Predicting Hepatic Steatosis in Living Liver Donors Via Controlled Attenuation Parameter.

BACKGROUND: Hepatic steatosis (HS) can cause substantial problems for both donors and recipients in living donor liver transplantation. The controlled attenuation parameter (CAP) is a noninvasive method of measuring HS using a process based on transient elastography. AIM: To evaluate the accuracy of CAP in quantifying HS during living donor liver transplantation. METHODS: A total of 54 liver donors who received CAP and intraoperative liver biopsy (LB) were enrolled in this study. The performance of CAP compared with LB for diagnosing HS was assessed using areas under receiver operating characteristic curves. HS was defined by the presence of steatosis in >5% of hepatocytes. RESULTS: No HS was found in 47 donors, while the remaining 7 donors showed HS ranging from 10% to 30%. Using CAP, the area under receiver operating characteristic curve was 0.96 (95% CI, 0.91-1; P < .001) for HS; the optimal cutoff value for HS was 257 dB/m (sensitivity: 100%, specificity: 89.4%, positive predictive value: 58.3%, negative predictive value: 100%). Among the 42 candidates with CAP <257 dB/m, none had HS, while of the 12 candidates with CAP ≥257 dB/m, 7 had HS. In a multivariate linear regression analyses, body mass index (ß = 0.71, P < .001) was found to be independently associated with CAP in those without HS. CONCLUSIONS: CAP might be a promising tool to exclude HS in East Asian living liver donors. Body mass index was found to be independently associated with CAP values in those without HS.

Long-term incidence and predictors of hepatitis B surface antigen loss after discontinuing nucleoside analogues in noncirrhotic chronic hepatitis B patients.

OBJECTIVE: To investigate the long-term incidence and predictors for hepatitis B surface antigen (HBsAg) loss after nucleoside analogue therapy. METHODS: The study included 411 noncirrhotic chronic hepatitis B patients (148 hepatitis B e antigen (HBeAg)-positive and 263 HBeAg-negative patients) who were treated with lamivudine (n = 110) or entecavir (n = 301) with posttreatment follow-up of at least 12 months. RESULTS: In HBeAg-positive patients, the 8-year cumulative rates of virologic relapse, clinical relapse and HBsAg loss were 55.6%, 47.7% and 19.6%, respectively. In HBeAg-negative patients, the rates were 69.3%, 58.9% and 33.1%, respectively. Cox regression analysis showed that hepatitis B virus genotype C and lower end-of-treatment HBsAg levels were independent predictors of HBsAg loss in HBeAg-positive and -negative patients. The 5-year HBsAg loss rate was 47.3% in HBeAg-positive patients with end-of-treatment HBsAg levels <300 IU/mL, while the 8-year HBsAg loss rate was 69.3% in HBeAg-negative patients with end-of-treatment HBsAg levels <200 IU/mL. Five patients experienced hepatitis flares with decompensation after stopping nucleoside analogue therapy, and one died after retreatment. Of the 48 patients who developed off-therapy HBsAg loss, two developed hepatocellular carcinoma. CONCLUSIONS: The rate of HBsAg loss was relatively high and the rate of hepatic events was low in noncirrhotic patients who discontinued nucleoside analogue therapy.

Comparison of the efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue-naive chronic hepatitis B patients with high viraemia: a retrospective cohort study.

