Kohsaku Sakaguchi

Continued high albumin production by multicellular spheroids of adult rat hepatocytes formed in the presence of liver-derived proteoglycans

Adult rat hepatocytes formed floating multicellular spheroids, when they were cultured with proteoglycan fraction isolated from rat liver reticulin fibers. Cells in the spheroid showed only low growth activity. Albumin production by the spheroids increased up to 1.5 micrograms/micrograms DNA/day (180 micrograms/mg Protein/day) during the first 6 days and remained constant thereafter. In contrast, the albumin production by the monolayer markedly decreased after 4 days. The spheroid culture appears to be more suitable than the monolayer in studying differentiated functions of adult hepatocytes.

Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C

In contrast to the United States, Japanese patients with chronic hepatitis C currently treated with interferon are generally 10 to 15 years older. Older patients, however, tend to experience more frequent adverse events. This study was conducted to clarify the effect of patient age on the efficacy and safety of combination therapy. We consecutively enrolled 208 patients with naïve chronic hepatitis C. Patients were classified into three groups according to age: younger than 50 years of age (n = 52); 50 to 59 years old (n = 83); and 60 years of age or older (n = 73). Interferon alpha‐2b therapy was administered daily for 2 weeks, followed by 3 times per week for 22 weeks, while ribavirin was administered daily. Of the 208 study patients, discontinuation of therapy or dose reduction was required in 116 (56%) and was more frequent in older patient groups: 38%, 48%, and 77% for the <50, 50–59, and ≥60‐year‐old patient groups, respectively (P < .001). Multivariate analysis showed patient age to be independently associated with adherence to therapy. A sustained virological response was achieved in 77 (37%) patients, with genotype, viral load, and adherence to therapy associated with this achievement. A tendency toward a lower sustained virological response rate was seen in the older patients. In conclusion, patient age is an important factor contributing to the safety of combination therapy. Thus, treatment schedule should be modified, or other therapeutic modalities should be considered for older patients with chronic hepatitis C. (HEPATOLOGY 2006;43:54–63.)

Sensitivity and specificity of des-gamma-carboxy prothrombin for diagnosis of patients with hepatocellular carcinomas varies according to tumor size

OBJECTIVES:Serum levels of des-gamma-carboxy prothrombin (DCP) and alpha-fetoprotein (AFP) are known to be useful tumor markers for the diagnosis of hepatocellular carcinoma (HCC). The aim of this study was to examine the diagnostic efficacy of DCP and AFP in differentiating HCC from chronic liver diseases.METHODS:We examined 1,377 HCC patients and 355 patients with chronic hepatitis or cirrhosis (non-HCC) who visited our institute and affiliated hospitals between June 1997 and September 2003.RESULTS:The median values of DCP and AFP were 60 mAU/mL and 34 ng/mL in HCC patients, respectively, and 18 mAU/mL and 3 ng/mL in non-HCC patients, respectively. The areas under the receiver operating characteristic (ROC) curves of DCP and AFP were 0.812 and 0.887, respectively (p < 0.0001). The area under the DCP ROC curve was significantly smaller than that of AFP in tumors less than 3 cm in diameter (p < 0.0001). However, the ROC area of DCP was significantly larger than that of AFP in tumors greater than 5 cm in diameter (p < 0.0001).CONCLUSIONS:The utility of DCP for the diagnosis of HCC was lower than that of AFP for small tumors, but higher than that of AFP for large tumors.

Clinicopathological features of acute-onset autoimmune hepatitis

The clinicopathological features of nine acute-onset autoimmune hepatitis (AIH) patients were compared with those of 29 classical AIH patients. The clinical features of acute-onset AIH showed significantly higher serum ALT levels, lower serum IgG levels and AIH score than those of classical AIH, although the type of auto-antibodies, age and gender were not different between the two groups. Pathological features showed that the stages of acute-onset AIH varied from stage 1 to stage 4 and were less advanced compared with those of classical AIH. One patient showed submassive hepatic necrosis. Both centrilobular necrosis and interface hepatitis were observed in 7 and 8 of 9, respectively. Three stage 1 patients with centrilobular necrosis and one patient with submassive hepatic necrosis were suggestive of acute presentation, while patients with stages 2 and 4 fibrosis were suggestive of acute exacerbation of chronic disease. An immunohistochemical study demonstrated that CD8 T cells were predominant at both interface hepatitis and centrilobular necrosis, while CD79alpha-positive B lineage cells were predominant at interface hepatitis. These results suggest that acute-onset AIH includes both acute presentation and acute exacerbation of chronic disease and that centrilobular necrosis might be a prevailing pathological feature.

Risk factors for hepatocellular carcinoma in Hepatitis C patients with sustained virologic response to interferon therapy

Abstract: Background: Although a variety of papers demonstrated inhibited hepatocarcinogenesis with interferon (IFN) therapy for chronic hepatitis C, a small number of hepatocellular carcinomas (HCCs) were still observed even in sustained virologic responders.

Sensitivity of immunochemical fecal occult blood test to small colorectal adenomas.

