Hepatitis C virus relapse was suppressed by long-term self-injection of low-dose interferon in patients with chronic hepatitis C after pegylated interferon plus ribavirin treatment.

AIM: The recommended treatment for chronic hepatitis C is a combination of pegylated interferon (PEG IFN) plus ribavirin (RBV). However, the sustained virological response (SVR) rate of PEG IFN-RBV therapy was approximately 50% in patients with genotype 1b and a high viral load. Thus, we compared the efficiencies and side-effects of PEG IFN-RBV and self-injected low-dose natural (n) IFN-α in patients with hepatitis C virus (HCV). METHODS: A prospective, multicenter, open-label study was conducted in 12 Japanese institutions. A total of 129 patients with chronic hepatitis C and no detectable HCV after 24-72 weeks of PEG IFN-RBV treatment were assigned to the control (n = 82) or treated (n = 47) group. Treated patients received 3 million units of nIFN-α 2-3 times/week over 96 weeks. The groups were compared regarding treatment efficiency and side-effects. RESULTS: Significant treatment success regarding virus negativation rates was found, with 89% and 73% for the treated and control groups, respectively (P = 0.039). In contrast, there was no difference in relapse rate between the groups 24 weeks after the 96-week nIFN-α treatment (P = 0.349). However, when early viral responders and late viral responders (LVR) were separated, LVR patients responded significantly to the treatment with 90% sustained virological response, compared to 53% for the control group (P = 0.044). The side-effects of nIFN-α were less than that of PEG IFN-RBV treatment. CONCLUSION: Self-injected nIFN-α has larger benefits than prolonged PEG IFN-RBV for chronic hepatitis C patients with high viral loads of genotype 1b who fail to achieve early viral response during initial combination treatment.

Portal venous tumor growth-type of hepatocellular carcinoma without liver parenchyma tumor nodules: a case report.

The patient was a 43-year-old man with chronic hepatitis B without history of hepatocellular carcinoma (HCC), who was first diagnosed with thrombosis in right portal vein trunk and portal vein branches and ruptured esophageal varices in October 2011. He underwent endoscopic variceal ligation, but ruptured repeatedly. Despite anti-coagulant therapy, the thrombosis expanded from right portal vein trunk to upper mesenteric vein in March 2012. Computed tomography (CT) scan showed that portal vein thrombosis had low density from early to late phase. No focal liver lesions were identified by CT scan or ultrasound, and alpha-fetoprotein (AFP) was within normal range. He died by intractable esophageal variceal bleeding in April 2012. Pathological examination of autopsy specimen showed that portal vein thrombosis was consistent with poorly-differentiated HCC. The portal vein tumor thrombosis (PVTT) had only a few tumor vessels, which were compressed by fibromatous change originating from HCC formation, so were represented as low-density lesions from arterial to portal phase of CT. In addition, PVTT was negative for AFP, so representing serum value of AFP within normal range. PVTT had positive staining for c-kit, which is a liver stem cell marker. Liver tumors in the whole liver parenchyma were not found pathologically. PVTT might have the characteristics of presumed liver cancer stem cells. We experienced the first case of HCC only in portal vein without liver parenchyma tumor nodules, with difficult differential diagnosis from a non-malignant portal vein thrombosis. We also reported new tumor profiles of the portal venous tumor growth- type of HCC.

Activation of the aryl hydrocarbon receptor induces hepatic steatosis via the upregulation of fatty acid transport.

