Eradication of hepatitis C virus profoundly prolongs survival in hepatocellular carcinoma patients receiving transarterial chemoembolization.

Adjuvant pegylated interferon plus ribavirin treatment (PegIFN/RBV) reduces recurrence and prolongs survival in early stage hepatocellular carcinoma (HCC) patients with chronic hepatitis C (CHC) infection receiving resection or ablation. However, the impact of antiviral therapy in intermediate and advanced stage of CHC-HCC patients is uncertain. This study aimed to investigate the impact PegIFN/RBV treatment on recurrence-free interval and survival in patients with HCC receiving transarterial chemoembolization (TACE). From 2010 to 2013, 274 CHC patients from a 1073 patient-based cohort composed of freshly diagnosed HCC and receiving TACE treatment the Chang Gung Memorial Hospital, Linkou Medical Center were recruited. Propensity score matching (PSM) (age, gender, AST to Platelet Ratio Index (APRI), tumour size, tumour number and Child-Turcotte-Pugh score) with the ratio 1:2 for patients with and without PegIFN/RBV treatment was performed. Statistics were performed with SPSS V.20 (IBM, USA). After matching, 153 patients were analysed and 27 patients (17.6%) achieved sustained virologic response (SVR). The 2-year cumulative overall survival rate and recurrence-free survival rate among patients with SVR, non-SVR, and untreated were 85.2% vs 58.3% vs 69.6% (P=.001) and 73.3% vs 53.8% vs 58.5% (P=.013). By Cox regression analysis, non-SVR, untreated, increase CTP score and nonresponder to TACE were independent factors related to mortality. The SVR achieved by PegIFN/RBV treatment markedly improves survival and reduces tumour recurrence in CHC-HCC patients receiving TACE treatment after complete response.

IL28B genetic variations are associated with high sustained virological response (SVR) of interferon-α plus ribavirin therapy in Taiwanese chronic HCV infection.

Chronic hepatitis C virus (HCV) infection patients exhibit different sustained virological responses (SVRs) following the treatment with pegylated interferon-α (IFN-α) and ribavirin. Genome-wide association studies consistently linked SVR of IFN-α-based therapy to the IL28B single-nucleotide polymorphisms (SNPs) on chromosome 19q.13 in various populations. This study was undertaken to investigate the association of IL28B SNPs with SVR in a cohort of Taiwanese chronic HCV patients. Ten SNPs of IL28B were genotyped in 728 chronic HCV patients and 960 healthy controls. Genotype distributions, allele frequencies and haplotypes were tested for SVR and susceptibility in Taiwanese chronic HCV patients. Non-genotype 1 infection (adjusted P=3.3 × 10(-12), odds ratio (OR) 0.179; 95% confidence interval (CI): 0.110-0.290) and low HCV viral load (<400 000 IU ml(-1)) (adjusted P=3.5 × 10(-9), OR 0.299; 95% CI: 0.200-0.446) were two major factors identified for high SVR. Notably, eight IL28B SNPs including previously described disease-associated SNPs (Trend test P=0.005) were significantly associated with SVR. Our data indicate that IL28B polymorphisms are the essential contributing factors for high SVR in Taiwanese chronic HCV patients. Combination of virus genotyping and host genetic data may be used to select the optimal treatment regimes in IFN-based therapy.

A randomised phase II study of pegylated arginine deiminase (ADI-PEG 20) in Asian advanced hepatocellular carcinoma patients.

BACKGROUND: Human hepatocellular carcinoma (HCC) cells are largely deficient of argininosuccinate synthetase and thus auxotrophic for arginine. This study aims to investigate the efficacy and pharmacodynamics of pegylated arginine deiminase (ADI-PEG 20), a systemic arginine deprivation agent, in Asian HCC patients. METHODS: Patients with advanced HCC who were not candidates for local therapy were eligible and randomly assigned to receive weekly intramuscular injections of ADI-PEG 20 at doses of 160 or 320 IU m(-2). The primary end point was disease-control rate (DCR). RESULTS: Of the 71 accruals, 43.6% had failed previous systemic treatment. There were no objective responders. The DCR and the median overall survival (OS) of the intent-to-treat population were 31.0% (95% confidence interval (CI): 20.5-43.1) and 7.3 (95% CI: 4.7-9.9) months respectively. Both efficacy parameters were comparable between the two study arms. The median OS of patients with undetectable circulating arginine for more than or equal to and <4 weeks was 10.0 (95% CI: 2.1-17.9) and 5.8 (95% CI: 1.4-10.1) months respectively (P=0.251, log-rank test). The major treatment-related adverse events were grades 1-2 local and/or allergic reactions. CONCLUSIONS: ADI-PEG 20 is safe and efficacious in stabilising the progression of heavily pretreated advanced HCC in an Asian population, and deserves further exploration.

