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1.  A case report of human immunodeficiency virus-associated anaplastic lymphoma kinase protein-negative anaplastic large cell lymphoma 
SpringerPlus  2013;2:400.
Human immunodeficiency virus (HIV)-associated anaplastic large cell lymphoma (ALCL) is not so common, and anaplastic lymphoma kinase protein (ALK)-negative ALCL is rare and has a low survival rate. We report a case of a 31-year-old Japanese man diagnosed with HIV-associated ALK-negative ALCL who presented with long-lasting fever of unknown origin. The diagnosis was based on a full work-up that included inguinal lymph-node biopsy. Eight-cycle chemotherapy that included cyclophosphamide, doxorubicin, vincristine, and prednisone in addition to antiretroviral therapy for HIV infection provided a complete remission of his ALCL and over 5-year survival for him.
PMCID: PMC3756731  PMID: 24010049
Human immunodeficiency virus; Anaplastic large cell lymphoma; Anaplastic lymphoma kinase
2.  Interferon-α-Induced Changes to Natural Killer Cells Are Associated with the Treatment Outcomes in Patients with HCV Infections 
Aim. We analyzed the pretreatment natural killer (NK) cell functions with the aim of predicting the sustained virological response (SVR) or the interleukin (IL) 28B polymorphism that is strongly associated with the treatment response. Methods. The peripheral NK cells from chronic hepatitis patients with HCV genotype 1 and high virus titers were activated using a Toll-like receptor (TLR) 4 ligand and IFN-α. The cell surface markers were evaluated using a flow cytometric analysis, and IFN-γ production was evaluated using an enzyme-linked immunosorbent assay (ELISA). The genotyping of the polymorphisms in the IL28B gene region (rs8099917) on chromosome 19 was performed on the DNA collected from each patient. Results. The production of IFN-γ was significantly higher in the SVR patients compared with the no-response (NR) patients, whereas the cell surface markers were similar between the SVR and the NR patients. There were no significant differences found in the IL28B genotype distribution associated with the production of IFN-γ. Conclusion. Differences in the NK cell functions were observed between the SVR patients and the NR patients, suggesting that NK cells play a potential role in the treatment response independent of the IL28B genotype.
PMCID: PMC3755421  PMID: 23997950
3.  Pre-treatment role of inosine triphosphate pyrophosphatase polymorphism for predicting anemia in Egyptian hepatitis C virus patients 
AIM: To investigate and clarify, for the first time, the role of inosine triphosphate pyrophosphatase (ITPA) polymorphism in Egyptian chronic hepatitis C virus (HCV) patients.
METHODS:The human genomic DNA of all patients was extracted from peripheral blood cells in order to determine the single nucleotide polymorphism (SNP) of ITPA (rs1127354). SNP genotyping was performed by real time polymerase chain reaction (PCR, ABI TaqMan allelic discrimination kit) for 102 treatment-naive Egyptian patients with chronic HCV. All patients had no evidence of cardiovascular or renal diseases. They received a combination treatment of pegylated interferon α (PEG-IFNα) as a weekly subcutaneous dose plus an oral weight-adjusted dose of ribavirin (RBV). The majority received PEG-IFNα2a (70.6%) while 29.4% received PEG-IFNα2b. The planned duration of treatment was 24-48 wk according to the viral kinetics throughout the course of treatment. Pre-treatment liver biopsy was done for each patient for evaluation of fibrosis stage and liver disease activity. The basal viral load level was detected quantitatively by real time PCR while viral load throughout the treatment course was performed qualitatively by COBAS TaqMan assay.
RESULTS: Ninety-three patients (91.2%) had ITPA SNP CC genotype and 9 (8.8%) had non-CC genotype (CA and AA). The percentage of hemoglobin (Hb) decline was higher for CC patients than for non-CC patients, particularly at weeks 4 and 8 (P = 0.047 and 0.034, respectively). During the first 12 wk of treatment, CC patients had significantly more Hb decline > 3 g/dL than non-CC patients: 64.5% vs 22.2% at weeks 8 and 12, respectively, (P = 0.024 and 0.038). Reduction of the amount of the planned RBV dose was significantly higher for CC patients than non-CC patients during the first 12 wk (18% ± 12.1% vs 8.5% ± 10.2%, P = 0.021). The percentage of CC patients with RBV dose reduction was significantly greater than that of non-CC patients (77.4% vs 44.4%, P = 0.044). Multivariate analysis identified only the percentage of RBV dose as a predictor for Hb decline. Platelet decline was significantly higher in non-CC patients than CC patients at weeks 12, 24 and 48 (P = 0.018, 0.009 and 0.026, respectively).
CONCLUSION: Rs1127354 ITPA polymorphism plays a decisive role in protecting against treatment-induced anemia and the need for RBV dose reduction in Egyptian HCV patients.