The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix/Per-ARNT-Sim domain transcription factor, which is activated by various xenobiotic ligands. AHR is known to be abundant in liver tissue and to be associated with hepatic steatosis. However, it has not yet been elucidated how the activation of AHR promotes hepatic steatosis. The aim of this study is to clarify the role of AHR in hepatic steatosis. The intraperitoneal injection of 3-methylcholanthrene (3MC), a potent AHR ligand, into C57BL/6J mice significantly increased the levels of triglycerides and six long-chain monounsaturated fatty acids in the livers of mice, resulting in hepatic microvesicular steatosis. 3MC significantly enhanced the expression level of fatty acid translocase (FAT), a factor regulating the uptake of long-chain fatty acids into hepatocytes, in the liver. In an in vitro experiment using human hepatoma HepG2 cells, 3MC increased the expression level of FAT, and the downregulation of AHR by AHR siRNA led to the suppression of 3MC-induced FAT expression. In addition, the mRNA level of peroxisome proliferator-activated receptor (PPAR) α, an upstream factor of FAT, was increased in the livers of 3MC-treated mice. Taking together, AHR activation induces hepatic microvesicular steatosis by increasing the expression level of FAT.

Anti-tumor effect of pegylated interferon in the rat hepatocarcinogenesis model.

Interferon (IFN) is a multifunctional cytokine which works as a suppressor of hepatocarcinogenesis. Pegylated interferon (PEG-IFN) is a modified form of IFN with different pharmacokinetics. We evaluated the anti-tumor effect of PEG-IFN using a rat hepatocarcinogenesis model. Male Fisher Rats were treated using the Solt and Faber model to induce liver cancer. IFN and PEG-IFN were administered from chemical initiation, and pre-neoplastic foci and neoplastic hepatocellular carcinoma (HCC) were examined at 4 and 40 weeks after chemical initiation, respectively. Apoptosis-related molecules such as p53 and Fas-L, proliferating cell nuclear antigen (PCNA), and oxidative stress-related molecules such as 8-hydroxydeoxyguanosine (8-OHdG) and thioredoxin (TRX) were assessed by immunohistochemical analysis and reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of Notch-1, a molecule related to the regenerative and oncogenic processes was also examined. The generation of foci and HCC were significantly suppressed in IFN and PEG-IFN groups compared with the control group. Whereas PCNA and Notch-1 were strongly expressed in the foci and HCC, Fas-L was mainly detected in the surrounding hepatocytes. 8-OHdG and TRX were also detected in the foci. Although PCNA and Notch-1 were down-regulated in IFN- and PEG-IFN-treated groups, Fas-L was up-regulated in those groups. The activation of Notch-1 signaling and the accumulation of oxidative stress in the pre-neoplastic foci might be associated with the progression of HCC in the DEN-induced hepatocarcinogenesis model. The inhibitory effect of the PEG-IFN and IFN on hepatocarcinogenesis was almost the same, and this might be induced by the Fas-related apoptosis in the surrounding tissues.

Abdominal apparent diffusion coefficient measurements: effect of diffusion-weighted image quality and usefulness of anisotropic images.

This study aimed to assess the effect of diffusion-weighted image (DWI) quality on abdominal apparent diffusion coefficient (ADC) measurements and the usefulness of anisotropic images. Twenty-six patients (10 men and 16 women; mean, 58.1 years) who underwent DW imaging and were diagnosed not to have any abdominal diseases were analyzed. Single-shot spin-echo echo-planar DW imaging was performed, and one isotropic and three orthogonal anisotropic images were created. ADCs were calculated for liver (four segments), spleen, pancreas (head, body, tail) and renal parenchyma. Image quality for each organ part was scored visually. We estimated the correlation between ADC and image quality and evaluated the feasibility of using anisotropic images. ADCs and image quality were affected by motion probing gradient directions in the liver and pancreas. A significant inverse correlation was found between ADC and image quality. The r values for isotropic images were -.46, -.48, -.70 and -.28 for the liver, spleen, pancreas and renal parenchyma, respectively. Anisotropic images had the best quality and lowest ADC in at least one organ part in 17 patients. DWIs with the best quality among isotropic and anisotropic images should be used in the liver and pancreas.

Genotype and variations in core promoter and pre-core regions are related to progression of disease in HBV-infected patients from Northern Vietnam.