A liver slice culture-based ex vivo assay to predict the outcome of antiviral therapy for chronic hepatitis C.

A liver slice culture-based, ex vivo drug suppression assay was developed as a pre-therapeutic predictor for the outcome of antiviral therapy. To investigate its clinical application, 106 consecutive patients with chronic hepatitis C virus (HCV) infection were evaluated. Ex vivo drug suppression assay was performed before administrating a standard course of peginterferon plus ribavirin combination therapy. Stepwise logistic regression model was used to estimate sustained virological response (SVR) on the presence of various clinicopathological parameters. Suppression of HCV replication in the ex vivo assay was present in 32 patients, 29 (90.6%) of whom achieved SVR. Stepwise logistic regression analysis indicated that the presence of interferon suppression effect in the ex vivo assay (odds ratio [OR], 5.552; 95% confidence interval [CI], 1.114-27.673; P = 0.036), genotype 1 (OR; 0.045, 95% CI, 0.008-0.259; P = 0.001), HCV-RNA level (OR, 0.739; 95% CI, 0.617-0.885; P = 0.001), the presence of fatty metamorphosis (OR, 0.205; 95% CI, 0.053-0.793; P = 0.022), and albumin (OR, 9.687; 95% CI, 2.237-41.940; P = 0.002) were independent determinants of SVR. Categorical analysis revealed that 17 of 17 (100%) patients with genotype non-1 and positive ex vivo suppression test achieved SVR, while 20 of 40 (50%) with genotype 1 and negative ex vivo suppression test achieved SVR. In conclusion, the ex vivo drug suppression assay may serve as an independent pre-therapeutic predictor for the SVR in interferon-based antiviral therapy.

Liver injury is associated with enhanced regulatory T-cell activity in patients with chronic hepatitis B.

Chronic hepatitis B virus (HBV) infection is associated with impairment of HBV-specific immune responses. Recently, it has been shown that regulatory T (Treg) cells downregulate HBV-specific immune responses but their role in chronic hepatitis B is still controversial. We hypothesized that liver injury enhances the influence of Treg cells on HBV-specific immune responses. The frequency of Treg cell and the in vitro expansion of HBV-specific CD8+ T cell detected by the tetramer method were investigated in 79 patients with chronic hepatitis B. Thirty-three healthy volunteers were enrolled to measure the frequency of Treg cell as controls. The results showed that in chronic hepatitis B cases, the frequency of Treg cells in peripheral blood was significantly higher than that in normal volunteers. The higher level of serum transaminase was associated with higher frequency of Treg cells, which both had a linear correlation relationship. HBV-DNA level, HBe status, age and sex had no statistical association with Treg cell frequency. Furthermore, in patients with higher serum transaminase levels, the expansion of HBV-specific CD8+ T cells was higher after removal of Treg cells when compared with patients with lower serum transaminase levels. In conclusion, our data indicate a significant association between serum transaminase level and frequency/activity of Treg cells. Based on this observation, we propose that liver-injury enhances Treg cell frequency/activity in chronic hepatitis B patients.

Sustained virological response to interferon reduces cirrhosis in chronic hepatitis C: a 1,386-patient study from Taiwan.

