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In this study, we investigated the real‐world data of the first approved interferon‐free regimen in Japan, daclatasvir and asunaprevir (DCV+ASV), in chronic hepatitis C patients infected HCV genotype 1b with no or subtle amount of baseline resistant associated substitutions (RAS). Among 924 patients registered in our multicenter study, 750 patients who were proven not to be infected with NS5A‐Y93H RAS by direct sequencing and to have no or subtle amount (less than 20%) of NS5A‐Y93H RAS by probe assays (Cycleave or PCR invader assay) were included in this study. We investigated the anti‐viral effect and factors associated with SVR12. In statistical analysis, P < 0.05 was considered as significant. The SVR12 rate in this population was 92.1% (562/618). Factors associated with SVR12 were male (odds ratio: 2.128; 95%CI: 1.134‐4.000, P = 0.019); lower serum γGTP (odds ratio: 1.007; 95%CI: 1.002‐1.012, P = 0.006); lower HCV‐RNA (odds ratio: 1.848; 95%CI: 1.087‐3.145, P = 0.023), and RVR (odds ratio: 6.250; 95%CI: 2.445‐15.873, P < 0.001). No patients with γGTP ≧ 80 IU/L without RVR showed SVR12 (0/4, 0%) and one patients with γGTP ≧ 20‐< 80 IU/L and HCV‐RNA ≧ 6.5 logIU/mL without RVR (5/10, 50%) and two female patients with RVR but γGTP ≧ 80 IU/L and HCV‐RNA ≧ 6.5 logIU/mL (7/13, 53.8%) showed a low SVR12 rate. In the present study, we showed a good viral response with DCV‐ASV treatment and identified four predictive factors associated with SVR12. These four markers could be a good predictive markers for the viral effect of this treatment regimen in patients with no or subtle amount of RAS in NS5A‐Y93. [ABSTRACT FROM AUTHOR]

Background and Aim In this study, we investigated the real-world data of the first approved interferon-free regimen in Japan: daclatasvir and asunaprevir in chronic hepatitis C patients with severe fibrosis. Methods Among 924 patients registered in our multicenter study, 535 patients were defined as having severe fibrosis with Fib-4 index ≧ 3.25 and were included in this study. We investigated antiviral effect and factors associated with sustained viral response 12 (SVR12), and the additional effects on serum α-fetoprotein and albumin levels by eradicating virus in patients who attained SVR were investigated. In statistical analysis, P < 0.05 was considered as significant levels. Results Antiviral effect was lower in patients with severe fibrosis at 8 and 12 weeks after start of the treatment (96.3%, 97.1% with severe fibrosis vs 99.5%, 99.2% without severe fibrosis, P = 0.002 and P = 0.036, respectively), and more early relapse (SVR4; 90.4% with severe fibrosis vs 95.4% without fibrosis, P = 0.008) was seen in patients with severe fibrosis; however, there were no differences in SVR12 and SVR24. In the safety profiles, discontinuation rate due to liver injury (2.8% with severe fibrosis vs 3.3% without severe fibrosis) or other causes of discontinuation was not different between two groups. Serum α-fetoprotein significantly decreased, and serum albumin levels significantly increased as early as 4 weeks after the start of treatment. Conclusion Although the antiviral effect was slightly lower in patients with severe fibrosis compared with those without, treatment with daclatasvir and asunaprevir is basically an effective and well-tolerable treatment in these populations. [ABSTRACT FROM AUTHOR]

Background and Aims The population of patients chronically infected with hepatitis C virus ( HCV) is aging, and the number of older patients with HCV-related hepatocellular carcinoma ( HCC) is increasing. The purpose of this study was to elucidate the effects of peginterferon and ribavirin combination therapy on prevention of HCC in older patients with chronic hepatitis C ( CH- C). Methods We compared the sustained virological response ( SVR) and treatment discontinuation rates between older (≥ 65 years) and younger patients (< 65 years) among 1280 CH- C patients treated with peginterferon alfa-2b and ribavirin. Cumulative incidence of HCC was determined by Kaplan- Meier analysis, and factors associated with liver carcinogenesis were analyzed by Cox proportional hazards regression. Results Older patients had a significantly lower SVR rate and a significantly higher discontinuation rate of treatment than younger patients. Fifty patients developed HCC during median follow-up period of 47 months. Cox proportional