Vietnam is one of the countries with a high rate of hepatitis B virus (HBV) infection, but there are only a few reports about relation of HBV genotypes and mutations to clinical course in Northern Vietnam. The characteristics of HBV and its relationship to clinical outcome in patients from Northern Vietnam were analyzed. Serum samples were collected from 183 HBV-infected Vietnamese patients. They were clinically categorized into 4 groups: hepatocellular carcinoma (HCC), liver cirrhosis (LC), chronic hepatitis (CH), and asymptomatic carriers (ASC). HBV serology, alpha-fetoprotein, HBV genotypes, HBV-DNA level and mutations in the core promoter and pre-core regions of HBV-DNA were examined. The majority of sera contained HBV genotype B (67.8%) and C (27.9%). The median age was matched between genotype B and C (38.2 vs. 42.9 years). The rates of HBeAg seroconversion and G1896A for genotype B were significantly higher than those for genotype C (P<0.05). Genotype C had a higher HBV-DNA level than genotype B. C1858 was frequent, especially in genotype C (62.7%). The most prevalent genotype in ASC and CH was genotype B. The presence of the mutation A1762T/G1764A correlated with disease progression. The triple mutation T1753C/A1762T/ G1764A was quite common and was more prevalent in LC and HCC than in CH and ASC. In Northern Vietnamese, HBV genotypes B and C were prevalent. Genotype C and mutations in the core promoter region were associated with progressive, severe liver diseases.

Japanese case of hepatitis B virus genotypes C/D hybrid.

Hepatitis B virus (HBV) is classified into eight genotypes based on complete genome sequence. Each genotype is related to geographic distribution and race. In Japan, most of the genotypes are B and C. In the present study, we report the first Japanese strain of HBV having a recombination between genotypes C and D. A 30-year-old woman was admitted to Kobe Medical Center because of liver dysfunction. She was diagnosed with spontaneous reactivation of chronic hepatitis B. She had no history of blood transfusion and her parents were negative for HBV. The phylogenetic analysis based on the complete genome sequences revealed that this strain was classified into genotype C, whereas the analysis based on Sgene sequence showed that this strain was genotype D. By using a SimPlot program, this strain was confirmed as a recombinant strain between genotypes C and D. Compared with previous recombinant strains in China, the breakpoint was the same and the difference was only 0.8% of the complete genome sequence. It was unclear whether or not this strain was transmitted from China, but the recombinant strains and intergenotypes of HBV have already existed in Japan.

Factors associated with the decrease in hepatitis B surface antigen titers following interferon therapy in patients with chronic hepatitis B: Is interferon and adefovir combination therapy effective?

The purpose of antiviral therapy in chronic hepatitis B (CHB) is generally to achieve a decrease and ultimately disappearance of HBs antigen (HBsAg). Interferon (IFN) therapy of CHB appears to be less effective in Asian countries than in European countries, and the advantage of IFN and nucleotide(s) analog (NA) combination therapy has yet to be fully investigated. The present study focused on the factors associated with a decrease in HBs antigen following IFN monotherapy or IFN + NA combination therapy. A total of 35 patients with CHB who received IFN-based therapy (mean ± standard deviation age 36.7±8.5 years; 27 males and 8 females) were enrolled in this study. Of the 35 patients, 21 patients received pegylated IFN monotherapy and 14 patients received IFN and adefovir (ADV) combination therapy. We examined the factors associated with reductions in the HBsAg titer of >1.0 log IU/ml from the initial HBsAg titer to the end of treatment and to 24 weeks after treatment. Although 13 patients (37%) had a reduction in HBsAg of >1.0 IU/ml at the end of treatment, it was only maintained to 24 weeks after treatment in 7 patients (20%). The HBV core-related antigen (HBcrAg) titer before treatment was significantly higher in patients with a decrease in HBsAg at the end of treatment than in patients without a decrease in HBsAg (6.56±0.78 vs. 5.30±1.66 log IU/ml, P<0.05). Moreover, an increase in alanine aminotransferase (ALT) of >2 times from baseline occurred significantly more frequently in patients with a decrease in HBsAg (62 vs. 14%, P<0.05). The proportion of patients with a decrease in HBsAg was significantly greater in patients who received IFN monotherapy than in patients who received IFN and ADV combination therapy (43 vs. 29%, P<0.05). The present results revealed that the HBcr antigen titer before therapy and an on-treatment elevation of ALT (indicative of host instruction flare) are important factors associated with a decrease in HBsAg titers after IFN-based therapy. The efficacy of IFN and ADV combination therapy was not apparent in terms of a reduction in the HBsAg titer.