BACKGROUND: The long-term benefits of interferon-based therapy on preventing cirrhosis at non-cirrhotic stage in chronic hepatitis C patients are not fully clarified. AIM: To evaluate the effectiveness of interferon-based therapy regarding to cirrhosis prevention in non-cirrhotic chronic hepatitis C patients. METHODS: A total of 1386 biopsy-proven, non-cirrhotic chronic hepatitis C patients (892 received interferon-based therapy and 494 untreated) were enrolled. RESULTS: Fifty-six untreated and 51 treated (24 sustained virologic responders and 27 non-responders) patients developed cirrhosis during a mean follow-up period of 5.0 (1-16) and 5.1 (1-15.3) years, respectively. The annual incidences of cirrhosis in untreated and treated groups were 2.26 and 1.11% (non-responders: 1.99%, sustained responders: 0.74%), respectively. The 15-year cumulative incidence of cirrhosis was significantly lower in treated (9.9%) than untreated patients (39.8%, P = 0.0008, log-rank test). The 14.5-year cumulative incidence of cirrhosis was significantly lower in sustained responders (4.8%) compared with non-responders (21.6%, P = 0.0007) and untreated patients (36.6%, P < 0.0001). The difference was not significant between non-responders and untreated controls. Cox proportional hazards regression showed sustained virologic responders and younger age were independent negative factors for cirrhosis development. CONCLUSION: A sustained virologic response secondary to IFN-based therapy could reduce cirrhosis development in chronic hepatitis C patients.

Nuclear HBcAg and histology activity index as independent predictors of the expression of singly spliced HBV-RNA.

Although hepatitis B virus (HBV) RNA splicing has been reported by many researchers, the clinical significance of this event remains illusive. The present study was designed to investigate the clinical roles of singly spliced HBV-RNA. Liver biopsy tissues obtained from 32 consecutive patients were subjected to reverse transcriptase-polymerase chain reaction for the detection of singly spliced and unspliced HBV-RNA. Stepwise linear regression model was used to estimate the ratio of singly spliced to unspliced (S/US) HBV-RNA in the presence of the following variables: age, gender, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alpha-foetoprotein, status of HBV e antigen (HBeAg), status of antibody to HBeAg, HBV-DNA, histology activity index (HAI), fibrotic score, grade of cytoplasmic HBV core antigen (HBcAg), grade of nuclear HBcAg, genotype, status of precore-stop-mutation, basal core promoter mutation, previous lamivudine therapy and superinfection by other hepatitis viruses. The results showed that HAI (beta = -0.2616; P = 0.011) and grade of nuclear HBcAg expression (beta = 0.5599; P =0.0067) were two independent predictors for the expression of singly spliced HBV-RNA. Further categorical analysis showed that patients with HAI score or=2 have significantly higher S/US ratios. In conclusion, nuclear HBcAg and HAI are two independent predictors for the expression of singly spliced HBV-RNA.

Low-level hepatitis C viremia and humoral immune response to NS4 in chronic hepatitis B virus-hepatitis C virus coinfection.

BACKGROUND: There is a limited amount of published data on the interference of hepatitis B virus (HBV) on hepatitis C virus (HCV). The aim of this study was to investigate the effect of concurrent HBV infection on serum titers of HCV RNA and HCV antibody profiles in chronic HCV infection. METHODS: The clinical and virological profiles (serum titers of HCV RNA, HCV genotypes and antibody profiles) of 25 patients with chronic HBV-HCV coinfection were compared with those of 25 age- and sex-matched patients with HCV infection alone. RESULTS: Among the 25 patients with HBV-HCV coinfection, only 3 were found hepatitis Be antigen (HBeAg) and HBV DNA positive by hybridization assays, and the other 11 were found HBV DNA positive by polymerase chain reaction. Genotype 1b was dominant in both HBV-HCV coinfection and HCV infection alone (64% versus 84%, P > 0.1). Patients with HBV-HCV coinfection had significantly lower alanine aminotransferase (ALAT) levels and inflammatory scores but higher fibrosis scores than those with HCV infection alone. Serum titers of HCV RNA were significantly lower in HBV-HCV coinfection than in HCV infection alone. The frequency and relative intensity of antibody response to core, E2/NS1, NS3, and NS5 showed no significant difference between the two groups, but antibody response to NS4 was diminished significantly in HBV-HCV coinfection. CONCLUSIONS: In HBV-HCV coinfection, serum levels of HBV DNA are usually low or undetectable. Concurrent HBV infection, however, could interfere with HCV replication and suppress antibody response to NS4. The biological significance of selective inhibition of humoral immune response to NS4 in HBV-HCV coinfection should be further studied.

Comparison of long-term effects of lymphoblastoid interferon alpha and recombinant interferon alpha-2a therapy in patients with chronic hepatitis B.

