Kōbe-shi, Japan
Kōbe-shi, Japan

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Mita K.,Kobe Asahi Hospital | Kim S.R.,Kobe Asahi Hospital | Kudo M.,Kinki University | Imoto S.,Kobe Asahi Hospital | And 6 more authors.
World Journal of Gastroenterology | Year: 2010

AIM: To compare the imaging results with histology and to evaluate the diagnostic sensitivity of imaging modalities for hepatocellular carcinoma (HCC) smaller than 2 cm. METHODS: Nodules smaller than 2 cm (n = 34) revealed by ultrasonography (US) in 29 patients with liver cirrhosis were analyzed. Histological diagnosis of HCC was performed by ultrasonographic guidance: moderately-differentiated HCC (n = 24); well-differentiated HCC (n = 10). The patterns disclosed by the four imaging modalities defined the conclusive diagnosis of HCC: (1) contrast-enhanced computed tomography (CECT), hypervascularity in the arterial phase and washout in the equilibrium phase; (2) Sonazoid contrast-enhanced US (CEUS), hypervascularity in the early vascular phase and defect in the Kupffer phase; (3) gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOBDTPA)-enhanced magnetic resonance imaging (MRI), hypervascularity in the arterial phase and/or defect in the hepatobiliary phase; and (4) CT arterioportal angiography: hypervascularity by CT during arteriography and/or perfusion defect by CT during arterial portography. RESULTS: Overall, the sensitivity of diagnosing HCC smaller than 2 cm was 52.9% (18/34) (95% CI: 35.1-70.2) by CECT; 67.6% (23/34) (95% CI: 49.5-82.6) by Sonazoid CEUS; 76.5% (26/34) (95% CI: 58.8-89.3) by Gd-EOB-DTPA MRI; and 88.2% (30/34) (95% CI: 72.5-96.7) by CT arterioportal angiography. The diagnostic sensitivity of detecting moderately-differentiated HCC by CECT, Sonazoid CEUS, Gd-EOB-DTPA MRI and CT arterioportal angiography was 62.5% (15/24) (95% CI: 40.6-81.2), 79.2% (19/24) (95% CI: 57.8-92.9), 75.0% (18/24) (95% CI: 53.3-90.2) and 95.8% (23/24) (95% CI: 78.9-99.9), respectively. A significant difference (P < 0.05) was observed between CECT and CT arterioportal angiography in all nodules. There was no difference between Sonazoid CEUS, Gd-EOB-DTPA MRI, and CT arterioportal angiography. The combined sensitivity of Sonazoid CEUS and Gd-EOB-DTPA MRI was 94.1% (32/34). CONCLUSION: Changing the main diagnostic modality for HCC smaller than 2 cm from CT arterioportal angiography to Sonazoid CEUS and Gd-EOB-DTPA MRI is recommended. © 2010 Baishideng.


Hasegawa Y.,Shinko Hospital | Kim S.R.,Kobe Asahi Hospital | Hatae T.,Shinko Hospital | Ohta M.,Kobe Asahi Hospital | And 8 more authors.
Digestive Diseases | Year: 2015

Objective: The aim of this study was to evaluate cytokeratin-18M65 (CK-18M65) for distinguishing between simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) against healthy individuals (HIs) in Japanese population. Methods: The serum from 24 HIs, 21 patients with SS and 20 patients with NASH were examined. Serum CK-18M65 was measured by enzyme-linked immunosorbent assay. Results: Aspartate aminotransferase was significantly different between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001), as was alanine aminotransferase between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001). Serum CK-18M65 increased in a stepwise fashion in HIs and also in SS and NASH patients. Multivariate logistic regression analysis revealed that NASH could be diagnosed with the use of CK-18M65 alone (p = 0.0285, OR 1.0038, 95% CI 1.0004-1.0073). At the optimal cut-off level of 548 U/l, CK-18M65 had an AUC value of 0.7369, 60.00% sensitivity and 85.70% specificity. In patients with NASH, no significant difference was observed between low fibrosis (Stage 0-1, 794.30 ± 454.41, n = 10) and high fibrosis (Stage 2-3, 809.70 ± 641.43, n = 10; p = 0.5967) and between slight steatosis (<33%, 512.89 ± 229.65, n = 9) and moderate steatosis (≥33%, 655.13 ± 480.78, n = 32) in patients with non-alcoholic fatty liver disease (NAFLD; p = 0.7647) with the use of CK-18M65. Conclusion: Serum CK-18M65 distinguished NASH from SS, but could not assess the severity of steatosis in NAFLD patients or the grade of fibrosis in NASH patients in Japanese population. © 2015 S. Karger AG, Basel.


