Shinichi Kakumu

Differential diagnosis of pancreatic cancer and focal pancreatitis by using EUS-guided FNA

BACKGROUNDnDespite advances in diagnostic imaging techniques, the differentiation between pancreatic cancer and focal pancreatitis remains difficult. This study evaluated the effectiveness of EUS-guided FNA in the differential diagnosis between pancreatic cancer and focal pancreatitis, with particular reference to detection of the K-ras point mutation.nnnMETHODSnThe study included 62 consecutive patients with pancreatic ductal cancer and 15 patients with focal pancreatitis demonstrated as a pancreatic mass lesion by EUS.nnnRESULTSnSensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of cytopathologic diagnosis were 82%, 100%, 86%, 100%, and 58%, respectively. Sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of histopathologic diagnosis were 44%, 100%, 55%, 100%, and 32%, respectively. The K-ras point mutation was found in 74% of pancreatic cancers and 0% of focal pancreatitis lesions. No complication of EUS-guided FNA was observed.nnnCONCLUSIONSnEUS-guided FNA is useful for the differential diagnosis of pancreatic mass lesions caused by pancreatic cancer and focal pancreatitis. Analysis for the K-ras point mutation in specimens obtained by EUS-guided FNA may enhance diagnostic accuracy in indeterminate cases.

Th1/Th2 cytokine profiles and their relationship to clinical features in patients with chronic hepatitis C virus infection

Purpose. An imbalance in helper T-cell type 1 (Th1) and type 2 (Th2) cytokines is suggested to play an important role in the pathogenesis of chronic viral infections, but this issue is not resolved in patients with hepatitis C virus (HCV) infection. The aim of this study was to clarify the relationship between the balance of Th1 and Th2 cytokines and liver damage. Methods. We investigated cytokine levels in the peripheral blood and liver tissue of patients with chronic HCV infection (n = 59) by three different methods; we used flow cytometry to detect intracellular cytokines, and we measured cytokine titers in sera and in the supernatants of lymphocyte cultures with enzyme-linked immunosorbent assays (ELISAs). Results. In both CD4+ and CD8+ cells, interferon (IFN) γ-producing cell populations increased, while there was no difference in interleukin (IL)-10 production, indicating a shift to a Th1 cytokine profile with the progression of liver disease. With respect to the ratio of IFN-γ to IL-10, a correlation was found in CD4+ cells between peripheral blood and liver tissue (r = 0.98; P = 0.0011). Th1 cytokine was predominant in intrahepatic CD4+ cells, while it was predominant in peripheral blood CD8+ cells. Conclusions. These findings indicate a correlation between dominant Th1 response and disease activity and progression. In addition, we suggest that intrahepatic CD4+ T cells play a pathogenetic role in the hepatic injury of HCV infection.

Prevalence of diabetes mellitus in Japanese patients infected chronically with hepatitis C virus.

Background: To examine the relationship between hepatitis C virus (HCV) infection and diabetes mellitus (DM) in Japanese populations, a retrospective study was done in 866 patients with chronic viral disease. Methods: The present study included 707 HCV-infected and 159 hepatitis B virus (HBV)-infected patients. The prevalences of HBV- and HCV-related cirrhosis were 32% and 33%, respectively. A case-control study was also conducted to determine the seroprevalence of HCV infection in a cohort of 459 diabetics. Results: The prevalence of DM was higher in HCV-infected patients (20.9%; P < 0.02) than in HBV-infected subjects (11.9%). In the cirrhotic patients, DM was observed in 30.8% of the subjects with HCV compared with 11.8% of those with HBV (P < 0.01). Multivariate analysis revealed that the major independent variables associated with type II DM were male sex (odds ratio, 1.54; p = 0.020) and cirrhosis (odds ratio, 1.97; P = 0.0007). The relative odds of the development of DM were calculated to be 3.2 times higher in HCV-infected cirrhotic patients than in HBV-infected ones. In the case-control study of the diabetic cohort, 10.5% of patients were infected with HCV compared with 1.1% with HBV (P < 0.0001). The results indicate that HCV infection is closely associated with DM, compared with HBV infection. Cirrhosis was an independent risk factor for DM. Conclusions: Taken together, the findings indicate that cirrhosis appears to be a more important predictor of glucose intolerance than HCV infection, and the combination of both factors increases the risk of DM in our populations.

