBV)‐associated HCC compared with hepatitis C virus (HCV)‐associated HCC (P = 0.017). The cumulative recurrence rates of MTA1‐positive HCCs were markedly greater than those of MTA1‐negative HCCs (P < 0.0001). The cumulative survival rates of patients with MTA1‐positive HCCs were significantly shorter than those of patients with MTA1‐negative HCCs (P < 0.0001). In conclusion, our data indicate that MTA1 is closely associated with microvascular invasion, frequent postoperative recurrence, and poor survival of HCC patients, especially in those with HBV‐associated HCC. (HEPATOLOGY 2008;47:929–936.)

Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma†

Sorafenib currently sets the new standard for advanced hepatocellular carcinoma (HCC). It has been suggested that Asian patients with HCC have increased susceptibility to hand‐foot skin reaction (HFSR) related to sorafenib therapy. The authors investigated the association between sorafenib‐induced HFSR and genetic polymorphisms in Korean patients with HCC.

Transforming growth factor beta 1 overexpression is closely related to invasiveness of hepatocellular carcinoma.

Objectives: The study was aimed to investigate the relationship between plasma transforming growth factor beta 1 (TGF-β1) expression and the characteristics of hepatocellular carcinoma (HCC). Methods: Five hundred and seventy-one patients with HCC were subjected. Plasma TGF-β1 levels were measured by enzyme-linked immunosorbent assay at diagnosis and compared in accordance with clinical and radiological characteristics. Results: Plasma TGF-β1 levels were significantly higher in the diffuse infiltrative type (n = 159) than in the nodular type of HCC (n = 412; 3.94 ± 0.34 vs. 3.79 ± 0.29 log10 pg/ml; p < 0.001). They were much higher in patients with portal vein thrombosis or extrahepatic metastasis than in those without (3.88 ± 0.34 vs. 3.81 ± 0.29 log10 pg/ml, p = 0.008; 3.94 ± 0.35 vs. 3.82 ± 0.30 log10 pg/ml, p = 0.013, respectively). Also, plasma TGF-β1 levels showed a positive correlation with the size of HCC (r = 0.014, p < 0.001). Additionally, plasma TGF-β1 levels were inversely related to the survival periods (p < 0.001). Conclusion: TGF-β1 was overexpressed in invasive types of HCC and it may be involved in the rapid progression of HCC.

Close correlation of p53 mutation to microvascular invasion in hepatocellular carcinoma.

Mutation of p53 is a poor prognostic indicator of hepatocellular carcinoma (HCC). Although poor histologic differentiation of HCC has been associated with p53 mutations, the exact reasons for unfavorable clinical outcomes in patients with HCC remain to be clarified. In this study, we evaluate the association between p53 mutation and histopathologic features of HCCs, as well as tumor recurrences and survival. We examined 20 HCCs and surrounding liver tissues from patients who underwent surgical resection, and we performed direct sequencing of p53 gene. p53 mutations were found in 9 of 20 HCCs; none were found in the surrounding liver tissue. p53 mutations were frequent in large, multinodular, and poorly differentiated HCCs. Five of 9 with p53 mutation (in contrast, none of 11 with wild-type mutation) showed microvascular invasions. Hepatocellular carcinoma recurred in 6 of 9 with p53 mutation, in contrast to only 2 of 11 with wild-type mutation. The 1-year survival rate with p53 mutation was significantly lower than that with wild-type. In conclusion, it is suggested that p53 mutations tend to be commonly associated with microvascular invasions, which may result in micrometastasis, followed by frequent recurrences.

Polymorphisms of DNA repair genes in Korean hepatocellular carcinoma patients with chronic hepatitis B: Possible implications on survival

BACKGROUND & AIMS We aimed at determining whether single nucleotide polymorphisms (SNPs) of DNA repair genes influence the development and clinical outcomes of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). METHODS We evaluated 14 SNPs of eight DNA repair genes in 708 patients with HCC and 388 HBsAg positive controls without HCC. The Kaplan-Meier methods with log-rank test and Cox regression models were used to compare survival of HCC patients according to the genotype. RESULTS The SNP of XRCC4 rs1805377 was significantly associated with decreased risk of HCC development (OR, 0.592; p=0.028) and improved overall survival of patients with HCC (median survival time (MST) of 48, 72, and 89 months for the AA, AG, and GG genotypes, respectively; p=0.044). In addition, SNP of OGG1 rs1053133 was significantly associated with postoperative recurrence (OR, 0.604; p=0.049), tumor differentiation (OR, 0.571; p=0.041), and improved survival of resected HCC (MST of 55 and 108 months for the GG and GC/CC genotypes, p=0.001). The multivariate analysis showed that OGG1 rs1052133, XRCC1 rs25487, ERCC5 rs2018836, ERCC5 rs3818356, and XRCC4 rs1805377 had a significant effect on survival. Moreover, a strong dose-dependent association was observed between the number of putative high-risk genotypes of OGG1, XRCC1, ERCC5, and XRCC4 with the overall survival. The MST of HCC with ≥2 putative high-risk genotypes was significantly prolonged compared to those with ≥3 high-risk genotypes (76 vs. 46 months, respectively, p=0.002). CONCLUSIONS Polymorphisms of DNA repair genes play a potential role in the development, progression, and survival of Korean HCC patients with chronic HBV infection.