PMCID: PMC3602498  PMID: 23538996
Anemia; Dose reduction; Hepatitis C; Inosine triphosphate; Ribavirin; Rs1127354
4.  Effect of laparoscopic splenectomy in patients with Hepatitis C and cirrhosis carrying IL28B minor genotype 
BMC Gastroenterology  2012;12:158.
IL28B and ITPA genetic variants are associated with the outcome of pegylated-interferon and ribavirin (PEG-IFN/RBV) therapy. However, the significance of these genetic variants in cirrhotic patients following splenectomy has not been determined.
Thirty-seven patients with HCV-induced cirrhosis who underwent laparoscopic splenectomy (Spx group) and 90 who did not (non-Spx group) were genotyped for IL28B and ITPA. The outcome or adverse effects were compared in each group. Interferon-stimulated gene 15 (ISG15) and protein kinase R expression in the spleen was measured using total RNA extracted from exenterate spleen.
Sustained virological response (SVR) rate was higher in patients carrying IL28B major genotype following splenectomy (50% vs 27.3%) and in patients carrying minor genotype in the Spx group compared to non-Spx group (27.3% vs 3.6%, P < 0.05). Pretreatment splenic ISG expression was higher in patients carrying IL28B major. There was no difference in progression of anemia or thrombocytopenia between patients carrying each ITPA genotype in the Spx group. Although splenectomy did not increase hemoglobin (Hb) level, Hb decline tended to be greater in the non-Spx group. In contrast, splenectomy significantly increased platelet count (61.1 × 103/μl vs 168.7 × 103/μl, P < 0.01), which was maintained during the course of PEG-IFN/RBV therapy.
IL28B genetic variants correlated with response to PEG-IFN/RBV following splenectomy. Splenectomy improved SVR rate among patients carrying IL28B minor genotype and protected against anemia and thrombocytopenia during the course of PEG-IFN/RBV therapy regardless of ITPA genotype.
PMCID: PMC3503804  PMID: 23145809
IL28B; ITPA; Splenectomy; Liver cirrhosis
5.  Treatment for Eradication of Helicobacter pylori Infection among Chronic Hepatitis C Patients 
Gut and Liver  2011;5(4):447-453.
Helicobacter pylori infection causes gastritis, peptic ulcers and gastric malignancies, and its eradication has been advocated by many groups. We determined the H. pylori carrier status and eradication rates of patients with chronic hepatitis C virus (HCV) infection.
In total, 76 chronically HCV-infected patients were enrolled for comparison with 228 HCV-noninfected, age- and sex-matched controls. H. pylori infection was confirmed by H. pylori antibody and urea breath testing.
The H. pylori infection rate was significantly higher for HCV-infected patients (67 of 76, 88.2%) than for HCV-noninfected controls (158 of 228, 69.3%). Endoscopic findings showed that the rates of gastric ulcers and gastritis were significantly higher for the 67 HCV-infected patients with H. pylori infection (34.3% and 77.6%) than for the 158 HCV-noninfected controls with H. pylori infection (15.2% and 57.6%). Treatment to eradicate H. pylori had a significantly higher success rate for HCV-infected patients (61 of 67, 91.0%) than for HCV-noninfected controls (115 of 158, 72.8%).
The markedly high H. pylori eradication rate observed in this study shows that eradication of H. pylori holds promise for the improvement of the long-term health condition of patients with chronic HCV infection.
PMCID: PMC3240787  PMID: 22195242
Helicobacter pylori; Chronic hepatitis C
6.  Long-term effects of lamivudine treatment in Japanese chronic hepatitis B patients 
AIM: To analyze the association between the emergence of tyrosine-methionine-asparatate-asparatate (YMDD) mutants (reverse transcription; rtM204I/V) and deterioration of liver function during long-term lamivudine treatment of Japanese patients with chronic hepatitis B virus (HBV) infection.
METHODS: The data of 61 consecutive Japanese patients with chronic hepatitis B who underwent continuous lamivudine treatment for more than 24 mo and had a virological response were analyzed. Analysis of YMDD mutants was done by real-time polymerase chain reaction with LightCycler probe hybridization assay for up to 90 mo (mean, 50.8 mo; range, 24-90 mo).
RESULTS: A mixed mutant-type (YMDD + tyrosine-isoleucine-asparatate-asparatate: YIDD or tyrosine-valine-asparatate-asparatate: YVDD) or a mutant-type (YIDD or YVDD) were found in 57.4% of 61 patients at 1 year, 78.7% of 61 patients at 2 years, 79.6% of 49 patients at 3 years, 70.5% of 34 patients at 4 years, 68.4% of 19 patients at 5 years, 57.1% of 14 patients at 6 years, and 33.3% of 6 patients at 7 years. Of the 61 patients, 56 (92%) had mixed mutant- or a mutant-type. Only 5 (8%) had no mutants at each observation point. Virological breakthrough was found in 26 (46.4%) of 56 patients with YMDD mutants, 20 of whom had a hepatitis flare-up: the remaining 30 (53.6%) had neither a virological breakthrough nor a flare-up. All 20 patients who developed a hepatitis flare-up had a biochemical and virological response after adefovir was added to the lamivudine treatment.