Mechanisms of increased insulin resistance in non-cirrhotic patients with chronic hepatitis C virus infection

Background and Aim:u2002 Evidence showing a higher prevalence of diabetes mellitus (DM) in patients with chronic hepatitis C virus (HCV) infection has been accumulating. However, the reason why chronic HCV infection promotes DM remains unknown. In the present study, the authors focused on non‐cirrhotic and non‐diabetic patients with chronic HCV infection and evaluated the factors responsible for increases in insulin resistance.

Lack of Tumor Necrosis Factor Alpha Induces Impaired Proliferation of Hepatitis B Virus-Specific Cytotoxic T Lymphocytes

ABSTRACT Recent studies have shown that tumor necrosis factor alpha (TNF-α) plays critical roles in not only viral clearance but also lymphoid tissue development and stem cell differentiation. In this study, we attempted to induce hepatitis B virus (HBV)-specific cytotoxic T lymphocytes (CTLs) by immunization of TNF-α knockout (TNF-α−/−) mice with HBsAg-encoding plasmid DNA. An immunization with the HBV plasmid failed to induce CTL responses in TNF-α−/− mice, although CTLs were readily induced in wild-type mice by the same protocol. Weak CTL responses were produced in TNF-α−/− mice after two sessions of immunization with the HBV plasmid; however, TNF-α was required to maintain the responses of these CTL lines to in vitro stimulation and, even then, the responses were lost after 3 weeks. Interestingly, a limiting dilution of a CTL line showed that HBV-specific CTL clones with high specific cytotoxicity were present in TNF-α−/− mice, but these clones again failed to proliferate for more than 3 weeks. Furthermore, since exogenously added TNF-α enhanced the proliferation of a TNF-α−/− clone but suppressed that of a TNF-α+/+ clone in vitro, TNF-α also has a direct effect on the proliferation of CTLs. In conclusion, TNF-α is essential rather than important for the proliferation of HBV-specific CTLs both in vivo and in vitro and this effect is not only due to the activation of dendritic cells but is also induced by the direct effect on CTLs.

Interferon therapy for aged patients with chronic hepatitis C : improved survival in patients exhibiting a biochemical response

BackgroundIn Japan, generally, patients with chronic hepatitis C are aged. The aim of this study was to investigate the effect of interferon (IFN) therapy on the mortality of chronic hepatitis C patients over age 60.MethodsSeven-hundred and seven patients with histologically proven chronic hepatitis C were enrolled in this study; 649 received IFN therapy (IFN group) and 58 did not (control group). The standardized mortality ratio (SMR) and Cox proportional hazard regression analysis were used to evaluate the effect of IFN on the survival of the patients.ResultsMean follow-up periods in the IFN and control groups were 5.7 and 6.7 years, respectively. During follow-up, 13 patients in the control group died (7 of liver-related diseases) and 42 in the IFN group died (29 of liver-related diseases). The SMRs of the control and IFN groups were 1.40 (95% confidence interval [CI], 0.76–2.45) and 0.73 (95% CI, 0.52–0.98) for overall death, and 10.70 (95% CI, 4.29–22.05) and 5.05 (95% CI, 3.38–7.26) for liver-related death, respectively. Sustained and transient biochemical responders in the IFN group (SMR, 0.53; 95% CI, 0.01–2.97 and SMR, 3.25; 95% CI, 0.87–8.32, respectively) showed lower liver-related mortality compared with the control group. In patients with sustained virological response, liver-related mortality was also very low (SMR, 0.65; 95% CI, 0.01–3.61). The risk for liver-related death of sustained and transient biochemical responders was also low compared with that of the control group (adjusted risk ratios 0.10 [95% CI, 0.01–0.95] and 0.50 [95% CI, 0.11–2.21], respectively).ConclusionsThese results suggest that IFN treatment could reduce liver-related mortality in chronic hepatitis C patients over age 60, notably in patients showing a biochemical response and in those showing a sustained virological response.