El-Shamy A.,Kobe University | El-Shamy A.,Suez Canal University | Shoji I.,Kobe University | Kim S.-R.,Kobe Asahi Hospital | And 10 more authors.
PLoS ONE | Year: 2012

Pegylated-interferon plus ribavirin (PEG-IFN/RBV) therapy is a current standard treatment for chronic hepatitis C. We previously reported that the viral sequence heterogeneity of part of NS5A, referred to as the IFN/RBV resistance-determining region (IRRDR), and a mutation at position 70 of the core protein of hepatitis C virus genotype 1b (HCV-1b) are significantly correlated with the outcome of PEG-IFN/RBV treatment. Here, we aimed to investigate the impact of viral genetic variations within the NS5A and core regions of other genotypes, HCV-2a and HCV-2b, on PEG-IFN/RBV treatment outcome. Pretreatment sequences of NS5A and core regions were analyzed in 112 patients infected with HCV-2a or HCV-2b, who were treated with PEG-IFN/RBV for 24 weeks and followed up for another 24 weeks. The results demonstrated that HCV-2a isolates with 4 or more mutations in IRRDR (IRRDR[2a]≥4) was significantly associated with rapid virological response at week 4 (RVR) and sustained virological response (SVR). Also, another region of NS5A that corresponds to part of the IFN sensitivity-determining region (ISDR) plus its carboxy-flanking region, which we referred to as ISDR/+C[2a], was significantly associated with SVR in patients infected with HCV-2a. Multivariate analysis revealed that IRRDR[2a]≥4 was the only independent predictive factor for SVR. As for HCV-2b infection, an N-terminal half of IRRDR having two or more mutations (IRRDR[2b]/N≥2) was significantly associated with RVR, but not with SVR. No significant correlation was observed between core protein polymorphism and PEG-IFN/RBV treatment outcome in HCV-2a or HCV-2b infection. Conclusion: The present results suggest that sequence heterogeneity of NS5A of HCV-2a (IRRDR[2a]≥4 and ISDR/+C[2a]), and that of HCV-2b (IRRDR[2b]/N≥2) to a lesser extent, is involved in determining the viral sensitivity to PEG-IFN/RBV therapy. © 2012 El-Shamy et al.


Enomoto M.,Osaka City University | Nishiguchi S.,Hyogo College of Medicine | Tamori A.,Osaka City University | Kobayashi S.,Osaka City University | And 7 more authors.
Journal of Gastroenterology | Year: 2013

Background The outcomes of sequential therapy with lamivudine followed by interferon have been unsatisfactory in Japanese patients with hepatitis B envelope antigen (HBeAg)-positive chronic hepatitis B. However, the efficacy of sequential therapy with entecavir and interferon remains unclear. Methods Twenty-four HBeAg-positive patients (23 men and 1 woman; mean age 39 ± 7 years) received entecavir 0.5 mg alone for 36-52 weeks, followed by entecavir plus interferon-α for 4 weeks, and lastly by interferon-a alone for 20 weeks. Twenty-three patients had genotype C infection, and one had genotype A infection. Results No entecavir-resistant mutant variants emerged in any patient. Hepatitis flare occurred in three patients during interferon-a treatment after the withdrawal of entecavir, but none had hepatic decompensation. Serum hepatitis B surface antigen levels did not change during or after therapy. Serum hepatitis B core-related antigen levels were significantly decreased at the start (P <0.0001) and at the end of interferon-a treatment (P <0.0001), but returned to baseline levels after treatment. Twenty-four weeks after the completion of the sequential therapy, a sustained biochemical, virological, and serological response was achieved in 5 (21 %) patients. The proportion of patients in whom HBeAg was lost during entecavir treatment was significantly higher among those with a sustained response than among those with no response (P = 0.015). Conclusions The rate of response to sequential therapy with entecavir and interferon-α in Japanese patients with HBeAg-positive chronic hepatitis B was not higher than the rate in previous studies of lamivudine followed by interferon. © Springer 2012.