To compare the long-term effect of natural lymphoblastoid interferon-alpha (IFN-alpha nl) and recombinant IFN-alpha 2a therapy in patients with chronic hepatitis B, 210 patients in two trials were followed-up for 1.1-15.5 years following the end of therapy. They included 34 patients who received placebo (control), 67 treated with IFN-alpha nl (36 after prednisolone priming) and 109 treated with IFN-alpha 2a (56 after prednisolone priming). The cumulative sustained response was higher in patients who had been treated with IFN-alpha nl after prednisolone priming than was exhibited using IFN-alpha nl alone, IFN-alpha 2a alone or the placebo (P < 0.05), or IFN-alpha 2a following prednisolone priming (P = 0.052) at the end of 11 years. Hepatocellular carcinoma (HCC) was detected in 1.5% of the IFN-alpha nl group, 3.7% of the IFN-alpha 2a group and 14.7% of the control group (control vs IFN-alpha nl or IFN-alpha 2a, P < 0.05). The cumulative HCC development was higher in the control group than in the IFN-alpha nl group (P < 0.002) and the IFN-alpha 2a group (P = 0.06). The cumulative survival rate was lower in the control group than in the IFN-alpha nl group (P < 0.01) and the IFN-alpha 2a group (P = 0.02). Multivariate analysis revealed that IFN-alpha nl therapy and female gender are significant predictors of sustained response; preexisting cirrhosis, age at entry and IFN therapy are significant factors in both HCC development and survival. In conclusion, IFN-alpha nl treatment may have a better long-term effect on hepatitis B virus (HBV) clearance than IFN-alpha 2a and placebo, and IFN therapy may provide better long-term beneficial effects than placebo in terms of HBV clearance, reduction of HCC and prolonged survival.

Sequential changes of hepatitis C virus antibody profiles during treatment of chronic hepatitis C of genotype 1b: pretreatment antibody response to E2/NS1 correlated sustained response.

BACKGROUND: This study aimed to investigate the relation between hepatitis C virus (HCV) antibody profiles and response to therapy of chronic HCV infection of genotype 1b. MATERIALS AND METHODS: Quantitative assays of antibody response to HCV antigens were performed sequentially using immunoblot confirmatory assays in 25 patients with genotype 1b chronic hepatitis C who received a 24-week course of interferon and ribavirin therapy. RESULTS: 12 patients had a sustained response (group A), and 13 did not (group B). Serum titers of HCV RNA were significantly higher in group B than in group A (p = 0.02). Pretreatment antibody reactivity to core, NS3, NS4, and NS5 antigens did not differ significantly between the two groups, but group A had significantly higher titers of anti-E2/NS1 than group B (p = 0.04). Sustained response was noted in none of seven patients with HCV RNA > 10(6) copies/ml, but did occur in 12 of 18 patients with HCV RNA < 10(6) copies/ml (p < 0.01). Among the latter, all seven patients with anti- E2/NS1 had sustained responses, as did five (45%) of 11 without (p = 0.04). Antibody profiles changed little or not at all at the end of treatment or at 6 months after treatment in both groups. CONCLUSION: In chronic hepatitis C of genotype 1b, patients with HCV RNA > 10(6) copies/ml respond poorly to therapy compared to those with HCV RNA < 10(6) copies/ml. Among the latter, the presence of pretreatment anti-E2/NS1 correlated with sustained response. Quantitative assay of antibody response to HCV antigens at the end of treatment had no additional value to predict a sustained response.

Unintentional rechallenge resulting in a causative relationship between ketoconazole and acute liver injury.

We present the case of a female patient in whom acute overt hepatitis developed after 60 days of ketoconazole administration (200 mg/day). A prompt renewed hepatic injury 48 hours after an unintentional rechallenge 30 months later provided definitive evidence for a causative relationship between ketoconazole and acute liver injury. Histological examination revealed acute hepatitis with bridging hepatic necrosis. Clinicians should be aware of this cause and effect relationship between ketoconazole and acute liver injury, which can result in prompt severe acute liver injury after rechallenge.

Long-term results of endoscopic hemorrhoidal ligation: two different devices with similar results.