ADC measurement of abdominal organs and lesions using parallel imaging technique.

OBJECTIVE: The purpose of our study was to assess the reliability and usefulness of parallel imaging for apparent diffusion coefficient (ADC) measurement of abdominal organs and lesions. MATERIALS AND METHODS: Single-shot spin-echo echo-planar diffusion-weighted MRI (TE = 66, b = 0, 600 s/mm2) was performed in phantom and clinical studies. The b value was set to minimize the effects of perfusion in tissue and to maintain signal-to-noise ratio. Bottle phantoms were scanned with and without parallel imaging and with various parallel imaging factors and at various positions to evaluate the effects of parallel imaging on ADCs. In 200 consecutive clinical patients (122 men and 78 women: mean age, 61.9 years), ADCs were calculated for liver (four segments), spleen, pancreas (head, body, tail), gallbladder, renal parenchyma, and back muscle, and then compared to evaluate the reliability of clinical ADC measurements with parallel imaging. ADCs were also calculated for diffuse diseases and focal lesions (94 malignant and 93 benign) of abdominal organs to evaluate the clinical usefulness of ADC. RESULTS: Location-dependent changes in water ADCs were minimal with parallel imaging factors first of 3, then of 4, and were small except for measurements at the image periphery. Acetone ADCs were saturated at 4.00 x 10(-3) mm2/s. Degraded image quality prevented ADC measurement of the left hepatic lobe and pancreas in 7-18 patients. There was no significant difference among ADCs of four liver segments (1.50 +/- 0.24 [SD] x 10(-3) mm2/s - 1.56 +/- 0.31 x 10(-3) mm2/s) and between ADCs of the right and left kidneys (2.65 +/- 0.30 x 10(-3) mm2/s, 2.59 +/- 0.33 x 10(-3) mm2/s). ADC of the pancreas tail (1.65 +/- 0.37 x 10(-3) mm2/s) was significantly lower than those of the head (1.81 +/- 0.40 x 10(-3) mm2/s) and body (1.81 +/- 0.41 x 10(-3) mm2/s) (p < 0.005). Renal ADCs were significantly lower in patients with renal failure (right: 2.15 +/- 0.30 x 10(-3) mm2/s; left: 2.11 +/- 0.25 x 10(-3) mm2/s) than in those without disease (right: 2.67 +/- 0.29 x 10(-3) mm2/s; left: 2.60 +/- 0.32 x 10(-3) mm2/s) (p < 0.005). ADC of pancreatic cancer was significantly higher than that of healthy pancreas (p < 0.05). ADC of renal angiomyolipoma was significantly lower than those of renal cell carcinoma and healthy renal parenchyma (p < 0.0005). CONCLUSION: Clinical ADC measurements of abdominal organs and lesions using parallel imaging appear to be reliable and useful, and the effect of parallel imaging on calculated values is considered to be minimal.

Expression of thioredoxin and thioredoxin-binding protein-2 in the liver of patients with chronic hepatitis C as a predictor of response to interferon therapy.