Expression of Transforming Growth Factor beta - 1 in Chronic Hepatitis and Hepatocellular Carcinoma Associated with Hepatitis C Virus Infection

Background Transforming growth factor beta-1 (TGFβ 1) has been suggested to play a role in the development, growth or progression of hepatocellular carcinoma (HCC). Genotype and serum titer of HCV also affect the occurrence of HCC in chronic hepatitis C. In this study, we were to evaluate the effects of genotype or serum titer of HCV on the expression of TGFβ 1. We also intended to examine the correlation between the up-regulation of TGFβ 1 and the association with HCC in patients with chronic hepatitis C. Methods We studied 19 patients with chronic hepatitis C and 18 with HCC associated with HCV infection. HCV genotype was determined by line probe reverse hybridization assay and the amount of HCV-RNA was quantitated by branched DNA signal amplification assay. Serum TGFβ 1 level was measured by enzyme linked immunosorbent assay. Results HCV genotypes of patients with HCC were similar to those without it. Serum HCV-RNA titer was higher in genotype 1b than in non-1b (p<0.05). Serum TGFβ 1 levels were higher in HCC than in chronic hepatitis (p<0.05). However, there was no significant difference in the serum TGFβ 1 level between genotype 1b and non-1b. Also, it was not correlated with the serum HCV-RNA titer or alanine aminotransferase levels. Conclusion TGFβ 1 seems to be overexpressed in HCC compared to that of chronic hepatitis C; it was not affected by serum ALT levels, genotype or serum HCV titer. It is suggested that TGFβ 1 may be associated with the malignant transformation of hepatocyte or the progression of HCV-associated HCC.

Prognostic impact of telomere maintenance gene polymorphisms on hepatocellular carcinoma patients with chronic hepatitis B

Our goal was to determine whether single‐nucleotide polymorphisms (SNPs) of telomere maintenance genes influence the development and clinical outcomes of patients with hepatitis B virus (HBV)‐associated hepatocellular carcinoma (HCC). We evaluated 20 SNPs of five telomere maintenance genes in 702 patients with HCC and 351 hepatitis B virus surface antigen‐positive controls without HCC. Significant SNPs were then validated in an independent cohort of 857 HCC patients and 429 controls. We assessed the association of each SNP with the development of HCC and overall survival through a multivariate Cox proportional analysis. A significantly increased risk of HCC development was identified for the telomerase‐associated protein 1 (TEP1) rs1713449 SNP in both the discovery and replication phases (combined odds ratio = 1.42, P = 9.378 × 10−5). In addition, the TEP1 rs1713449, TEP1 rs872072, protection of telomeres 1 homolog rs7784168, telomerase reverse transcriptase rs13167280, and telomeric repeat binding factor 1 rs2306494 SNPs had a significant effect on the overall survival, and a similar survival effect was validated in the replication cohort. Moreover, there was a significant dose‐dependent association between the number of putatively high‐risk genotypes of the five aforementioned SNPs and overall survival. The median survival time was significantly prolonged for patients with HCC with two or fewer putatively high‐risk genotypes versus those with three or more high‐risk genotypes (85 versus 44 months, log‐rank P = 4.483 × 10−5), and this was demonstrated in the replication cohort (52 versus 37 months, log‐rank P = 0.026). Conclusion: These observations suggest that the SNPs of telomere maintenance genes play a potential role in the development of HCC and the survival of HCC patients with chronic HBV infections. (Hepatology 2014;59:1912–1920)

Clinical Implications of Arrest-Defective Protein 1 Expression in Hepatocellular Carcinoma: A Novel Predictor of Microvascular Invasion

Objective: The associations between arrest-defective protein 1 (ARD1) gene expression and the clinicopathological characteristics and clinical outcomes of 94 patients undergoing hepatectomy for hepatocellular carcinoma (HCC) were investigated. Methods: ARD1 mRNA levels in HCC and corresponding non-cancerous tissues were quantified by real-time PCR. The gene expression of the tumor relative to that in the non-tumor tissues was calculated using the 2–ΔΔCT method. The subjects were classified into high expression (2–ΔΔCT > 1, n = 38) and low expression (2–ΔΔCT ≤ 1, n = 56) groups. Results: The HCCs did not differ from matched liver tissues in terms of ARD1 mRNA levels. The high expression group had more often microvascular invasion than the low expression group (32 vs. 14%; p = 0.045). The two groups did not differ significantly in terms of other patient or tumor variables. The median follow-up period was 92.1 months. The 5-year recurrence-free and overall survival rates were 34 and 76% for the high expression group, respectively, which were similar to the rates of the low expression group (46 vs. 73%, p = 0.98 and p = 0.52, respectively). Conclusions: Intratumoral ARD1 mRNA overexpression was involved in the microvascular invasion process in patients with HCC, although it did not associate strongly with postresectional outcomes.