Salubrinal reduces expression and activity of MMP13 in chondrocytes.

OBJECTIVE: Stress to the endoplasmic reticulum (ER) and inflammatory cytokines induce expression and activity of matrix metalloproteinase 13 (MMP13). Since a synthetic agent, salubrinal, is known to alleviate ER stress and attenuate nuclear factor kappa B (NFκB) signaling, we addressed a question whether upregulation of MMP13 by ER stress and cytokines is suppressed by administration of salubrinal. METHODS: Using C28/I2 human chondrocytes, we applied ER stress with tunicamycin and inflammatory distress with tumor necrosis factor α (TNFα) and interleukin 1ß (IL1ß). RNA interference with siRNA specific to NFκB p65 (RelA) was employed to examine a potential involvement of NFκB signaling in salubrinal's action in regulation of MMP13. We also employed primary human chondrocytes and evaluated MMP13 activity. RESULTS: The result showed that tunicamycin activated p38 mitogen-activated protein kinase (MAPK), while inflammatory cytokines activated p38 MAPK and NFκB. In both cases, salubrinal significantly reduced expression and activity of MMP13. Silencing NFκB reduced inflammatory cytokine-driven upregulation of MMP13 activity. CONCLUSIONS: The results demonstrate that salubrinal downregulates expression and activity MMP13 through p38 and NFκB signaling, suggesting its potential usage to treat degenerative diseases such as osteoarthritis.

Visceral fat accumulation is an independent risk factor for hepatocellular carcinoma recurrence after curative treatment in patients with suspected NASH.

BACKGROUND AND AIMS: Visceral fat accumulation reportedly increases the risk of hepatocellular carcinoma (HCC) development in patients with chronic liver disease. However, it has not been fully elucidated whether visceral fat accumulation increases the risk of HCC recurrence after curative treatment in patients with suspected non-alcoholic steatohepatitis (NASH). Therefore this was investigated in the current study. METHODS: 62 patients with naive HCC with suspected NASH were enrolled. All were curatively treated with percutaneous radiofrequency ablation between 1999 and 2006. The visceral fat area (VFA) was determined in each patient from CT images, taken at the time of HCC diagnosis. Patients were divided into two groups based on VFA: the high VFA group (>130 cm(2) in males, >90 cm(2) in females, n = 27) and the others (n = 35). The effects of VFA on HCC recurrence were analysed together with other factors including patients' background, tumour-related factors and liver function-related factors. RESULTS: The cumulative recurrence rates differed significantly between the two groups; 15.9, 56.5 and 75.1% at 1, 2 and 3 years, respectively, in the high VFA group, and 9.7, 31.1 and 43.1%, respectively, in the controls (p = 0.018). Multivariate analysis indicated visceral fat accumulation (risk ratio 1.08, per 10 cm(2), p = 0.046) and older age (risk ratio 1.06 per 1 year, p = 0.04) as independent risk factors of HCC recurrence. CONCLUSIONS: Visceral fat accumulation is an independent risk factor of HCC recurrence after curative treatment in patients with suspected NASH.

Percutaneous ethanol injection therapy for liver tumors.

Percutaneous ethanol injection therapy (PEIT) has been widely practiced in the treatment of liver tumors, especially of hepatocellular carcinoma (HCC). Histopathologic examinations, findings in imaging modalities and serum tumor marker levels have shown a remarkable anticancer effect of this procedure. In addition, PEIT has achieved considerably high long-term survival rates. For small HCC, PEIT has been generally accepted as an alternative to surgery. Here we will describe PEIT from the viewpoints of patient selection, technique, various evaluation procedures of efficacy, long-term results, side effects and complications, and relationship with other therapies.

Risk factors for recurring hepatocellular carcinoma differ according to infected hepatitis virus-an analysis of 236 consecutive patients with a single lesion.

Patients with hepatocellular carcinoma (HCC) frequently experience intrahepatic HCC recurrence even after complete ablation of primary lesions. Because the oncogenic process may be different for hepatitis B viral (B-viral) and hepatitis C viral (C-viral) HCC, the present study was conducted to elucidate the factors contributing to HCC recurrence with respect to the infected hepatitis virus. Two hundred thirty-six patients with a single HCC lesion who underwent complete ablation of the tumor by PEIT and/or PMCT or surgical resection at Tokyo University and its affiliated hospitals from 1993 to 1997 were enrolled. The patients were classified into 3 groups: the B-viral group, C-viral group, and NBNC group. After complete removal of tumors, the patients were followed for a mean period of 39 months. The factors contributing to HCC recurrence were analyzed by univariate and multivariate analysis using the Cox proportional hazard model. The rate of intrahepatic recurrence in enrolled patients at 1, 3, and 5 years was 19%, 50%, and 64%, respectively. The intrahepatic recurrence rate in C-viral and B-viral HCC was higher than that in the NBNC-related HCC. Fibrosis staging, pathological grading of HCC, and serum AFP levels were significantly linked to intrahepatic recurrence by univariate analysis, and fibrosis staging was strongest in the multivariate analysis for C-viral HCC (P = .004). In contrast, fibrosis staging did not affect the recurrence in B-viral (P = .51) and NBNC-related (P = .77) HCC. Risk factors for HCC recurrence differed according to the infected viral state.

[Percutaneous tumor ablation therapy for the advanced stage of HCC].