hazards regression analysis indicated that the following were independent risk factors associated with the development of HCC: older age, male, advanced fibrosis, non- SVR in all patients: higher gamma-glutamyltranspeptidase, and non- SVR in older patients. Older patients who achieved SVR had a significantly reduced rate of HCC compared with those who did not achieve SVR, especially those who had gamma-glutamyltranspeptidase over 44 IU/ L. Conclusions The SVR rate was lower and the combination therapy discontinuation rate was higher in older CH- C patients than in younger patients. However, older patients who achieved SVR had a markedly lower rate of HCC development compared with older patients who did not achieve SVR. [ABSTRACT FROM AUTHOR]

Aim Previous studies have suggested that patients with chronic hepatitis C with a low pretreatment hepatitis C virus ( HCV) level have a high sustained virological response ( SVR) rate, and that there would be a subpopulation of patients in which HCV can be eradicated with pegylated interferon ( PEG IFN) alone without a decrease in SVR. However, the efficacy of PEG IFN monotherapy in patients with low HCV RNA levels is unclear. Several studies have reported that interferon sensitivity-determining region ( ISDR) and the single-nucleotide polymorphism ( SNP) of interleukin-28 B ( IL-28B) contribute to IFN response, but these relationships are controversial. The aim of this study was to determine whether the SNP of IL-28B (rs8099917) and amino acid substitutions in the ISDR among patients with low HCV levels affect the response to PEG IFN monotherapy. Methods One hundred and four patients with low-level HCV infection were studied. Low HCV level was defined as 100 KIU/m L or less. Results SVR was achieved in 94 patients (92.2%). HCV levels (≤50 KIU/m L) and ISDR (≥2 mutations) were associated with SVR on univariate analysis. The rates of SVR in the patients with IL-28B genotypes TT, TG and GG were 94.5%, 77.8% and 100%, respectively. The G allele tended to be associated with poor response to IFN therapy ( P = 0.0623). On multivariate analysis, the ISDR was the factor predictive of SVR ( P = 0.004). Conclusion The ISDR is significantly associated with a good response to PEG IFN monotherapy in patients with low HCV levels. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the utility of contrast-enhanced transabdominal ultrasonography (CEUS) in the diagnosis of ampullary cancer (AC). Methods: In 12 patients with AC, the presence of tumor enhancement, histological type, amount of connective tissue in cancer, and tumor growth pattern were evaluated. The correlation between the tumor growth pattern and enhancement shape, that between the enhancement pattern and surrounding tissue, and the presence of pancreatic infiltration were evaluated. The depth of cancer invasion was mucosa in five patients, within Oddi's sphincter in four, beyond the duodenum but not to the pancreas in two, and pancreatic invasion less than 5 mm in one. Results: The tumor was enhanced in 11 patients but not in the patient with much connective tissue in the tumor. Enhancement was observed in all patients with the intraluminal papillary or mixed type, but not in those with the periductal invasive type. The enhancement shape was predominantly round or irregular in the intraluminal papillary type and predominantly serrated in the mixed type. The enhancement shape differed among the growth patterns. The normal pancreatic parenchyma around the tumor was enhanced in all patients, and pancreatic infiltration was regarded as absent when there was a continuous unenhanced area between the tumor and pancreatic parenchyma. Conclusion: CEUS correlates with pathological findings of ampullary cancer. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) genotype 1a is rare in Japanese patients and the clinical characteristics of this genotype remain unclear. The interferon (IFN) sensitivity-determining region (ISDR) and single-nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) among patients with HCV genotype 1b are associated with IFN response, but associations among patients with genotype 1a are largely unknown. This study investigated the clinical characteristics of genotype 1a and examined whether genomic heterogeneity of the ISDR and SNPs of IL28B among patients with HCV genotype 1a affects response to combination therapy with pegylated-IFN-α2b and ribavirin. Subjects