BACKGROUND AND STUDY AIMS: To evaluate the efficacy of two different endoscopic hemorrhoidal ligation (EHL) devices for symptomatic internal hemorrhoid. PATIENTS AND METHODS: From November 2000 to February 2001, 218 consecutive patients with symptomatic internal hemorrhoids were enrolled. A total of 109 patients were treated with an EHL device 9 mm in diameter (group A); the rest were treated with a device 13 mm in diameter (group B). The patients' clinical presentations were rectal bleeding and prolapse. The severity of the hemorrhoid was classified using Goligher's grading. RESULTS: All patients were treated for one session, and were followed from 19 to 24 months (mean 22.4 months). The number of band ligations averaged 2.59 in group A and 1.68 in group B. Most patients had their hemorrhoids reduced by at least one grade (82.8 % in group A and 90.8 % in group B). Rectal bleeding was controlled in 108 patients (99.1 %) in group A and 109 patients (100 %) in group B, while rectal prolapse was reduced in 93 patients (85.3 %) in group A and 99 patients (90.8 %) in group B. Eleven patients in group A and 12 in group B experienced anal pain after treatment, and eight patients in group A and six in group B had mild bleeding. The patients' subjective satisfaction rates were 90.8 % in group A and 93.6 % in group B. The 1-year recurrence rates were 3.9 % in group A and 2.3 % in group B. CONCLUSIONS: Both EHL devices can effectively treat symptomatic internal hemorrhoids. A device with a smaller diameter requires more band ligations, but appears equivalent with regard to treatment outcome and complications.

Are modified procedures significantly better than conventional procedures in percutaneous transhepatic treatment for complicated right hepatolithiasis with intrahepatic biliary strictures?

BACKGROUND: Conventional percutaneous procedures for treating patients with recurrent hepatolithiasis associated with complicated intrahepatic biliary strictures require multiple dilation sessions before stone extraction. We modified the approach, reducing the number of dilation sessions required and using newer lithotripsy and irrigation methods. We suggest that the modified procedures are superior to conventional management and demonstrate their utility in clearing hepatolithiasis. METHODS: Percutaneous transhepatic stricture dilation and cholangioscopic lithotripsy were performed to treat patients with right recurrent hepatolithiasis with complicated intrahepatic biliary strictures. Conventional methods were used in 40 patients (Group A). Modified methods, including simplification of tract establishment and stricture dilation and electrohydraulic lithotripsy (EHL) were used in 60 patients (Group B). RESULTS: Group B patients had fewer complications (massive hemobilia: 0% versus 15%, P = 0.0032, cholangitis: 0% versus 17.5%, P=0.0012), tolerated the procedures better (intolerable pain: 0% versus 12.5%, P=0.0087), had a higher rate of success (residual stones: 3.3% versus 20%, P=0.0132; remaining asymptomatic and stone-free: 81% versus 50%, P = 0.0021), a shorter hospital stay (17.8 +/- 4.4 days versus 36.2 +/- 5.5 days, P < 0.001) and lower overall expense (USD 2689 versus USD 3848) than Group A patients. CONCLUSION: We believe that the modified methods are superior to conventional treatment in that they effectively decrease procedural complications and cost, and significantly improve treatment results.

Acute hepatitis C virus (HCV) infection in chronic carriers of hepatitis B virus (HBV): the impact of underlying active HBV replication on persistence of HCV infection and antibody responses to HCV.

BACKGROUND AND AIMS: The aim of this study was to assess whether underlying chronic hepatitis B virus (HBV) infection interferes with persistence of hepatitis C virus (HCV) infection and humoral immune responses to HCV in acute HCV infection. METHODS: Serial sera from 12 patients with acute HCV infection (group A) and 12 hepatitis B surface antigen (HBsAg) carriers with acute HCV infection (seven anti-hepatitis B e antigen (anti-HBe) positive (group B1) and five hepatitis B e antigen (HBeAg) positive (group B2)) were tested for HCV RNA by polymerase chain reaction, and anti-HCV by third generation enzyme immunoassay and confirmatory assay. Serial serum samples from HBsAg carriers were also tested for HBeAg, anti-HBe, and HBV DNA by hybridisation assay. RESULTS: Persistent HCV viraemia for more than six months was significantly more frequent in groups A (83%) and B1 (86%) than in group B2 (0%). Anti-HCV was detected in 100% and 86% of group A and group B1 one month after onset while only one group B2 patient was transiently anti-HCV positive 1-2 months after onset. Of the latter, three had anti-core 1 less than two months after onset while no patient responded to other HCV antigens. Overall, of six HBsAg carriers with acute self limiting HCV infection, only one had transient anti-HCV and three had transient anti-core 1. HBV DNA became undetectable transiently in four and persistently in one group B2 patient. CONCLUSION: The presence of active HBV replication can inhibit the persistence of HCV infection and antibody responses to HCV. Acute HCV infection in HBsAg carriers with active HBV replication usually presents transient HCV viraemia with poor antibody responses to HCV.