OBJECTIVES: The aims of this study are to compare the long-term efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue (NA)-naive patients with chronic hepatitis B (CHB) with high hepatitis B virus (HBV) DNA (> 6 log10 IU/mL). METHODS: We recruited 419 NA-naive patients for analysis (313 entecavir, 106 tenofovir). We used propensity-score matching to match 106 patients in the tenofovir group with 212 patients in the entecavir group by age, baseline HBV DNA levels and cirrhosis after subgrouping by hepatitis B e antigen (HBeAg) status. RESULTS: There was no significant difference in 3-year cumulative rates of virological response (VR) (96.4% versus 92.1%, p 0.26 in HBeAg-positive or 98.2% versus 98.6%, p 0.64 in HBeAg-negative patients), HBeAg loss (53.8% versus 47.4%, p 0.89) or seroconversion (40.2% versus 41.3%, p 0.77), and hepatocellular carcinoma (HCC) development (4% versus 2.7%, p 0.55) between the tenofovir and entecavir groups in either cohort or propensity-score matching patients. In subgroup analysis of patients with HBV DNA >108 IU/mL, entecavir and tenofovir showed similar effectiveness in achieving VR (90.9% versus 87.7% at 3 years; p 0.13). Tenofovir and diabetes mellitus were independent factors for acute kidney injury during treatment. Multivariate analysis showed that HBeAg-negative status, and lower baseline HBV DNA and HBV surface antigen levels were independent factors for achieving VR. Older age, lower baseline HBV DNA levels, cirrhosis and α-fetoprotein ≥8 ng/mL at 12 months of treatment were independently associated with HCC development. CONCLUSIONS: Tenofovir and entecavir have similar effectiveness in NA-naive CHB patients with high viraemia. Tenofovir might have a higher incidence of acute kidney injury compared with entecavir during treatment.

Hepatitis B surface antigen loss and clinical outcomes between HBeAg-negative cirrhosis patients who discontinued or continued nucleoside analogue therapy.

We investigated the incidence and predictors of post-treatment hepatitis B virus (HBV) relapse and hepatitis B surface antigen (HBsAg) loss. After cessation of nucleoside analogue (NA) treatment in hepatitis B e antigen (HBeAg)-negative patients with cirrhosis. The rates of HBsAg loss and hepatocellular carcinoma (HCC) development in HBeAg-negative patients with cirrhosis who continued NA treatment were compared with those who discontinued treatment. Patients with compensated cirrhosis who had discontinued NA treatment for at least 12 months (discontinuing group; n=73) and patients who continued entecavir treatment for at least 4 years (continuing group; n=158) were recruited. Serum HBsAg levels were analysed at the end of treatment (discontinuing group) or at 2.5-3 years of treatment (continuing group). In the discontinuing group, the 6-year cumulative incidence of post-treatment virological relapse and HBsAg loss were 56.3% and 46.7%, respectively. The end-of-treatment HBsAg level of 300 IU/mL was a cut-off value for subsequent post-treatment HBsAg loss and sustained response. In the continuing group, HBsAg loss occurred in five of 158 patients. Cox regression analysis showed that HBsAg levels in the discontinuing group were independent predictors for HBsAg loss in all patients and 104 propensity score (PS)-matched patients. There was no significant difference in HCC development between the groups in all patients and 104 PS-matched patients. Two patients experienced post-treatment alanine aminotransferase flare with hepatic decompensation, and neither of them died after retreatment. In conclusion, HBeAg-negative patients with cirrhosis who discontinued NA treatment might have a higher rate of HBsAg loss and their risk of developing HCC did not increase compared with those who continued entecavir treatment.

Comparison of renal safety and efficacy of telbivudine, entecavir and tenofovir treatment in chronic hepatitis B patients: real world experience.

This study aims to assess the nephrotoxicity and efficacy of tenofovir disoproxil fumarate (tenofovir), telbivudine and entecavir. A retrospective study of 587 patients with chronic hepatitis B treated with tenofovir (n = 170), telbivudine (n = 184) and entecavir (n = 233) for at least 1 year. Renal function and efficacy were assessed. The estimated glomerular filtration rate (eGFR) decreased significantly in the tenofovir group after a mean of 17 months treatment (from 92.2 to 85.6 mL/min/1.73 m(2), p < 0.001), but increased in the telbivudine group after a mean of 32 months of treatment (from 86.1 to 95 mL/min/1.73 m(2), p < 0.001). There was no significant change in eGFR in the entecavir group after a mean of 44 months. By multivariate analysis, pre-existing renal insufficiency (p = 0.003), tenofovir (p = 0.007) and diuretic treatment (p = 0.001) were independent predictors for renal function deterioration. Cumulative virological breakthrough was 0% in tenofovir after 2 years, 3.4% in entecavir after 7 years and 22.9% in telbivudine after 5 years. Liver cirrhosis (p = 0.008) and virological breakthrough (p = 0.040) were independently associated with increased risk of hepatocellular carcinoma development. Tenofovir may lead to deterioration in renal function as assessed by serial eGFR measurements. Although telbivudine appeared to be associated with an improvement in eGFR, it was associated with high rates of virological breakthrough, which was an independent risk factor for HCC development. With low rates of virological breakthrough and preservation of renal function, entecavir could be the best choice among these three agents.