We have performed percutaneous tumor ablation (PTA) including percutaneous ethanol injection therapy (PEIT) for 90% of the patients with hepatocellular carcinoma. Until December 1998, the 793 patients received PTA, 5 years survival rate reached 39.8%. Excluding the patients with Child C whose hepatic function were extremely low, 5 years survival rate reached to the level of 41.2%. Since 5 years survival rate in stage IV-A reached 24.4%, the patients of stage IV-A may be considered to have an indication for PTA. We have confirmed the effectiveness of the local treatment including radiotherapy for advanced hepatocellular carcinoma with portal vein invasion. We are attempting to perform PTA for the extra-hepatic lesions that had no indication of other treatment. However the indication of PTA is limited by the presence of diffuse nodules, exacerbation of the hepatic function, or tumor invasion to portal vein, bile duct, inferior vena cava.

Early detection of haemobilia associated with percutaneous ethanol injection for hepatocellular carcinoma.

OBJECTIVE: Haemobilia often results from iatrogenic injury caused by therapeutic procedures. The objective of this study was to evaluate the efficacy of early diagnosis of haemobilia based on ultrasonography in patients with hepatocellular carcinoma undergoing percutaneous ethanol injection. PATIENTS AND METHODS: A combination retrospective and prospective study on the early detection of haemobilia caused by percutaneous ethanol injection was conducted on 365 patients in 1995-1996. The retrospective study reviewed the clinical, laboratory and imaging data of 172 patients who had undergone ethanol injection therapy in 1995. The results showed that ultrasonographic changes in the gallbladder, namely the rapid appearance of echogenic material in the gallbladder lumen, are a useful early sign of haemobilia. Based on the results of the retrospective study, a prospective study on the early detection of haemobilia was carried out in 1996. In the prospective study, percutaneous ethanol injection was halted as soon as haemobilia was detected. RESULTS: The incidence of haemobilia in the prospective group (3.6%) was not different from that in the retrospective group (4.7%). However, the mean duration between percutaneous ethanol injection and diagnosis of haemobilia was only 0.3 +/- 0.2 days in the prospective group, compared with 2.8 +/- 2.1 days in the retrospective group (P < 0.001), and the mean duration of jaundice in the prospective group (4.3 days) was significantly shorter than in the retrospective group (40.0 days) (P< 0.05). CONCLUSION: Early diagnosis of haemobilia based on ultrasonographic findings of the gallbladder lumen effectively reduces the severity of haemobilia-related complications due to immediate interruption of the interventional procedure.

Unique clinical characteristics of patients with hepatocellular carcinoma who present with high plasma des-gamma-carboxy prothrombin and low serum alpha-fetoprotein.

BACKGROUND: Although the importance of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP) in the clinical treatment of hepatocellular carcinoma (HCC) has been studied extensively, the authors examined the clinical picture of HCC with regard to the state of these two tumor markers. METHODS: The authors categorized 237 HCC cases into 4 groups according to levels of AFP and DCP: high levels of AFP with low DCP levels, high DCP levels with low AFP levels, high levels of both tumor markers, and low levels of both tumor markers. Comparisons of survival rates were made among these groups using the Kaplan-Meier product limit method, and for other comparisons of clinical parameters the Fisher PSLD test was used. Prognostic significance was tested with the Cox proportional hazards model. RESULTS: The cutoff values were set at 100 ng/mL for AFP and 0.0625 AU/mL for DCP. Forty-eight patients (20.7%) had high levels of AFP and low levels of DCP, 22 (9.3%) had high DCP levels and low levels of AFP, 12 (4.6%) had high levels of both AFP and DCP, and 155 (65.4%) had low levels of both DCP and AFP. Patients with high levels of DCP but low levels of AFP were predominantly male and had large lesions but few nodules. Patients with high levels of both tumor markers had the most discouraging outcome observed in this study (death within 3 years). CONCLUSIONS: Patients with high levels of DCP and low levels of AFP exhibited the unique clinical characteristic of large HCC nodules that were few in number. In addition, it was observed that measurement of both AFP and DCP can predict the survival of patients.

A critical role of VLA-4 in erythropoiesis in vivo.

Hematopoiesis requires specific interactions with the microenvironments, and VLA-4 has been implicated in these interactions based on in vitro studies. To study the role of VLA-4 in hematopoiesis in vivo, we performed in utero treatment of mice with an anti-VLA-4 monoclonal antibody. Although all hematopoietic cells in fetal liver expressed VLA-4, the treatment specifically induced anemia. It had no effect on the development of nonerythroid lineage cells, including lymphoids and myeloids. In the treated liver almost no erythroblast was detected, whereas the erythroid progenitors, which give rise to erythroid colonies in vitro, were present. These results indicate that VLA-4 plays a critical role in erythropoiesis, while it is not critical in lymphopoiesis in vivo.

[A case of dermatomyositis complicated by thrombotic thrombocytopenic purpura (TTP) which responded to combination of gamma globulin and vincristine--clinical analysis on TTP cases in the Japanese literatures].

A rare case of dermatomyositis and thrombotic thrombocytopenic purpura (TTP), which responded dramatically to high-dose gamma globulin and vincristine is presented. A 42-year old man was admitted for evaluation of polymyalgia and skin change of the face and fingers. Findings of muscle biopsy was consistent with the diagnosis of dermatomyositis. During the course of his hospital stay, he had diffuse purpura, hematuria, high fever, and his consciousness became disturbed. The hemoglobin level and the platelet count decreased. Based on microangiopathic hemolytic anemia, thrombocytopenia and neurological abnormality, a clinical diagnosis of TTP was made. Therapy included high-dose gamma globulin, vincristine, corticosteroids and dextran. One week later, his consciousness became clear, hematological findings improved, and prolonged remission has been maintained for more than 19 months at the time of this report. This case suggests that gamma globulin and vincristine are effective in some with TTP cases. Case reports that have appeared in the Japanese literature are summarized and reviewed in terms of treatment.