Kim S.R.,Kobe Asahi Hospital | Yang J.,Kobe Asahi Hospital | Kudo M.,Kinki University | Hino O.,Juntendo University
Hepatitis Monthly | Year: 2011

There are seven approved treatments for adults with chronic hepatitis B virus infection in the United States and European countries: interferon-α, pegylated interferon-α, lamivudine, adefovir dipivoxil, entecavir, telbivudine, and tenofovir disoproxil fumarate. At present, two new analogues, entecavir and tenofovir are recommended as the first line therapy by the guidelines of European Association for the Study of the Liver and American Association Study for the Liver Diseases. On the other hand, regarding interferon therapy, use of pegylated interferon-α is recommended as the first line therapy instead of standard interferon-α by both guidelines. Therefore, the main scientific interests and unmet medical needs for treatment of chronic hepatitis B have been narrowed down to long-term efficacy and safety of the two said analogues-entecavir and tenofovir-and combination therapy of pegylated interferon-α with the two analogues. To put it concretely, further studies are needed to assess (1) the long-term efficacy and safety and resistance to entecavir and tenofovir; (2) the efficacy of different durations (24 weeks to 2 years) and lower doses of pegylated interferon-α; (3) the role of combination therapy with two analogues to reduce resistance; and (4) the efficacy and safety of the two analogues with decompensated cirrhosis. Herein, we review the recent available data and results. © 2011 Kowsar M.P.Co. All rights reserved.


El-Shamy A.,Kobe University | El-Shamy A.,Suez Canal University | Kim S.-R.,Kobe Asahi Hospital | Ide Y.-H.,Kobe University | And 5 more authors.
Intervirology | Year: 2012

Objective: Hepatitis C virus (HCV genome) polymorphisms are thought to influence the outcome of pegylated-interferon/ribavirin (PEG-IFN/RBV) therapy. This study aimed to examine non-structural protein 5A (NS5A) polymorphisms, e.g. IFN/RBV resistance-determining region (IRRDR) and IFN sensitivity-determining region (ISDR), and core protein polymorphism as predictive therapeutic markers. Methods: Pretreatment sequences of NS5A and core regions were analyzed in 68 HCV-1b-infected patients treated with PEG-IFN/RBV. Results: Of 24 patients infected withHCV having an IRRDR with 6 or more mutations (IRRDR≥6), 18 (75%) patients achieved sustained virological response (SVR), whereas only 11 (25%) of 44 patients infected with HCV having IRRDR≤5 did. IRRDR≥6 was significantly associated with SVR (p < 0.0001). On the other hand, ISDR≥2 was significantly associated with relapse (either before [breakthrough] or after end-of-treatment response [ETR[-]relapse]) (p < 0.05) and a point mutation of the core protein from Arg to Gln at position 70 (Gln 70) was significantly associated with null-response (p < 0.05). Multivariate analysis identified IRRDR≥6 as the only viral genetic factor that independently predicted SVR. Conclusion: NS5A (IRRDR and ISDR) and core protein polymorphisms are associated with the outcome of PEG-IFN/RBV therapy for chronic hepatitis C. In particular, IRRDR≥6 is a useful marker for prediction of SVR. Copyright © 2011 S. Karger AG, Basel.


Kim S.R.,Kobe Asahi Hospital | El-Shamy A.,Kobe University | El-Shamy A.,Suez Canal University | Imoto S.,Kobe Asahi Hospital | And 8 more authors.
Journal of Gastroenterology | Year: 2012

Background: This study explores pretreatment predictive factors for ultimate virological responses to pegylated interferon-α (1.5 μg/kg/week) and ribavirin (600-1000 mg/day) (PEG-IFN/RBV) combination therapy for patients infected with hepatitis C virus (HCV)-1b and a high viral load. Methods: A total of 75 patients underwent PEG-IFN/RBV combination therapy for 48 weeks. HCV amino acid (aa) substitutions in non-structural protein 5a, including those in the IFN/RBV resistance-determining region (IRRDR) and the IFN sensitivity-determining region and the core regions, as well as the genetic variation (rs8099917) near the interleukin 28B (IL28B) gene (genotype TT) were analyzed. Results: Of the 75 patients, 49 % (37/75) achieved a sustained virological response (SVR), 27 % (20/75) showed relapse, and 24 % (18/75) showed null virological response (NVR). Multivariate logistic regression analysis identified IRRDR with 6 or more mutations (IRRDR ≥6) [odds ratio (OR) 11.906, p < 0.0001] and age <60 years (OR 0.228, p = 0.015) as significant determiners of SVR and IL28B minor (OR 14.618, p = 0.0019) and platelets <15 × 104/mm3 (OR 0.113, p = 0.0096) as significant determiners of NVR. A combination of IRRDR ≥6 and age <60 years improved SVR predictability (93.3 %), and that of IRRDR ≤5 and age ≥60 years improved non-SVR predictability (84.0 %). Similarly, a combination of IL28B minor and platelets <15 × 104/mm3 improved NVR predictability (85.7 %), and that of IL28B major and platelets ≥15 × 104/mm3 improved non-NVR (response) (97.1 %) predictability. Conclusion: IRRDR ≥6 and age <60 years were significantly associated with SVR. IL28B minor and platelets <15 × 10 4/mm3 were significantly associated with NVR. Certain combinations of these factors improved SVR and NVR predictability and could, therefore, be used to design therapeutic strategies. © 2012 Springer.