Factor VII promotes hepatocellular carcinoma progression through ERK-TSC signaling.

We previously demonstrated PAR2 starts upstreamed with tissue factor (TF) and factor VII (FVII), inhibited autophagy via mTOR signaling in HCC. However, the mechanism underlying for merging functions of PAR2 with the coagulation system in HCC progression remained unclear. The present study aimed to investigate the role of TF, FVII and PAR2 in tumor progression of HCC. The expressions of TF, FVII and PAR2 from HCC specimens were evaluated by immunohistochemical stains and western blotting. We found that the expression of FVII, but not TF and PAR2, directly related to the vascular invasion and the clinical staging. Importantly, a lower level of FVII expression was significantly associated with the longer disease-free survival. The addition of FVII but not TF induced the expression of PAR2 and phosphorylation of ERK1/2, whereas knockdown of FVII decreased PAR2 expression and ERK1/2 phosphorylation in HCC cell lines. Furthermore, levels of phosphor-TSC2 (Ser664) were increased after treatment with FVII and PAR2 agonist whereas these were significantly abolished in the presence of a potent and specific MEK/ERK inhibitor U0126. Moreover, mTOR knockdown highly reduced Hep3B migration, which could be reverted by FVII but not TF and PAR2. These results indicated that FVII/PAR2 signaling through MEK/ERK and TSC2 axis for mTOR activation has potent effects on the migration of HCC cells. In addition, FVII/PAR2 signaling elicits an mTOR-independent signaling, which promotes hepatoma cell migration in consistent with the clinical observations. Our study indicates that levels of FVII, but not TF, are associated with tumor migration and invasiveness in HCC, and provides clues that evaluation of FVII expression in HCC may be useful as a prognostic indicator in patients with HCC and may form an alternative target for further therapy.

Interconnections between autophagy and the coagulation cascade in hepatocellular carcinoma.

Autophagy has an important role in tumor biology of hepatocellular carcinoma (HCC). Recent studies demonstrated that tissue factor (TF) combined with coagulation factor VII (FVII) has a pathological role by activating a G-protein-coupled receptor called protease-activated receptor 2 (PAR2) for tumor growth. The present study aimed to investigate the interactions of autophagy and the coagulation cascade in HCC. Seventy HCC patients who underwent curative liver resection were recruited. Immunohistochemical staining and western blotting were performed to determine TF, FVII, PAR2 and light chain 3 (LC3A/B) expressions in tumors and their contiguous normal regions. We found that the levels of autophagic marker LC3A/B-II and coagulation proteins (TF, FVII and PAR2) were inversely correlated in human HCC tissues. Treatments with TF, FVII or PAR2 agonist downregulated LC3A/B-II with an increased level of mTOR in Hep3B cells; in contrast, knockdown of TF, FVII or PAR2 increased LC3A/B. Furthermore, mTOR silencing restored the impaired expression of LC3A/B-II in TF-, FVII- or PAR2-treated Hep3B cells and activated autophagy. Last, as an in vivo correlate, we administered TF, FVII or PAR2 agonist in a NOD/severe combined immunodeficiency xenograft model and showed decreased LC3A/B protein levels in HepG2 tumors with treatments. Overall, our present study demonstrated that TF, FVII and PAR2 regulated autophagy mainly via mTOR signaling. The interaction of coagulation and autophagic pathways may provide potential targets for further therapeutic application in HCC.