Oxidative stress contributes to the pathogenesis of various hepatic injuries. Thioredoxin (TRX) is an indicator of oxidative stress, reported to be increased in the serum of patients with chronic hepatitis C with the progression of fibrosis. The aim of this study was to evaluate the clinical significance of the expression of TRX and thioredoxin-binding protein-2 (TBP-2), which is a negative regulator of TRX function, in the liver of patients with chronic hepatitis C and the relationship of this to the efficacy of interferon (IFN) treatment. A retrospective study was performed using the liver biopsy specimens obtained before IFN treatment from 69 patients with chronic serotype 1 hepatitis C virus (HCV) infection. TRX and TBP-2 mRNA levels in the liver biopsy specimens were amplified by real-time RT-PCR. The serum TRX protein level was estimated with a sandwich enzyme-linked immunosorbent assay kit, and the expression of TRX protein in the liver was examined immunohistochemically in 19 patients. There was no association between the serum TRX level and the TRX level in the liver. There was a significant correlation between the expression level of TRX protein in the liver and the TRX mRNA level in the liver. TRX and TBP-2 levels in the liver tended to decrease slightly with increased fibrosis stage, although not significantly. The TRX level in the liver tended to increase with hepatitis activity index, although not significantly. TBP-2 mRNA levels in the liver were significantly higher in responders than non-responders to the IFN therapy (p<0.05). Among patients who had a high viral load of >850 KIU/ml, the TRX level in the livers of non-responders was significantly lower than that in the livers of responders (p<0.05). TRX and TBP-2 mRNA levels in the liver before IFN therapy may predict the outcome of IFN therapy in patients with chronic serotype 1 HCV infection.

Evaluation of the therapeutic effect using MD-CT immediately after RFA for HCC.

BACKGROUND/AIMS: Radiofrequency ablation (RFA) is an effective modality for treatment of hepatocellular carcinoma (HCC), because it can induce large coagulation necrosis in a few sessions. The aim of this study is to evaluate whether we can assess the therapeutic effect of RFA immediately after RFA. METHODOLOGY: Twenty-one patients (25 nodules) with HCC undergoing RFA treatment were enrolled in this study. Fourteen patients were treated with combination therapy of lipiodol chemoembolization and RFA, while 7 patients were treated with RFA alone. Dynamic computed tomography (CT) using multidetector row helical CT (MD-CT) was performed before, immediately after and 1 week after RFA. Simultaneously, multiplanar reconstruction (MPR) images were also obtained for comparison. RESULTS: With or without chemoembolization, the size of coagulated necrosis was almost the same between the time immediately after and 1 week after RFA. The therapeutic effect was able to be evaluated by dynamic CT scans immediately after RFA in all patients. Moreover, MPR images facilitate the detailed evaluation of the therapeutic effect. CONCLUSIONS: Examination of dynamic CT using MD-CT immediately after RFA is useful to evaluate the therapeutic effect and may enable a shorter hospital stay.

Long-term follow-up of Japanese patients with chronic hepatitis B treated with interferon-alpha.

The long-term usefulness of interferon-alpha (IFN-alpha) in chronic hepatitis B remains controversial. To investigate the long-term efficacy of IFN-alpha therapy in chronic hepatitis B, 62 Japanese patients, including 27 patients treated with IFN-alpha (IFN group) and 35 patients without antiviral therapy matched by age and sex as controls (control group), were followed up for 2-14 years. At entry, the serum alanine aminotransferase (ALT) level in the IFN group was significantly higher than that in the control group (238.6+/-250.1 vs. 142.3+/-152.1 IU/l, P < 0.05). The prevalence of genotype C was 89%, with no difference between the two groups (93 vs. 86%). There was no significant difference in the presence of the precore mutation or the dual core promoter mutations between the IFN and control groups (37 vs. 46%, 74 vs. 66%). After long-term follow-up, the rate of sustained HBeAg seroconversion was comparable in the two groups (33 vs. 31%). Normalization of serum ALT level was seen in 44% of the IFN group and 51% of the control group, with no difference. There was also no difference in the percentage of cases with loss of serum HBV-DNA by PCR assay between the two groups (33 vs. 29%). During follow-up, two patients of the control group and three patients of the IFN group developed cirrhosis, and one of the IFN- treated patients progressed to hepatocellular carcinoma. The results of this long-term follow-up study showed that no benefit of IFN-alpha treatment was detectable during long-term follow-up in Japanese patients with chronic hepatitis B.