PubMed | Kobe Asahi Hospital, Kyoto University and Nagasaki University
Type: | Journal: Antiviral research | Year: 2017

Hepatitis B virus (HBV) infection evokes host immune responses that primarily determine the outcome of HBV infection and the clinical features of HBV-associated liver disease. The precise mechanisms by which host factors restrict HBV replication, however, are poorly understood due to the lack of useful animal models that recapitulate immune responses to HBV. Here, we performed comprehensive immunologic gene expression profiling of the liver of a mouse model recapitulating anti-HBV immune response using a high sensitivity direct digital counting system. Anti-HBV cellular immunity with liver inflammation was elicited in mice hydrodynamically injected with a CpG-depleted plasmid encoding hepatitis B surface antigen (HBsAg) gene after preimmunization with HBsAg vaccine. Comprehensive expression analyses revealed the upregulation of Th1-associated genes including tumor necrosis factor (Tnf) and negative regulators of T cell function in the inflamed liver. Interestingly, activation-induced cytidine deaminase (Aicda, termed AID in humans), which reportedly suppresses HBV infection in vitro, was upregulated in hepatocytes in the course of anti-HBV immunity. Hepatocytic expression of Aicda in a Tnf-dependent manner was confirmed by the administration of Tnf antagonist into Aicda-tdTomato mice with anti-HBV immunity. Our findings suggest that activation of Tnf-Aicda axis and co-inhibitory signals to T cells in coordination with Th1-type immunity has critical roles in the immune response against HBV infection.


PubMed | Kobe Asahi Hospital
Type: Journal Article | Journal: Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan | Year: 2016

Clinical identity of nonalcoholic steatohepatitis (NASH) has established it as a chronic liver disease since the 1990s in the USA and in the 21st century in Japan, although its significance is not well recognized in Japanese society. It is characterized as a chronic liver disease, differentiated from viral liver disease and alcoholic liver disease. Nonalcoholic fatty liver disease (NAFLD) comprises nonalcoholic fatty liver (NAFL) and NASH. NASH is considered to be the hepatic manifestation of a metabolic syndrome. It is understood that among individuals with NAFLD, NAFL is a benign condition, whereas NASH can progress to cirrhosis and ultimately to hepatocellular carcinoma. The precise mechanism of NASH is poorly understood, although insulin resistance, oxidative stress and multiple parallel hits theory have been reported. Computed tomography and ultrasonography are performed to detect NAFLD, but these are not sufficient to distinguish between NAFL and NASH. The distinct diagnosis of NAFL and NASH is currently made by liver biopsy, requiring hospitalization. Therefore, there is an urgent need to develop simple, non-invasive markers that can accurately distinguish between NASH and NAFL. In Japan, the number of NASH patients is estimated to be about 1 million. The treatment of NASH comprises changes in life style, including eating habits and exercise that will lead to weight loss, and drug intake, including vitamin E. Based on the global increase in obese people, NASH as a chronic liver disease will become the most important chronic liver disease in the 21st century, not only in Japan but also worldwide.


PubMed | Kobe Asahi Hospital
Type: Comparative Study | Journal: Digestive diseases (Basel, Switzerland) | Year: 2015

The characteristics of hypovascular and hypervascular well-differentiated hepatocellular carcinomas (HCCs) were compared in terms of tumor size, tumor markers and detectability by imaging modalities.Well-differentiated HCC nodules that are smaller than 2 cm (n = 27) were evaluated in 27 patients using histopathology and divided into 2 groups: hypovascular (n = 10) and hypervascular (n = 17). The diagnostic sensitivity of imaging modalities was then evaluated for efficiency in disclosing tumor size and tumor markers in the 2 types.No difference was observed in tumor size and tumor markers between the 2 types; however, the sensitivity of contrast-enhanced CT, contrast-enhanced ultrasonography and arterioportal angiography was significantly different between the 2 types, whereas that by Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid enhanced magnetic resonance imaging (Gd-EOB-DTPA MRI) demonstrated no difference.Hypovascular HCC could be diagnosed by Gd-EOB-DTPA MRI in the hepatobiliary phase.

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