Yoshiaki Katano

Objectives The aim of this study was to evaluate the efficacy and indication of combination therapy with ribavirin plus peginterferon-alpha-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.

Primary copper toxicosis due to Wilson disease is clinically complex, often leading to delayed diagnosis. Because the metabolic disorder is frequently complicated by iron overload due to hypoceruloplasminemia, either a special stain or microanalysis has been recommended for liver biopsy specimens. Liver biopsy was performed in three patients in whom Wilson disease was highly suspected. Light microscopic study included rubeanic acid stain for copper and Berlin blue stain for iron. To improve the resolution of ultra-structures and preservation of toxic metals, short-term fixation with a 0.1% osmic acid solution was applied for X-ray probe microanalysis. Their diagnosis was confirmed by genetic study and copper chelation therapy. Two patients at the age of 17 and 23 years, respectively, demonstrated cirrhotic livers surrounded by fibrous septa, while a 7-year-old patient demonstrated fatty liver with mildly expanded portal tracts. Both copper grains stained with rubeanic acid and cuprothionein by microanalysis were found in the cirrhotic livers of aged patients. However, either morphological method failed to detect copper deposition in fatty liver tissues from the young patient. Iron deposits were also found in the cirrhotic livers of aged patients. The molecular basis of Wilson disease was confirmed by gene analysis. All patients responded to copper chelation therapy. A morphological method of special staining or microanalysis improved with a new fixative may be unreliable for detecting diffusely distributed copper in the early stage of Wilson liver disease.

Objectives: Dendritic cell (DC) therapy frequently induces a measurable immune response. However clinical responses are seen in a minority of patients, presumably due to insufficient expansion of antigen-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor cells. To increase therapeutic efficacy of DC-based vaccination, we have undertaken the first clinical trial involving a combination therapy of gemcitabine (GEM) with immunotherapy for patients with inoperable locally advanced pancreatic cancer. Methods: Patients (n = 5) received the treatment course, which consisted of intravenous GEM administration at 1000 mg/m(2) (day 1) and the endoscopic ultrasound-guided fine-needle injection of OK432-pulsed DCs into a tumor, followed by intravenous infusion of lymphokine-activated killer cells stimulated with anti-CD3 monoclonal antibody (CD3-LAKs) (day 4), at 2-week intervals. Results: No serious treatment-related adverse events were observed during the study period. Three of the 5 patients demonstrated effective responses to this clinical trial; 1 had partial remission and 2 had long stable disease more than 6 months. In the patient with partial remission, it has been shown that DC-based vaccination combined with GEM administration induces tumor antigen-specific CTLs. Conclusion: This combined therapy was considered to be synergistically effective and may have a role in the therapy of pancreatic cancer for inducing tumor antigen-specific CTLs.

Background/Aims: Although the efficacy and safety of pegylated-interferon (PEG-IFN) alpha-2a and PEG-IFN alpha-2b have been comparatively studied, there are few study results available in which the two PEG-IFN products were strictly compared. To compare the effects of two PEG-IFN products on blood cell profile. Methodology: The time-course change in blood cell counts was compared between chronic hepatitis C patients with genotype 1b receiving PEG-IFN alpha-2a/ribavirin and PEG-IFN alpha-2b/ribavirin combination therapy. The comparison was made after matching patients from the two groups based on ribavirin apparent clearance (CL/F), a surrogate marker of the steady state blood ribavirin level, in order to eliminate the effect of ribavirin. Fifteen pairs of matched patients were selected. Results: The time-course change in hemoglobin did not differ significantly between the two groups. However, significantly greater reductions in both neutrophil and platelet counts were observed with PEG-IFN alpha-2a compared to PEG-IFN alpha-2b. A slightly longer period was required with PEG-IFN alpha-2a than with PEG-IFN alpha-2b for a reduction in neutrophil or platelet count large enough to necessitate dose reduction. Conclusions: Two types of PEG-IFN products affected the blood cell profile in different manners. Long-term monitoring of laboratory test values is necessary with PEG-TFN alpha-2a.

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 mu g) 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% Cl) 0.003-0.363; P = 0.0052) and the number of mutations in the ISDR (odds ratio: 0.025; 95% Cl 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. (C) 2009 Wiley-Liss, Inc.