A comparison of efficacy and safety of 2-year telbivudine and entecavir treatment in patients with chronic hepatitis B: a match-control study.

There are limited data comparing the clinical outcomes between telbivudine and entecavir. We consecutively enrolled 115 telbivudine-naive and 115 entecavir-naive chronic hepatitis B patients, who were matched for age, sex, hepatitis B e antigen (HBeAg) status and cirrhosis, and treated for at least 2 years or less than 2 years but had developed resistance. Except for the rate of HBeAg seroconversion, which was similar, patients in the entecavir group had better clinical outcomes than those in the telbivudine group for alanine aminotransferase normalization (85.2% vs 78.4%, p <0.048), undetectable HBV DNA (96.5% vs 74.8%, p <0.001), and viral resistance (0.9% vs 21.7%, p <0.001) after 2 years of treatment, After applying roadmap or super-responders concepts, entecavir still had better outcomes than telbivudine in undetectable HBV DNA and viral resistance. The cumulative incidence of hepatocellular carcinoma development was similar between telbivudine-naive and entecavir-naive patients (p 0.565). In renal function analysis, there were significantly more patients with estimated glomerular filtration rate (eGFR) category improvement in both the telbivudine and entecavir groups at year 1 (p 0.006 and p 0.047, respectively). The rate of virological improvement was significantly higher with entecavir than with telbivudine after 2 years of treatment, whether applying the concepts of roadmap or super-responders. The incidence of hepatocellular carcinoma was similar between telbivudine and entecavir. Both telbivudine and entecavir were associated with eGFR improvement, especially in patients with renal insufficiency.

Clinical-guide risk prediction of hepatocellular carcinoma development in chronic hepatitis C patients after interferon-based therapy.

BACKGROUND: Interferon (IFN)-based therapies could eradicate hepatitis C (HCV) and reduce the risk of hepatocellular carcinoma (HCC). However, HCC could still happen after sustained virological response (SVR). We aimed to develop a simple scoring system to predict the risk of HCC development among HCV patients after antiviral therapies. METHODS: From 1999 to 2009, 1879 patients with biopsy-proven HCV infection treated with IFN-based therapies were analyzed. RESULTS: Multivariable analysis showed old age (adjusted HR (aHR)=1.73, 95% CI=1.13-2.65 for aged 60-69 and aHR=2.20, 95% CI=1.43-3.37 for aged ≥ 70), Male gender (aHR=1.74, 95% CI=1.26-2.41), platelet count <150 × 10(9)/l (HR=1.91, 95% CI=1.27-2.86), α-fetoprotein ≥ 20 ng ml(-1) (HR=2.23, 95% CI=1.58-3.14), high fibrotic stage (HR=3.32, 95% CI=2.10-5.22), HCV genotype 1b (HR=1.53, 95% CI=1.10-2.14), and non SVR (HR=2.40, 95% CI=1.70-3.38) were independent risk factors for HCC. Regression coefficients were used to build up a risk score and the accuracy was evaluated by using the area under the receiver operating characteristic curve (AUC). Three groups as low-, intermediate-, and high-risk are classified based on the risk scores. One hundred sixty patients (12.78%) in the derivation and 82 patients (13.08%) in the validation cohort developed HCC with AUC of 79.4%, sensitivity of 84.38%, and specificity of 60.66%. In the validation cohort, the 5-year HCC incidence was 1.81%, 12.92%, and 29.95% in low-, intermediate-, and high-risk groups, with hazard ratios 4.49 in intermediate- and 16.14 in high-risk group respectively. The risk reduction of HCC is greatest in patients with SVR, with a 5-year and 10-year risk reduction of 28.91% and 27.99% respectively. CONCLUSION: The risk scoring system is accurate in predicting HCC development for HCV patients after antiviral therapies.

Role of viral genotypes and hepatitis B viral mutants in the risk of hepatocellular carcinoma associated with hepatitis B and C dual infection.