Serum hepatitis B virus DNA levels differentiating inactive carriers from patients with chronic hepatitis B.

OBJECTIVE: We compared serum hepatitis B virus (HBV)-DNA levels in different states of hepatitis B infection, and investigated whether there is an HBV-DNA value that can be used for differentiating inactive carriers from patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis. METHODS: A retrospective study using sera at a followed endpoint from 64 Japanese patients with chronic HBV infection seen in Kobe University Hospital between 1989 and 2002. Sera of patients were assayed using a polymerase chain reaction-based assay. RESULTS: Genotype C was dominant (95.4%). Patients with chronic hepatitis with an elevation of the serum alanine aminotransferase (ALT) level had significantly higher HBV-DNA levels than patients with persistently normal ALT. For one time observation at a followed endpoint, the mean HBV-DNA level of HBeAg-negative inactive carriers was significantly lower than that of HBeAg-negative chronic hepatitis patients (3.6+/-1.0 versus 4.8+/-1.5 log copies/ml, P<0.005). The use of a cutoff value of 4.5 or 5.0 log copies/ml misclassified 23 and 18% of HBeAg-negative inactive carriers and 50 and 55% of patients with HBeAg-negative chronic hepatitis. If testing were performed on two occasions with approximately a 4-month interval, the cutoff values of 4.5 and 5.0 log copies/ml would misclassify 20 and 10% of HBeAg-negative inactive carriers and 28.6 and 28.6% of patients with HBeAg-negative chronic hepatitis. CONCLUSIONS: The measurement of serum HBV DNA more than twice is useful for assessing chronic hepatitis B surface antigen carriers and confirms that 10 copies/ml may be an appropriate level of HBV for characterizing the inactive carrier state.

High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases.

PURPOSE: Overexpression of PRL-3 has been implicated in colorectal cancer metastases. We investigated the significance of PRL-3 expression in the progression and development of colorectal cancer. EXPERIMENTAL DESIGN: We transfected PRL-3-specific small interfering RNA into human colon cancer DLD-1 cells and analyzed its effect on proliferation, motility, and hepatic colonization. Using an in situ hybridization method, we examined the levels of PRL-3 expression in both primary (177 cases) and metastatic (92 cases) human colorectal cancers and elucidated the relationships with clinicopathological parameters including the incidence of metachronous liver and/or lung metastasis after curative surgery for primary tumor. RESULTS: Transient down-regulation of PRL-3 expression in DLD-1 cells abrogated motility (in vitro) and hepatic colonization (in vivo), but no effect on the proliferation of these cells was observed. In human primary colorectal cancers, the frequency of up-regulated PRL-3 expression in cases with liver (84.4%) or lung (88.9%) metastasis was statistically higher than that in cases without either type of metastasis (liver, 35.9%; lung, 42.3%). In metastatic colorectal cancer lesions, high expression of PRL-3 was frequently detected (liver, 91.3%; lung, 100%). Interestingly, metachronous metastasis was observed more frequently in the cases with high PRL-3 expression (P < 0.0001). CONCLUSIONS: These results indicate that PRL-3 expression in colorectal cancers may contribute to the establishment of liver metastasis, particularly at the step in which cancer cells leave the circulation to extravasate into the liver tissue. In addition, PRL-3 is expected to be a promising biomarker for identifying colorectal cancer patients at high risk for distant metastases.

Expression and localization of ecto-nucleotide pyrophosphatase/phosphodiesterase I-1 (E-NPP1/PC-1) and -3 (E-NPP3/CD203c/PD-Ibeta/B10/gp130(RB13-6)) in inflammatory and neoplastic bile duct diseases.