CONCLUSION: Our results suggest that it is possible to continue lamivudine treatment, even after the emergence of YMDD mutants, up to the time that the patients develop a hepatitis flare-up.
PMCID: PMC3129509  PMID: 21734806
Tyrosine-methionine-asparatate-asparatate mutant; Hepatitis B virus; Lamivudine; Drug resistance
7.  Pegylated interferon α-2b plus ribavirin for older patients with chronic hepatitis C 
AIM: To analyze the efficacy and safety of a combination therapy of pegylated interferon (PEG-IFN) α-2b plus ribavirin (RBV) in older Japanese patients (65 years or older) infected with hepatitis C virus (HCV).
METHODS: This multicenter study included 938 patients with HCV genotype 1 who received 1.5 μg/kg per week PEG-IFN α-2b plus RBV 600-1000 mg/d for 48 wk and 313 HCV genotype 2 patients who received this treatment for 24 wk.
RESULTS: At 24 wk after the end of combination therapy, the overall sustained virological response (SVR) for genotypes 1 and 2 were 40.7% and 79.6%, respectively. The SVR rate decreased significantly with age in each genotype, and was markedly reduced in genotype 1 (P < 0.001). Moreover, the SVR was significantly higher in patients with genotype 1 who were less than 65 years (47.3% of 685) than in those 65 years or older (22.9% of 253) (P < 0.001) and was higher in patients with genotype 2 who were less than 65 years (82.9% of 252) than in those 65 years or older (65.6% of 61) (P = 0.004). When patients received a dosage at least 80% or more of the target dosage of PEG-IFN α-2b and 60% or more of the target dosage of RBV, the SVR rate significantly increased to 66.5% in patients less than 65 years and to 45.2% in those 65 years or older (P < 0.001). Adverse effects resulted in treatment discontinuation more often in patients with genotype 1 (14.4%) than in patients with genotype 2 (7.3%), especially by patients 65 years or older (24.1%).
CONCLUSION: PEG-IFN α-2b plus RBV treatment was effective in chronic hepatitis C patients 65 years or older who completed treatment with at least the minimum acceptable treatment dosage.
PMCID: PMC2941062  PMID: 20845506
Hepatitis C virus; Gerontology; Pegylated interferon; Ribavirin
8.  Excellent superiority and specificity of COBAS TaqMan HCV assay in an early viral kinetic change during pegylated interferon alpha-2b plus ribavirin treatment 
BMC Gastroenterology  2010;10:38.
An early virological response (EVR) after the start of interferon (IFN) treatment for chronic hepatitis C leads to a successful virological outcome. To analyze an association between sustained virological response (SVR) and EVR by comparing TaqMan with Amplicor assays in HCV genotype 1-infected patients treated with pegylated (PEG)-IFN alpha-2b plus ribavirin (RBV).
We retrospectively analyzed a total of 80 HCV genotype 1 patients (39 SVR and 41 non-SVR patients), who received an enough dosage and a complete 48-week treatment of PEG-IFN alpha-2b plus RBV. Serum HCV RNA levels were measured by both TaqMan and Amplicor assays for each patients at Weeks 2, 4, 8 and 12 after the start of the antiviral treatment.
Of the 80 patients with undetectable HCV RNA by Amplicor, 17 (21.3%) patients were positive for HCV RNA by TaqMan at Weeks 12. The quantification results showed that no significant difference in the decline of HCV RNA level between TaqMan and Amplicor 10-fold method assays within the initial 12 weeks of the treatment was found. However, the qualitative analysis showed significant differences of the positive predictive rates for SVR were found between TaqMan (100% at weeks 4 and 100% at weeks 8) and Amplicor (80.0% and 69.6%, respectively).
The COBAS TaqMan HCV assay is very useful for monitoring HCV viremia during antiviral treatment to predict a SVR in HCV genotype 1 patients.