BACKGROUND/AIMS: The independent and interactive effects of hepatitis B virus (HBV) and hepatitis C virus (HCV) factors on the development of hepatocellular carcinoma (HCC) in chronic HBV/HCV dually-infected patients remain unclear. METHODS: In a cross-sectional and case-controlled study, the HBV and HCV loads and genotypes and the sequences of pre-S and precore/core promoter regions were determined in 146 HCC patients and 167 chronic carriers with HBV/HCV dual infection. RESULTS: Age (odds ratio (OR) 1.1), male sex (OR 2.3), pre-S deletion (OR 5.0), A1762T/G1764A mutant (OR 2.5), HCV genotype-1 (OR 2.4) and platelet count <15 × 10(4)/µl (OR 1.9) were independently associated with HCC by stepwise logistic regression analysis. Patients with combined HBV mutations (pre-S deletion and A1762T/G1764A mutant) and HCV genotype-1 had a 39-fold increased risk of developing HCC compared to those with A1762T/G1764A and pre-S wild-type strains and HCV genotype non-1. In the nested case-control study, patients with HCC had a higher HBV DNA level (p < 0.001), a higher frequency of pre-S deletion (p < 0.001) and A1762T/G1764A mutant (p = 0.005), a lower HCV RNA level (p = 0.012) and a higher prevalence of HCV genotype-1 (p = 0.002) than those without. CONCLUSIONS: Pre-S deletion, A1762T/G1764A mutation and HCV genotype-1 are important in hepatocarcinogenesis in chronic HBV/HCV dual infection.

Bioinformatics analysis with graph-based clustering to detect gastric cancer-related pathways.

Despite a dramatic reduction in incidence and mortality rates, gastric cancer still remains one of the most common malignant tumors worldwide, especially in China. We sought to identify a set of discriminating genes that could be used for characterization and prediction of response to gastric cancer. Using bioinformatics analysis, two gastric cancer datasets, GSE19826 and GSE2685, were merged to find novel target genes and domains to explain pathogenesis; we selected differentially expressed genes in these two datasets and analyzed their correlation in order to construct a network. This network was examined to find graph clusters and related significant pathways. We found that ALDH2 and CCNB1 were associated with gastric cancer. We also mined for the underlying molecular mechanisms involving these differently expressed genes. We found that ECM-receptor interaction, focal adhesion, and cell cycle were among the significantly associated pathways. We were able to detect genes and pathways that were not considered in previous research on gastric cancer, indicating that this approach could be an improvement on the investigative mechanisms for finding genetic associations with disease.

Risk factors influencing the outcome of peptic ulcer bleeding in end stage renal diseases after initial endoscopic haemostasis.

Background and Aims: Patients suffering from peptic ulcer (PU) bleeding who have end-stage renal disease (ESRD) may encounter more adverse outcomes. The primary objective is to investigate the risk factors that influence the outcomes of ESRD and chronic kidney disease (CKD) patients with PU bleeding after successful initial endoscopic haemostasis. Methods: A total of 540 patients with PU bleeding after initial endoscopic haemostasis in a tertiary hospital were investigated retrospectively. They were sorted into three groups after randomised age-matched adjustment: ESRD group (n = 90), CKD group (n = 90) and control group (n = 360). Main outcome measurements were rebleeding, requirement for blood transfusion and surgery, length of hospital stay and mortality. Results: The rebleeding rates were 43% for the ESRD group vs. 21% for the CKD group vs. 12% for the control group (overall p = < 0.001). Multivariate analysis showed the predictors of rebleeding were ESRD, time to endoscope, and non-high-dose proton-pump inhibitors (PPI) users. The risk factors for bleeding-related mortality were presence of moderate degree of CKD and ESRD group, time to endoscope, and Rockall score. All-cause mortality was related to presence of moderate degree of CKD and ESRD group, platelet count, time to endoscope, Rockall score and length of hospital stay. Conclusions: ESRD patients who suffered from PU bleeding were at risk of excessive rebleeding and mortality with frequent occurrence of delayed rebleeding. This study suggests that early endoscopy for initial haemostasis and high-dose intravenous PPI are associated with the reduction of rebleeding risk especially in patients with high Rockall scores.