Expression of Fas/Fas ligand (FasL) and its involvement in infiltrating lymphocytes in hepatocellular carcinoma (HCC)

Background. This study was conducted to examine the expression of Fas/Fas ligand (FasL), to elucidate its relationship with tumor-infiltrating lymphocytes (TILs), and to detect possible gene mutation of Fas/FasL in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). Methods. Indirect immunohistochemical staining was performed on formalin-fixed, paraffin-embedded sections of liver biopsy and surgery specimens from five normal livers, and from the livers of 30 patients with HCC. Fas/FasL mRNA-expressing cells and apoptotic cells were detected by in situ hybridization and DNA nick end labeling (TUNEL), respectively. We also performed polymerase chain reaction (PCR)-amplifying and direct sequencing for the Fas/FasL gene. Results. Fas/FasL and its mRNA were localized on the membrane or in the cytoplasm in some HCC cells, as well as hepatocytes. Their expression was enhanced in areas with infiltrating inflammatory cells in the noncancerous regions of liver tissue and on the margins of the cancerous tissue. The positivity rate for TUNEL was elevated along these margins. The labeling index of Fas/FasL was lower in the cancerous liver tissue than in the surrounding noncancerous region (P < 0.01), and tended to decrease in proportion to the malignancy of tumor cells; Fas/FasL expression was not found on poorly differentiated type cancer cells. Fas(−)/FasL(+), FasL-mRNA(+) HCC cells were seen in one specimen of moderately differentiated type. Some CD8+T lymphocytes were TUNEL-positive around the cancerous region. In this study, cancerous and noncancerous tissues in HCC revealed no genetic mutations in any exons of Fas/FasL. Conclusions. These findings suggest that Fas/FasL expression was decreased in proportion to the malignancy of tumor cells, and that infiltrating CD8+T lymphocytes play a role in apoptosis in HCC. The apoptosis in HCC could be regulated by the suppression of Fas/FasL expression, or, sometimes, by the enhancement of FasL expression.

Mutation at codon 130 in hepatitis B virus (HBV) core region increases markedly during acute exacerbation of hepatitis in chronic HBV carriers

Abstract: Mutations within T-cell or B-cell epitopes are suggested to have some influence on the clinical course of chronic hepatitis B virus (HBV) infection. To investigate the relationship between liver cell injury and heterogeneity of the HBV core gene, we focused on the sequence of codon 130, which is located on both T- and B-cell epitopes, and serially analyzed the proportion of mutant virus (core130Thr) to wild-type virus (core130Pro) during the exacerbation of chronic hepatitis B. Sera obtained serially from five HBV carriers who had exacerbation of hepatitis, and three asymptomatic HBV carriers (ASCs) with persistently normal serum aminotransferase (ALT) values were studied, using the restriction fragment length polymorphism (RFLP) method. Core130Pro predominated in the sera in the remission state, but core130Thr increased markedly in parallel with ALT elevation and decreased again after the ALT peak, followed by the predominance of core130Pro, in all the five patients. In one patient, the ratio of core130Thr/core130Pro (Thr/Pro) was more than 70% at the ALT peak. On the other hand, in sera from the three ASCs core130Pro always predominated, and no divergence was identified in the ratio of Thr/Pro. Our data suggest that codon 130 is one of the most important immunogenic regions in the HBV core gene and that elevation of Thr/Pro could be the result of immune selection.

Rebamipide Enemas–New Effective Treatment for Patients with Corticosteroid Dependent or Resistant Ulcerative Colitis

In this study we investigated the effect of rebamipide enema in patients with steroid-resistant and/or dependent ulcerative colitis. Rebamipide enemas were administered twice daily for a 12-week period; this treatment was further continued longer in patients who requested this. Disease activity index as reflecting the clinical condition and endoscopic index with histological grading were determined before and after the treatment period. Nine of 11 (81.8%) patients on 12-week treatment with rebamipide approved and were classified as colitis in remission. Moreover, seven of 11 patients requested long-term medication, the longest medication term being 80 weeks. These results medicated that rebamipide enemas may be effective in patients with steroid-resistant and/or dependent ulcerative colitis.