PMCID: PMC2873600  PMID: 20398383
9.  Effects of lamivudine on serum albumin levels correlate with pretreatment HBV-DNA levels in cirrhotic patients 
Lamivudine treatment has been recently demonstrated to increase the serum albumin levels in cirrhotic patients with hepatitis B virus (HBV) infection, but the precise mechanism remains unclear. We hypothesized that the improvement of hypoalbuminemia by lamivudine may be attributable to the reduction of HBV replication itself, rather than to cessation of hepatitis. In order to confirm this hypothesis, in this study we evaluated factors which correlated with the increase in serum albumin levels. Fifty-four patients (Child-Pugh A/B/C, 35/9/10) with HBV-related liver cirrhosis who had been treated with lamivudine for more than 12 months were evaluated. We analyzed the correlation between the increase in serum albumin levels at month 12 after starting treatment (Δ-albumin) and various pretreatment variables. We also analyzed the correlation between Δ-albumin and the reduction in serum levels of HBV-DNA (Δ-HBV-DNA) or alanine aminotransferase (Δ-ALT) at month 12.
The average Δ-albumin was 0.38 g/dL and only serum HBV-DNA levels before treatment correlated significantly with Δ-albumin. We also analyzed the correlation in patients whose alanine aminotransferase levels were normalized after 12 months so that the possible influence of breakthrough hepatitis could be excluded. Even among this subgroup of patients, there was no significant correlation between Δ-albumin and either pretreatment alanine aminotransferase levels or Δ-ALT. In contrast, in patients whose serum HBV-DNA was undetectable at month 12, we found a significant correlation between Δ-albumin and both pretreatment serum HBV-DNA levels and Δ-HBV-DNA.
Our results demonstrated that albumin levels are associated with pretreatment HBV-DNA but not with alanine aminotransferase levels.
PMCID: PMC1884174  PMID: 17470300
10.  Interferon alpha plus ribavirin combination treatment of Japanese chronic hepatitis C patients with HCV genotype 2: A project of the Kyushu University Liver Disease Study Group 
AIM: To determine the efficacy of an interferon alpha and ribavirin combination treatment for Japanese patients infected with hepatitis C virus (HCV) of genotype 2, a multi-center study was retrospectively analyzed.
METHODS: In total, 173 patients with HCV genotype 2 started to receive interferon-alpha subcutaneously thrice a week and 600–800 mg of ribavirin daily for 24 wk.
RESULTS: The overall sustained virological response (SVR), defined as undetectable HCV RNA in serum, 24 wk after the end of treatment, was remarkably high by 84.4 %, (146/173) by an intention-to-treat analysis. A significant difference in SVR was found between patients with and without the discontinuation of ribavirin (46.9% vs 92.9 %), but no difference was found between those with and without a dose reduction of ribavirin. A significant difference in SVR was also found between patients with less than 16 wk and patients with 16 or more weeks of ribavirin treatment (34.8 % vs 92.0 %).
CONCLUSION: The 24-wk interferon and ribavirin treatment is highly effective for Japanese patients with HCV genotype 2. The significant predictor of SVR is continuation of the ribavirin treatment for up to 16 weeks.
PMCID: PMC4066133  PMID: 16521196
Hepatitis C virus; Interferon; Ribavirin; Genotype 2
11.  Long-term lamivudine treatment for chronic hepatitis B in Japanese patients: A project of Kyushu University Liver Disease Study 
AIM: To determine the efficacy of long-term lamivudine treatment of a large number of Japanese patients with chronic hepatitis B.
METHODS: In this retrospective, multi-center trial, 318 Japanese patients with chronic hepatitis B received 100 mg of lamivudine daily for up to 36 (median 21) mo. Virological response was a decline to a serum HBV DNA level less than 3.7  log copies/mL. Virological breakthrough was defined as the reappearance of a serum HBV DNA level to more than 10-fold the minimum during treatment.
RESULTS: Lamivudine produced virological response in 86.8% of the 318 patients at 6 mo, in 80.2% of 252 patients at 12 mo, in 69.2% of 133 patients at 24 mo, and in 53.6% of 28 patients at 36 mo. Forward stepwise logistic regression analysis showed an HBV DNA level less than 6.8  log copies/mL (P < 0.0001), HBeAg negativity (P < 0.0001), a platelet count of 100 × 109/L or more (P = 0.0162) at baseline, and a decline of the HBV DNA level of more than 3.2  log copies/mL as compared with the baseline level at 3 mo after the start of treatment (P = 0.0003) to be significantly associated with virological response. Among patients with a virological response, virological breakthrough was seen in 5.3% of 19 patients who responded virologically at 1 mo, in 20.7% of 203 patients at 3 mo, in 27.5% of 51 patients at 6 mo, in 33.3% of 12 patients at 9 mo, and in 100% of 3 patients at ≥15 mo. A virological breakthrough was found significantly more often in patients with delayed virological response.
CONCLUSION: Lamivudine treatment could suppress serum HBV DNA in most of the tested Japanese patients. Long-term efficacy might be seen in patients without HBeAg at baseline, in the absence of cirrhosis, and in patients with a decline in HBV DNA level soon after the start of treatment.
PMCID: PMC4066088  PMID: 16489669
Hepatitis B virus; Lamivudine; HBeAg; Cirrhosis

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