Ecto-nucleotide pyrophosphatase/phosphodiesterase-I enzyme (E-NPP) consists of three closely related molecules: E-NPP1, E-NPP2 and E-NPP3. We investigated the expression and localization of E-NPP1 and -3 in human inflammatory and neoplastic bile duct diseases. Immunohistochemically E-NPP1 was located on the apical cytoplasmic side of cancer cells, whereas E-NPP3 was located in the apical plasma membrane. Western blot analysis revealed that the expression of E-NPP3, but not E-NPP1, was higher in tumor tissues than in surrounding tissues and the specific form of the E-NPP3 protein was readily detected in the sera of bile duct carcinoma (BDC) patients. Furthermore, it was confirmed that E-NPP3 was associated with migration ability by using of NIH3T3 cells that stably transfected with E-NPP3 cDNA. These results suggest that E-NPP3 is involved in the infiltration of neoplastic BDC and is possible to be a tumor marker.

Early response to interferon alpha treatment and long-term clinical outcome in Japanese patients with chronic HBV genotype C infection.

Genotype C of hepatitis B virus (HBV) has been shown to be associated with a poor clinical outcome and less favorable response to interferon (IFN) alpha therapy compared to genotype B. We evaluated the response to IFN alpha therapy and long-term clinical outcome in Japanese patients with chronic active HBV genotype C infection. Thirty Japanese patients with chronic active hepatitis who received natural IFN alpha therapy were followed for 2-12 years (mean 5.9 years). Twenty-four patients were treated short-term (daily for 4 weeks at a mean total dosage of 174 million units) and 6 patients were treated long-term (total of 26 weeks at a mean total dosage of 687 million units). Twelve of 30 (40%) patients had an antiviral response at 6 months after therapy. Clinical data before treatment in both responders and non-responders were comparable. Although not significant, responders tended to have younger age, a higher serum transaminase level, a lower frequency of precore mutation (G1896A) (67% vs. 92%) and a higher frequency of core promoter mutation (A1762T/G1764A) (89% vs. 58%) than non-responders. The patients treated long-term responded significantly better than those treated short-term (83% vs. 29%, P=0.026). Up to 12 years after therapy, a higher percentage of responders than non-responders had sustained clearance of HBeAg with seroconversion and normalization of transaminase concentration at the followed end point (83% vs. 17%, P<0.001). Two non-responder patients had cirrhosis after long-term follow-up. One non-responder patient died of hepatocellular carcinoma 8 years after IFN therapy; except in this patient there was no development of decompensated cirrhosis. Early responsiveness to IFN alpha therapy in Japanese patients with chronic active HBV genotype C infection improves the long-term clinical outcome.

Different apoptotic regulation of TRAIL-caspase pathway in HBV- and HCV-related hepatocellular carcinoma.

Human hepatocellular carcinoma (HCC) appears to be strongly associated with apoptosis and its breakdown may be involved in the occurrence of HCC. Like the Fas/Fas-L system, the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) transduces apoptosis in a number of cancers; it is also a clinical candidate for cancer therapy. To examine its applicability in future therapy, the apoptotic pathway through TRAIL was investigated in HBV- and HCV-related HCC that have different mechanisms of hepatocarcinogenesis. Caspase-3 activity and the expression of four types of TRAIL receptor mRNAs were quantitated in tumor and contiguous non-tumor tissues obtained from 27 patients with HCC (HBV-related in 10; HCV-related in 17). The expression of caspase-3 and TRAIL receptors was also examined immunohistochemically. A significantly positive correlation was observed between caspase-3 activity and TRAIL-R1, -R2. Caspase-3 activity and TRAIL-R1, -R2 expression in tumor tissue were significantly lower than those in non-tumor tissue in HBV-related HCC. Some HCV-related HCC cases, however, demonstrated elevated caspase-3 activity and TRAIL-R1, -R2 expression in tumor tissue. HBV-related HCC demonstrated significantly suppressed caspase-3 activity, signifying apoptosis. Both TRAIL-R1 and -R2 showed coefficient correlation with caspase-3 activity, and were strongly associated with apoptosis in human HCC.