Ano-perianal tuberculosis: 15 years of clinical experiences in Southern Taiwan.

OBJECTIVE: Ano-perianal tuberculosis (TB) is a rare extrapulmonary form of the disease. Most publications are in case report form. We report our cohort retrospective study on ano-perianal TB, which is one of the very few original reports in the literature. METHOD: Over a period of 15 years (January 1992-December 2006), file records revealed cases with confirmed diagnosis of ano-perianal TB after screening from a total of 1251 patients with the diagnosis of TB from Chang Gung Memorial Hospital-Kaohsiung, Taiwan. RESULTS: This study recruited 17 patients (14 male patients and 3 female patients). The age ranged from 18 to 81 years with a mean age of 44.8 +/- 18.2 years. Thirteen patients had coexistent pulmonary TB (76.5%). Eight patients had at least one concomitant co-morbid illness (47.1%). The most common clinical manifestations were anal fistulae (n = 16). All patients who completed a full course of anti-mycobacterial treatment for at least 6 months after surgical intervention were cured without recurrence except for one patient who was lost to follow-up after 2 months of treatment. Seven of the nine patients with complicated fistulae needed longer anti-mycobacterium treatment duration (9-18 months). CONCLUSION: Ano-perianal TB should be kept in mind for all patients with prolonged or repeatedly recurrent ano-perianal symptoms and signs such as complicated fistulae in an endemic TB area like Taiwan. Management strategy is with conventional anti-mycobacterium therapy for at least 6 months after surgery. An extension of the anti-mycobacterium treatment course to 9-18 months is mandatory for patients with complicated disease presentations.

A modified TNM-based Japan Integrated Score combined with AFP level may serve as a better staging system for early-stage predominant hepatocellular carcinoma patients.

BACKGROUND: Combinations of Child-Pugh classification and Liver Cancer Study Group of Japan/Tumor-Node-Metastasis (LCSGJ/TNM) have been reported as Japan Integrated Staging (JIS). We previously modified the 6th AJCC/TNM to serve as a better staging system than the 5th and 6th AJCC/TNM. AIMS: To develop a modified TNM-based JIS to predict the survival of hepatocellular carcinoma (HCC) patients more accurately. METHODS: 3764 HCC patients were enrolled from 1986 to 2002 (2882 patients from 1986 to 2000 and 882 patients from 2001 to 2002). We compared the performance of original JIS, modified TNM-based JIS, modified TNM-based JIS combined alpha-fetoprotein (AFP), BCLC, and CLIP. Lower Akaike information criteria (AIC) values indicated better discriminatory abilities. RESULTS: AIC value was lowest in CLIP during all periods. However, during 2001-2002, when early-stage HCC patients were predominant, AIC value was lowest when modified TNM-based JIS combined AFP was used. CONCLUSION: The CLIP system provided the best prognostic stratification in the present cohort of HCC patients who were mainly at late stages. However, early detection of HCCs has become more common in Taiwan in recent years, which has led to the predominance of early-stage HCC patients. Therefore, modified TNM-based JIS combined AFP may now be the most applicable system in recent years.

Hepatocellular carcinoma in renal transplant recipients.