BACKGROUND:Although the immunochemical fecal occult blood test (FOBT) is reportedly more sensitive to large adenomas or colorectal cancer (CRC) than the guaiac-based FOBT, the sensitivity of the immunochemical FOBT to small adenomas has scarcely been reported. Previous reports have indicated that the guaiac-based FOBT can detect small adenomas only by serendipity.OBJECTIVES:To investigate the sensitivity of immunochemical FOBT to small adenomas using a large-scale cohort.METHODS:We analyzed 21,805 consecutively enrolled asymptomatic persons who underwent colonoscopy and immunochemical FOBT.RESULTS:The sensitivity to adenomas ≤9 mm was significantly higher than the false-positive rate as revealed by analysis of all eligible subjects (7.0% vs 4.5%, P < 0.001). In men, the sensitivity was superior to the false-positive rate and increased with age (<50 yr 6.1% and >60 yr 11.3%). On the other hand, the sensitivity in women was not significantly different from the false-positive rate in any generation (5.1% vs 4.7% for all eligible women, P = 0.72).CONCLUSIONS:Immunochemical FOBT detected a small percentage of small adenomas in men at a rate that is significantly higher than the false-positive rate. Studies comparing the guaiac and immunochemical FOBTs using the end point of CRC-related death are expected.

Fine Specificity And Idiotype Diversity Of The Murine Anti-hla-a2, A28 Monoclonal Antibodies Cr11–351 And Ks1

The monoclonal antibodies (MoAb) CR11–351 and KS1 are secreted by hybridomas generated with splenocytes from BALB/c mice immunized with the cultured human B lymphoid cells LG-2 (HLA-A2,A2,B27,B27). The 2 monoclonal antibodies immunoprecipitated components with a superimposable 2-dimensional gel electrophoretic profile from the cultured B lymphoid cells LG-2 and inhibited the cytotoxicity of the anti-HLA-A2,A28 T cell clone MI#3 to a similar extent. In crossinhibition experiments, the MoAb CR11–351 and KS1 completely inhibited the binding of each other to lymphoid cells with the appropriate HLA phenotype. Testing with a panel of HLA-typed lymphoid cells showed that the MoAb CR11–3 51 and KS1 display the same serologic specificity, since both of them react with HLA-A2 and/or A28 antigens bearing cells. The 2 monoclonal antibodies recognize distinct, although spatially close, determinants, since only the MoAb CR11–351 displays differential reactivity with HLA-A2 variant cell lines and reacts with HLA-A9 bearing B lymphoid cells. Analysis of MoAb CR11–351 and KS1 with syngeneic polyclonal and monoclonal antiidiotypic antibodies detected no sharing of idiotopes between the 2 monoclonal antibodies. In view of their reactivity with distinct determinants, these results are in agreement with the concept that the antigenic specificity of an antibody controls at least in part the expression of its idiotypes.

Des-γ-carboxyl Prothrombin-promoted Vascular Endothelial Cell Proliferation and Migration

Des-γ-carboxyl prothrombin (DCP) is a well recognized tumor marker for hepatocellular carcinoma. Previously, we have demonstrated that DCP stimulates cell proliferation in hepatocellular carcinoma cell lines through Met-Janus kinase 1 signal transducer and activator of transcription 3 signaling pathway. In the present study, we demonstrated that DCP induces both cell proliferation and migration in human umbilical vein endothelial cells. DCP was found to bind with the kinase insert domain receptor (KDR), alternatively referred to as vascular endothelial growth factor receptor-2. Furthermore, DCP induced autophosphorylation of KDR and its downstream effector phospholipase C-γ and mitogen-activated protein kinase (MAPK). To support these results, we showed that DCP-induced cell proliferation and cell migration were inhibited by KDR short interfering RNA, KDR kinase inhibitor, or MAPK inhibitor. In conclusion, these results indicate that DCP is a novel type of vascular endothelial growth factor that possesses potent mitogenic and migrative activities.

Endoscopic deployment of multiple JOSTENT SelfX is effective and safe in treatment of malignant hilar biliary strictures.

BACKGROUND & AIMS For the treatment of unresectable biliary tract carcinoma with hilar biliary stricture, antitumor therapy and biliary stenting should be addressed in terms of prolonged survival with a good quality of life. However, the endoscopic management of malignant hilar biliary strictures is difficult even for an expert endoscopist. We evaluated the efficacy and safety of the endoscopic deployment of multiple JOSTENT SelfX units in patients with hilar biliary strictures treated with or without chemotherapy. METHODS Between November 2003 and December 2006, endoscopic deployment of multiple JOSTENT SelfX units in hilar biliary strictures by using a partial stent-in-stent procedure was performed on 41 consecutive patients with primary cholangiocarcinoma (n = 34) and gallbladder carcinoma (n = 7) at a gastroenterologic center of Okayama University Hospital. Thirty-three patients were treated with gemcitabine (n = 25) or S-1 (n = 8). RESULTS Metallic stent deployment was successfully accomplished in all cases via only endoscopic procedures. During the follow-up period (mean, 210 days), mean patency time was 150 days, and metallic stent obstruction occurred in 15 cases (37%). Although a repeat intervention was required in all metallic stent obstructed cases, the deployment of the second metallic or plastic stent was completed successfully. The remaining 26 cases (63%) required no interventions. The median overall survival period was only 235 days. However, that of the patients receiving chemotherapy was 392 days. CONCLUSIONS Endoscopic partial stent-in-stent deployment with multiple JOSTENT SelfX prostheses is effective and safe for the treatment of malignant hilar biliary stricture even in patients receiving chemotherapy.

Surveillance of hepatocellular carcinoma in patients with hepatitis C virus infection may improve patient survival

Abstract: Background: The benefit of surveillance of hepatocellular carcinoma (HCC) for patients with hepatitis C virus (HCV) infection, in terms of long‐term survival, has not yet been established.