comprised 977 patients infected with HCV genotype 1, including 574 men and 412 women (mean age, 55.2 ± 10.6 years). HCV was genotyped by direct sequencing of the 5′-untranslated region and/or core regions and confirmed by direct sequencing of the NS5A region. HCV genotypes 1a (n = 32) and 1b (n = 945) were detected. Twenty-three (71.9%) of the 32 patients with genotype 1a were patients with hemophilia who had received imported clotting factors. Prevalence of genotype 1a after excluding patients with hemophilia was thus 0.9%. Of the 23 patients with genotype 1a who completed IFN therapy, 11 (47.8%) were defined as achieving sustained virological response. Factors related to sustained virological response by univariate analysis were IL28B and ISDR. In conclusion, HCV genotype 1a is rare in Japan. The presence of IL28B genotype TT, and more than two mutations, in the ISDR are associated with a good response to IFN therapy in patients with HCV genotype 1a. J. Med. Virol. 84:438-444, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to evaluate the efficacy and indication of combination therapy with ribavirin plus peginterferon-α-2b in chronic hepatitis C virus (HCV) patients aged 65 years and older. Methods: Five hundred and ninety-one consecutive HCV patients were treated with combination therapy. These patients were divided into elder patients (≥65 years) ( n=115) and younger patients (<65 years) ( n=476). The clinical characteristics, sustained virological response (SVR) rates and discontinuation rates were compared between the two groups. Results: Compared with younger patients, baseline haemoglobin levels and baseline platelet counts were significantly lower ( P<0.0001, P=0.013 respectively) and fibrosis was more advanced in elderly patients ( P=0.0310). Moreover, the SVR rate was significantly lower (37.4 vs. 51.5%; P=0.0067) while the combination therapy discontinuation rate was significantly higher (32.2 vs. 17.0%; P=0.0003) in elderly patients. A multivariate analysis revealed that HCV load and genotype were significantly associated with an SVR in elderly patients. An SVR was achieved in over 50% of elderly male patients with genotype 1 and HCV RNA concentrations under 2 000 000 IU/ml. In contrast, the SVR rate was under 30% in elderly male patients with genotype 1 and with HCV RNA concentrations over 2 000 000 IU/ml and in all elderly female patients with genotype 1. Conclusions: The SVR rate was lower in elderly patients than in younger patients. However, in elderly patients combination therapy was most beneficial for genotype 1 patients, male patients with HCV RNA concentrations <2 000 000 IU/ml and patients with genotype 2. [ABSTRACT FROM AUTHOR]

The interferon sensitivity-determining region (ISDR) is thought to be inhibited by the double-stranded RNA-dependent protein kinase (PKR). Several studies have reported a relationship between the ISDR and interferon (IFN) responsiveness. However, this relationship is controversial. The aim of this study was to investigate whether genomic heterogeneity of the ISDR among patients with hepatitis C virus (HCV) genotype 2a affects the response to pegylated-IFN-alpha 2a monotherapy. Eighty patients (47 men, 33 women; mean age: 54.2 ± 12.9 years) infected with HCV genotype 2a were evaluated. HCV viral loads were determined by real-time PCR. The ISDR (amino acids 2193-2228) was examined by direct sequencing. Thirty-one patients received subcutaneous injections of pegylated-IFN-alpha 2a (180 µg) once weekly for 24 weeks, and 35 patients received injections for 48 weeks. Fourteen patients withdrew from treatment. Of the remaining 66 patients, 51 (77.3%) showed a sustained virologic response. Factors related to sustained virologic response on multivariate analysis were rapid virologic response (negative HCV at 4 weeks; odds ratio: 0.033; 95% confidence interval (95% CI) 0.003-0.363; P = 0.0052) and the number of mutations in the ISDR (odds ratio: 0.025; 95% CI 0.001-0.476; P = 0.0141). There were no significant differences in other factors, including sex, age, aspartate aminotransferase, alanine aminotransferase, platelet count, duration of treatment, and HCV viral load. Rapid virologic response and the ISDR sequence variations are significantly associated with response to pegylated-IFN-alpha 2a monotherapy in Japanese patients with HCV genotype 2a. J. Med. Virol. 