Epidemiological characteristics, risk factors, and clinical manifestations of acute non-A-E hepatitis.

A substantial proportion of acute non-A, non-B hepatitis was of unknown etiology and was termed non-A-E hepatitis. Analysis of the clinical features is needed while attempting to identify the causative agent(s). In this study, the clinical and biochemical features of 53 patients who were admitted to hospital with acute non-A-E hepatitis were compared with a cohort of patients with acute hepatitis C (n = 70) and E (n = 5). In acute non-A-E hepatitis, the sex ratio was 34:19, and ages ranged from 21 to 76 years (median 49). Biochemical tests [median (range)] revealed albumin 3.6 (2.2-4.4) g/dl, AST 714 (193-2311) U/l, ALT 896 (310-3,000) U/l, bilirubin 11.2 (0.9-36.3) mg/dl, and prothrombin time > 1.1 (0-11.5) seconds. No patients reported parenteral exposures or household contact. Forty-five percent had severe hepatitis (i.e., albumin < 3 g/dl, bilirubin > 15 mg/dl or prothrombin time > 3 sec), including 3% with fulminant hepatitis. Chronic evolution was noted in 7%. These features were similar to those of hepatitis C or E, except for a significantly high frequency of parenteral exposures (20%), household contact (16%), and chronicity (70%) in hepatitis C. In conclusion, there is no obvious parenteral risk factor identified in acute non-A-E hepatitis. Clinical severity is similar to that of hepatitis C at least in hospitalized patients, but the rate of chronic evolution is much lower.

The benefits of a second transhepatic route in failed percutaneous management of difficult intrahepatic biliary strictures with recurrent hepatolithiasis.

Percutaneous stricture dilatation and cholangioscopic lithotomy has become a mainstay in the treatment of patients with recurrent hepatolithiasis associated with intrahepatic biliary strictures. In a consecutive series of 125 patients who underwent percutaneous management of recurrent hepatolithiasis from 1987 to 1999, there were 15 patients in whom the procedure failed to clear the stones. A second percutaneous transhepatic route was established for subsequent treatment. A reappraisal of its indications and efficacy was done. Treatment through a second route was helpful for patients with bilateral strictures, angulated duct, difficult strictures, large impacted stones, a subcutaneous jejunal limb, or hemobilia developing in the first route. Strictures remained impacted in 1 of the 15 patients (failure rate, 7%), with the remaining having complete clearance of stones. Cholangitis occurred in two patients; no other complications were encountered. A second percutaneous route is very helpful for the management of complicated hepatolithiasis and biliary stricture.

Genome-wide hypomethylation in hepatocellular carcinogenesis.

Aberrant genome-wide hypomethylation has been thought to be related to tumorigenesis. However, its mechanism and implications in hepatocellular carcinogenesis remain to be elucidated. Samples of hepatoma (hepatocellular carcinoma, HCC) and paired non-HCC liver tissues were obtained from 17 HCC patients. Normal liver tissues obtained from three individuals were used as controls. Compared with the paired non-HCC liver tissues, genome-wide 5-methylcytosine content in HCC was reduced in all of the tested HCC samples (P < 0.001). Conversely, genome-wide 5-methylcytosine content did not significantly differ among normal, noncirrhotic, and cirrhotic liver tissues. Moreover, the degree of reduced DNA methylation was related to late histopathological HCC grade (P = 0.005) and large tumor size (P = 0.079). Compared with the paired non-HCC liver tissues, expression of DNA methyltransferases DNMT-1, DNMT-3A, and DNMT-3B and the DNA methyltransferase-like gene, DNMT-2, was up-regulated in 53, 41, 59, and 47% of the HCC samples, respectively. Surprisingly, small amounts of LINE-1 retrotransposon transcripts were detected in HCC and non-HCC as well as normal liver tissues, and the expression levels were not significantly different in HCC compared with the paired non-HCC or normal liver tissues. Of interest, the 3' ends of these LINE-1 transcripts were truncated. Our findings suggest that genome-wide hypomethylation in HCC is a continuing process that persists throughout the lifetime of the tumor cells rather than a historical event occurring in precancer stages or in cell origins for HCC. Up-regulation of DNA methyltransferases might simply be a result of increased cell proliferation in cancer. In addition, our results did not support the hypothesis of activation of transposable elements in HCC via genome-wide hypomethylation.