OBJECTIVE: Renal transplant recipients display an increased risk of malignancy due to long-term immunosuppression. The type and incidence of malignancies vary geographically. Hepatocellular carcinoma (HCC) is a leading cause of malignancy in posttransplantation recipients in Taiwan, which is an endemic area for hepatitis B. We performed a retrospective study to investigate the clinical features of HCC among our renal transplant recipients. METHODS: Between 1988 and 2006, 15 patients of the 554 kidney recipients followed up at our transplantation clinic were diagnosed with HCC. The medical records corresponding to these 15 patients were reviewed for age, gender, initial presentation and symptoms, posttransplant duration, immunosuppressive regimens, graft and patient survival, treatment of HCC, and outcomes. RESULTS: Fifteen recipients developed HCC, (2.7%), of whom 11 were men. Four patients were hepatitis B surface antigen (HBsAg)-positive, 4 were anti-hepatitis C antibody (anti-HCV Ab)-positive, and another 7 were negative for HBsAg and/or anti-HCV Ab. The mean age at the time of HCC diagnosis was 52 +/- 12 years, with a mean posttransplantation duration to HCC of 83 +/- 48.4 months. Over a follow-up period of 59.9 +/- 39.1 months, 8 patients remained alive and 7 died. Among these 7 individuals, 6 had no treatment for HCC and died rapidly (<3 months) and, 1 underwent hepatic lobectomy but died 6 months later due to liver failure. All 8 surviving patients received treatment: 4 underwent transarterial embolization (TAE) and the other 4 underwent surgery. As of July 2006, the average survival was 68 months. Three of these 8 patients had graft failure, including 2 whom have returned to maintenance hemodialysis and 1 who had a successful second graft. CONCLUSION: HCC is a major cancer among renal recipients in Taiwan. In our center the outcomes of treatable patients were good. Our study revealed that either TAE or surgery resulted in excellent survival rates. It is necessary to adjust the immunosuppressive regimen in patients with HCC and to detect a malignancy at an early stage to improve the outcomes.

Association of amino acid variations in the NS5A and E2-PePHD region of hepatitis C virus 1b with hepatocellular carcinoma.

NS5A and E2 proteins of the hepatitis C virus (HCV) have the potential to repress protein kinase R (PKR) that exerts a tumour suppressor function. We investigated the relationship between amino acid variations in the NS5A-PKR-binding domain and E2-PKR-eIF2alpha phosphorylation homology domain (PePHD) region and the development of hepatocellular carcinoma (HCC) in chronic HCV-1b patients. In a cross-sectional, hospital-based setting, we compared the amino acid sequences of NS5A-PKR-binding domain and E2-PePHD in the sera of 104 chronic hepatitis, 44 cirrhosis and 96 HCC patients. The nucleotide sequences were inferred by direct sequencing of the amplified HCV products and deduced amino acid were compared with the sequence of HCV-J. By univariate analysis, old age, lower viral load, fewer amino acid substitutions in the NS5A-PKR-binding domain (codons 2209-2274) and the interferon sensitivity-determining region (ISDR; codons 2209-2248), and wild-type amino acid at codon 2209 and codon 2240 was significantly correlated with HCC, whereas substitutions in the E2-PePHD was not. Patients with a mutated-type (> or = 4) NS5A-ISDR had a lower prevalence of HCC than those with intermediate or wild type (P < 0.05). Based on stepwise logistic regression analysis, age [odds ratio (OR): 1.132, P < 0.001], viral load (OR: 0.305, P < 0.001) and mutated-type ISDR (OR: 0.137, P = 0.001) were independently associated with HCC. In conclusion, NS5A-ISDR variations may play an important role in the development of HCV-related HCC.

Long-term effect of interferon alpha-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis.

We assessed the efficacy of interferon (IFN) alpha-2b plus ribavirin therapy in patients with hepatitis C virus (HCV)-related cirrhosis, and elucidated the risk factors for the development of hepatocellular carcinoma (HCC) to determine whether these therapies might reduce the incidence of HCC. One hundred and thirty-two HCV-cirrhotic patients receiving IFN alpha-2b (3 or 5 MU thrice weekly) and oral ribavirin (1,000-1,200 mg/day) for 24 or 48 weeks were analysed. Cumulative incidence of HCC was estimated by the Kaplan-Meier method. The prognostic relevance of clinical variables and HCC occurrence was evaluated by univariate analysis with the log-rank test and by multivariate Cox's regression analysis. A total of 116 patients completed the treatment and 73 (55%) achieved a sustained virological response (SVR). Stepwise logistic regression analysis showed that nongenotype 1b (P < 0.001) and low viral load (P = 0.018) were independent variables of SVR. During a median follow-up period of 37 (12-63) months, HCC developed in 11 patients with non-SVR and five with SVR (P = 0.0178), whereas there was no difference between those with transient biochemical response and nonresponse (P = 0.5970). The Kaplan-Meier method also showed that old age (>or=60 years) (P = 0.0034) and genotype 1b (P = 0.0104) were associated with HCC occurrence. Using Cox's regression analysis, non-SVR (odds ratio = 3.521, P = 0.036), male (odds ratio = 6.269, P = 0.011) and old age (odds ratio = 3.076, P = 0.049) were independent significant risk factors contributing to HCC development. Our results suggest that achieving SVR by IFN alpha-2b plus ribavirin therapy may decrease the incidence of HCC in patients with HCV-related cirrhosis.