81:459-466, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We aimed to elucidate clinicopathological variables associated with lymph node metastasis of submucosal invasive gastric cancer. Specimens were surgically resected from 201 patients who had primary submucosal gastric cancer. We studied 39 consecutive patients with lymph node metastasis and 162 patients without lymph node metastasis. We compared the following clinicopathological characteristics of the patients in relation to lymph node metastasis: age, sex, tumor size, histology, extent of submucosal invasion, lymphatic and venous invasion, and ulceration of the tumor. Submucosal invasion was divided subjectively into sm1, sm2, and sm3 (representing invasion of the upper-, middle-, and lower-third of the submucosa, respectively). We also studied the relationship between lymph node metastasis of submucosal gastric cancer and immunohistochemistry for p53, Ki67, vascular endothelial growth factor (VEGF), α-fetoprotein, sLea, and dendritic cells (DCs). In terms of conventional pathological factors, lymph node metastasis in submucosal gastric cancer was related to tumor size ( P = 0.002), depth of submucosal invasion ( P = 0.001), lymphatic invasion ( P < 0.0001), and venous invasion ( P = 0.012). Lymph node metastasis in sm1 gastric cancer was significantly related to VEGF expression ( P = 0.047). Also, lymph node metastasis in sm3 gastric cancer was significantly correlated with DC expression ( P = 0.016). Multivariate analysis showed that tumor size, tumor invasion depth in the submucosal layer, and lymphatic invasion were independent predictors of nodal metastasis in submucosal gastric cancer. Conventional pathological factors, such as tumor size, depth of submucosal invasion, and lymphatic invasion, have a significant influence on lymph node metastasis. VEGF expression and DC expression may be helpful predictors of lymph node metastasis in patients with sm1 and sm3 gastric cancer, respectively. [ABSTRACT FROM AUTHOR]

Background: In Japan, patients with hepatitis C virus (HCV)-associated liver disease are getting older, and thus the number of deaths due to such disease is increasing. The efficacy of combination therapy with ribavirin and interferon for chronic HCV infection in elderly patients has not been fully clarified. The aim of the present study was to evaluate the efficacy and tolerability of combination therapy in such patients. Methods: Two hundred and twenty consecutive patients with chronic hepatitis C were treated with combination therapy. These patients were divided into two groups according to age: patients ≥ 60 years ( n = 66) and patients < 60 years ( n = 154). Clinical characteristics, the sustained virologic response (SVR) rate obtained by intention-to-treat analysis, and the rate of reduction or discontinuation of ribavirin were compared between the two groups. Results: The ribavirin discontinuation rate was significantly higher in the patients aged ≥60 years than in the patients aged <60 years. However, the SVR rates did not differ significantly between patients aged ≥60 years and those aged <60 years (31.8% vs 38.3% by intention-to-treat analysis). According to multivariate analysis, genotype and HCV viral load were significantly associated with SVR while patient age did not affect SVR. Conclusions: Treatment of chronic hepatitis C with combination therapy was comparably effective between patients aged ≥60 years and those aged <60 years, although the ribavirin discontinuation rate was higher among the older patients than the younger patients. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to analyze clinicopathological findings in primary gastrointestinal stromal cell tumors (GIST) and to determine the clinical factors that indicate higher risk potential. Methods: Forty-seven patients with primary GIST were enrolled, and their clinical, endosonographic ultrasonography (EUS), microscopic and immunohistochemical findings were evaluated. Risk categorization of GIST was made on histological tumor size and the mitotic rate. Results: EUS features (a larger diameter, an irregular border, and cystic areas) were significantly correlated with higher risk and unfavorable prognosis. Pathological features (tumor size > 50 mm, > 10 mitoses per 50 high-power fields (HPF), necrosis, and high-risk category) were significant unfavorable prognostic factors. However, some high-risk GIST less than 50 mm in diameter did not have any cystic areas, an irregular border on EUS images. Among GIST that measured 50 mm or less on EUS, tumors with rapid growth and a change of internal echo (more inhomogeneity) were higher risk, while tumors that did not grow and showed no change of a homogeneous internal echo were lower risk. Conclusions: EUS parameters (a larger diameter, an irregular border, and cystic areas) indicate high-risk potential. Tumor growth rate and change of internal echo pattern will be a helpful prognosticator, especially for asymptomatic and incidentally detected small GIST, where the classical EUS high-risk parameters come up against limiting factors. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) can be classified into six major genotypes, the prevalences of which differ around the world. In Japan, the main genotypes are HCV 1 and HCV 2; others are found only rarely. Little is known about the prevalence in Japan of HCV genotype 4 which, is found frequently in North and Central Africa and the Middle East. Thus, we conducted a study to clarify distribution of HCV genotype 4 and the clinical demographics of patients with HCV genotype 4 in Japan. We examined HCV genotypes in 899 Japanese individuals with HCV viremia living in Aichi Prefecture, including 63 hemophiliacs. Four patients (0.4%) were infected with HCV genotype 4. All four of these patients were male hemophiliacs who had received clotting factors from foreign countries. Three patients were co-infected with human immunodeficiency virus (HIV); none were co-infected with GB virus-C/hepatitis G virus. Phylogenetic analysis of the El region indicated that all four patients were infected with subtype 4a. This subtype is related genetically to a subtype previously reported in Japanese and Italian hemophiliacs. HCV genotype 4 is indeed rare in Japan and may be detected only among hemophiliacs who have received inactivated clotting factor concentrates from foreign countries. [Copyright &y& Elsevier]

Liver biopsy specimens with or without liver diseases were examined immunohistochemically to determine the distribution of endothelial cell markers, factor VIII-related antigen (FVIII-RAg), Ulex europaeus agglutinin I (UEA-I) lectin and PAL-E. We also investigated the localization of laminin, a component of the basement membrane. In normal livers, FVIII-RAg, UEA-I and laminin were negative in sinusoidal endothelial cells, but positive in blood vascular endothelia of the portal area. The antigen detected by PAL-E was distributed in venous endothelial cells. PAL-E did not label endothelial cells of the artery. In the lobule, immunoreactivity with PAL-E was weakly detected only in some sinusoids of the periportal area. In chronic active hepatitis and liver cirrhosis, FVIII-RAg and UEA-I stained endothelial cells of neovasculatures in the enlarged portal areas of the fibrous septum surrounding pseudolobules. Some sinusoidal endothelial cells in cirrhotic livers were reactive to UEA-I and FVIII-RAg, whereas PAL-E-positive cells were found rarely in the pseudolobules. In carcinomatous sinusoidal endothelial cells, FVIII-RAg, UEA-I and PAL-E were strongly stained. Laminin underlay these carcinomatous sinusoids. These suggest capillarization of sinusoids in hepatocellular carcinoma. The histochemical approach using endothelial cell markers could be a practical tool in the diagnosis of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

The localization of tissue inhibitor of metalloproteinases (TIMP) in normal and pathological livers was examined by immunohistochemistry using monoclonal antibodies at the light microscopic level. In normal liver, immunoreactive TIMP was detected in smooth muscle cells and endothelial cells of blood vessels, fibroblasts, bile duct cells and Kupffer cells, indicating that TIMP is likely to be a general element of the liver. Immunoreactivity was observed in newly-formed blood vessels, proliferating bile ductules, and fibroblasts in the expanded portal area and fibrous septa of chronic active hepatitis and cirrhosis. TIMP was strongly stained in the capsule of hepatocellular carcinoma. The intensity of the immunoreaction in the capsule was generally greater than that in cirrhotic liver apart from the tumor mass. In three of five cases with hepatocellular carcinoma, endothelial walls in contact with tumor cells were positive. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about hepatitis C virus RNA in urine, saliva and sweat.