A case of well-differentiated hepatocellular carcinoma arising in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic progressive, autoimmune liver disease that increases the risk of hepatobiliary malignancies at a late stage. We report a 66-year-old woman with PBC combined with hepatocellular carcinoma (HCC) accompanied by hypoglycemia. Two large tumors were detected on admission and the patient died because of tumor rupture and subsequent liver failure. Histological analysis revealed well-differentiated HCC in both of the tumors. Sometimes the patient had suffered from hypoglycemic attacks of unknown origin, but serum immunoreactive insulin (IRI) was within the normal range. It was interesting that such large well-differentiated hepatocellular carcinomas were generated in PBC.

Short- and long-term outcome of interferon therapy for chronic hepatitis B infection.

Hepatitis B virus (HBV) infection is a serious clinical problem worldwide. Conventional interferon (IFN)-α has been approved for the treatment of chronic hepatitis B (CHB). Short-term studies have demonstrated that IFN-based therapy is moderately effective in inducing the loss of hepatitis e antigen (HBeAg) or seroconversion (30%-40%) in HBeAg-positive patients and also produces sustained HBV DNA suppression (20%-30%) in HBeAg-negative patients. Many studies have reported a correlation between the HBV genotype and response to IFN treatment. The highest response rate to IFN treatment was found in patients infected with HBV genotype A, followed by HBV genotypes B, C, and D. The long-term effect of IFN-α on CHB has not yet been elucidated. The ability of IFN-α treatment to prevent new cirrhosis, complications associated with cirrhosis, and development of hepatocellular carcinoma (HCC) is controversial. The beneficial effect of IFN-α treatment in reducing the development of HCC has mainly been observed in treatment responders who already have cirrhosis. These inconsistent findings may be attributed to the inevitable limitations of comparisons across studies, including differences in the baseline characteristics of the study and the moderate suppression of HBV replication by IFN-α relative to nucleoside/nucleos(t)ide analogs.

Mutational diversity of NS5A and NS3 during triple therapy (telaprevir, pegylated-interferon-α 2b and ribavirin) for genotype 1b chronic hepatitis C: The Kobe Hepatitis Therapeutic Group.

Telaprevir, a non-structural (NS)3/4A protease inhibitor, is a direct-acting antiviral drug that inhibits viral replication. Triple therapy with telaprevir, pegylated interferon, and ribavirin is a standard therapeutic regimen for patients with genotype 1b chronic hepatitis C virus (HCV) infection and a high viral load. Several factors, including mutations in the NS5A gene, are important predictors of the efficacy of interferon therapy. In this study, we examined the mutational diversity of NS5A and its impact on the efficacy of triple therapy. We enrolled patients with genotype 1b chronic HCV infection and a high viral load (31 males/17 females; mean age, 57.6 years), who were treated with triple therapy. This study was conducted at Kobe University Hospital and at three affiliated hospitals in Hyogo prefecture, Japan, between November 2011 and June 2013. A sustained viral response after 12 weeks (SVR12) was achieved in 37/48 patients (77%). Based on intent-to-treat analysis, SVR12 was significantly greater in patients with the major allele than in those with the minor allele for the IL28B single nucleotide polymorphism (SNP; 88 vs. 56%; P<0.05). The prevalence of the V2334I mutation in NS5A was significantly higher in patients who achieved SVR12, while that of G2356E was significantly higher in patients who did not achieve SVR12 (P<0.05). Mutations in the NS3 region that are thought to confer resistance to telaprevir were detected in 3/27 patients who achieved SVR12 (Val36, n=3) and in 5/10 patients who did not achieve SVR12 (Val36, n=4; Thr54, n=1). In conclusion, the IL28B SNP and mutations in the NS5A region were associated with the therapeutic response to triple therapy. Half of the patients who did not achieve SVR12 had mutations conferring resistance to telaprevir. However, pre-existing mutations in NS3 did not affect the efficacy of triple therapy.