Mutations in the NS5A and E2-PePHD region of hepatitis C virus type 1b and correlation with the response to combination therapy with interferon and ribavirin.

Nonstructural 5A (NS5A) and the second envelope (E2) proteins of hepatitis C virus (HCV) have the potential to block interferon (IFN)-induced RNA-dependent protein kinase (PKR) and may therefore interfere with the response to IFN therapy, but controversy still exists regarding the relevance of this. This study aimed to assess whether mutations in these regions correlated with the response to combination therapy, IFN and ribavirin. Pretreatment parameters were analysed in 57 HCV-1b patients who had received IFN-alpha2b (3 or 5 MU three times weekly) and ribavirin (800-1200 mg per day) for 24 weeks. The amino acid sequences of the NS5A and PKR-eIF2alpha phosphorylation homology domain (E2-PePHD) were deduced from the corresponding coding sequence, which were determinated by direct sequencing of the HCV genome amplified by the polymerase chain reaction. Twenty (36%) patients achieved a sustained virological response (SVR). The mean number of amino acid substitutions in the NS5A-PKR binding domain (2209-2274), interferon sensitivity-determining region (ISDR) (2209-2248), and E2-PePHD sequence (659-670) in patients with and without SVR were 4.53 +/- 3.31 vs 2.83 +/- 1.78 (P = 0.094), 2.45 +/- 2.74 vs 1.03 +/- 1.32 (P = 0.042) and 0.25 +/- 0.70 vs 0.03 +/- 0.17 (P = 0.109), respectively. Patients with a mutant-type (>/= 4) NS5A-ISDR had a higher rate of SVR (six of nine, 67%) than those with wild-type (five of 22, 23%) (P = 0.038). Stepwise multiple logistic regression analysis of the factors (age, gender, viral load, cirrhosis rate, IFN dosage and amino acid substitutions) revealed that the mutation in NS5A-ISDR (>/= 4 vs < 4) was the only independent variable of treatment outcome. Our study showed that NS5A-ISDR mutations were correlated with the SVR to combination therapy in chronic HCV-1b patients in Taiwan.

Sonographic patterns of splenic abscess: an analysis of 34 proven cases.

BACKGROUND: The sonographic patterns of splenic abscess are seldom reported. We report the different sonographic patterns in 34 proven cases. METHODS: From 1984 to June 2000, 42 patients were diagnosed with splenic abscess by abscess aspiration or pathologic findings of surgical specimens. Among them, 34 cases underwent sonographic studies. RESULTS: Fifteen cases had typical abscess echo patterns that included gas in the abscess (two cases) and debris in the abscess cavity (13 cases). Five cases of abscess showed subcapsular lesions with or without echo in the lesion. Two cases of abscess showed a thickened wall mimicking a tumor with central necrosis. Two cases showed a pattern suggesting a cyst. Ten cases showed a pattern suggesting tumor: eight had multiple lesions and two had solitary lesions. Of those 10 cases, seven multifocal abscesses were hypoechoic, and two solitary and one multifocal abscess were mixed echoic. Mortality from multiple splenic abscesses was higher than that from solitary abscess (p = 0.032). Both patients with gas in the abscess expired. CONCLUSION: Sonography of a splenic abscess is variable. A typical pattern was seen in only 44.1% (15 of 34) of patients in our series. We suggest using needle aspiration in each suspected case. Multiple and gas-containing abscesses indicate a poor prognosis.