Is the p53 gene mutation of prognostic value in hepatocellular carcinoma after resection?

HYPOTHESIS: Mutant p53 gene has lost its tumor suppression function and is considered to be a very important step in hepatocellular carcinoma development. We propose that the mutant p53 gene plays a role in its invasiveness and prognosis after resection. DESIGN: A case-controlled study. SETTING: A referral center. PATIENTS: Seventy-nine consecutive patients who underwent surgical resection for hepatocellular carcinoma entered this study. INTERVENTION: Tissue sections of resected hepatocellular carcinoma (deparaffinized and rehydrated from formalin-fixed and paraffin-embedded sections) were incubated with antihuman p53 monoclonal antibody and immunostained. The p53 result was scored without prior knowledge of the patients' status. A 10% immunopositivity was regarded as the threshold value. MAIN OUTCOME MEASURE: The immunopositive rate of p53 was 69.6% (55 of 79 patients). The clinical variables (age, sex, associated liver cirrhosis, hepatitis B virus infection, hepatitis C virus infection, serum alpha-fetoprotein, and Child-Pugh class); the histological variables (size, capsule, vascular permeation; grade of differentiation, and multinodularity); and postoperative course (recurrence, tumor-free interval, death, and survival period) were correlated with p53 immunopositivity. RESULTS: From univariate analysis, more patients with p53 positivity were male (92.7 vs 0%) (P<.001); had vascular permeation (80% vs 50%) (P =.007) (odds ratio [OR], 4.0); no complete capsule (83.6% vs 62.5%) (P =.04) (OR, 3.1); and daughter nodules (90.9% vs 70.8%) (P =.04) (OR, 4.1) than patients with negative p53 staining. From multivariate analysis, only sex and vascular permeation remained significant (P =.001 and P =.008, respectively). Although more patients with p53 positivity had tumor recurrence (78% vs 50%) (P =.01) and death (64% vs 33%) (P =. 01), the Cox proportional hazards model showed that p53 overexpression had only weak correlations with tumor-free interval and survival time (P =.09 and P =.08, respectively). CONCLUSIONS: Our results show that the biological behavior of the mutant p53 gene is strongly related to the invasiveness of hepatocellular carcinoma and may also influence the postoperative course. We suggest that the immunopositivity of the mutant p53 gene has a predictive role in the prognosis of patients with resected hepatocellular carcinoma.

Percutaneous transhepatic cholangioscopy in the treatment of complicated intrahepatic biliary strictures and hepatolithiasis with internal metallic stent.

For recurrent hepatolithiasis coexisting with a complicated long-segment intrahepatic biliary stricture, repeated surgeries, balloon dilation of the stricture, and external-internal stenting may still fail to solve the problem. We tried using a Gianturco-Rosch metallic Z internal stent (Wilson-Cook Medical, Inc., Bloomington, IN, USA) with the aid of percutaneous transhepatic cholangioscopy (PTCS) to treat such patients. Eight patients had a Z stent placed through a percutaneous transhepatic biliary drainage tract. Immediately after stent placement, PTCS was inserted via the percutaneous transhepatic biliary drainage route and a part of the wire skirt not firmly anchored in one of the eight patients was detected. It was successfully repositioned using PTCS. Recurrent cholangitis developed in three patients 6, 7, and 30 months, respectively, after stent placement. PTCS was undertaken again through a reestablished percutaneous transhepatic biliary drainage route and revealed sludge in their stent lumens. We cleared it by PTCS. No further cases of cholangitis occurred in later follow-up. PTCS is useful in ensuring adequate stent position, diagnosing and treating the causes of recurrent cholangitis, and prolonging the function of stents.