The optimal doses of tacrolimus (FK) needed to reach and maintain a target blood level vary among cases of living donor liver transplantation (LDLT). One hundred and twenty four LDLTs in 122 patients were included in this study. Tacrolimus was administered by continuous intravenous infusion at a rate of 2.5 microg/kg/h just after the operation. The time needed to reach the target blood level and the dose needed to maintain this level for 1 week (17-18 ng/mL) were defined as the initial duration (ID) and secondary dose (SD), respectively. In the first 100 LDLTs, the correlations between ID or SD and some clinical factors were examined and equations for predicting ID or SD were derived. In the latest 24 LDLTs, FK was administered using these equations and the actual and calculated ID and SD values were compared. A multiple regression analysis revealed that only the graft weight/recipient standard liver volume (GW/SLV) ratio (%) correlated with ID or SD. Stepwise regression analysis led to the equations ID (h) = 0.4 x GW/SLV ratio + 0.2; SD (microg/kg/h) = 0.02 x GW/SLV ratio - 0.4. Simple regression analysis revealed a significant correlation between the actual and calculated ID and SD values (p < 0.0001). Initial duration and SD can be estimated from equations using the GW/SLV ratio.

Adolescent↗

PubMed2001

Tranilast inhibits transplant-associated coronary arteriosclerosis in a murine model of cardiac transplantation.

Accelerated coronary arteriosclerosis remains a major problem for the long-term survival of cardiac transplant recipients. However, the pathogenesis of graft vasculopathy is poorly understood and there is no effective therapy. Tranilast is a promising drug that may prevent post-angioplasty restenosis. Here, we investigated whether orally administered tranilast inhibits the development of intima hyperplasia in a mouse model of cardiac transplantation. Cardiac allografts from BALB/c mice were transplanted heterotopically into C3H/He mice. Mice were administered either vehicle or tranilast everyday by gavage. Morphometrical analysis of the cardiac allografts harvested at 2 months revealed that the administration of tranilast significantly reduced the development of coronary atherosclerosis. In the mice treated with tranilast, up-regulation of the cyclin-dependent kinase inhibitor p21 was observed in the allografts, accompanied by a reduced number of proliferating cells. Tranilast also suppressed transforming growth factor-beta (TGF-beta) expression. Tranilast may be effective in preventing transplant-associated arteriosclerosis through its anti-inflammatory and anti-proliferative effects.

Animals↗

PubMed2001

A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables.

BACKGROUND: The objective of this study was to analyze the clinicopathologic variables and the postoperative outcome in patients with mass-forming intrahepatic cholangiocarcinoma (ICC) to identify important factors for predicting postresection prognosis. Although it has been reported that mass-forming ICC has a different etiology and biologic features compared with hepatocellular carcinoma (HCC), patients with ICC have been dealt with clinicopathologically in the same manner as patients with HCC. METHODS: Sixty patients who underwent hepatectomy for mass-forming ICC with curative intent between 1981 and 1999 were studied. Fourteen preoperative clinical and diagnostic parameters and 12 postoperative surgicopathologic parameters were analyzed. RESULTS: The rate of operative mortality in this patient cohort was 5%, and the overall 1-year, 3-year, and 5-year survival rates were 68%, 35%, and 29%, respectively, with a median survival of 19.6 months. A multivariate analysis revealed that independent negative prognostic factors were 1) hepatic regional lymph node metastasis, 2) multiple tumor presentation, 3) symptomatic tumor, and 4) the presence of vascular invasion. Using these factors, a new staging system was devised: Stage I disease was defined as a solitary tumor without vascular invasion, Stage II disease was defined as a solitary tumor with vascular invasion, Stage IIIA disease was defined as multiple tumors with or without vascular invasion, Stage IIIB disease was defined as any tumor with regional lymph node metastasis, and Stage IV disease was defined as any tumor with distant metastases. The Kaplan-Meier estimated 3-year survival rate and the median survival for each subgroup were 74% for patients with Stage I disease (median survival is the time when the cumulative survival rate of some patients' group declined to 50%; thus, the median survival could not be calculated in patients with Stage I disease because survival was 74% at the latest follow-up), 48% and 26.2 months for patients with Stage II disease, 18% and 16.8 months for patients with Stage IIIA disease, and 7% and 11.2 months for patients with Stage IIIB disease, respectively (P < 0.0001). None of the patients met the criteria for Stage IV disease. CONCLUSIONS: The current results support the use of a new staging system for patients with ICC that is simple and predicts well the differences in survival after patients undergo hepatic resection.

Adult↗

PubMed2001

Living-related liver transplantation for primary biliary cirrhosis.

BACKGROUND: The prognosis of patients with primary biliary cirrhosis has improved since the introduction of transplantation. However, there has been limited experience with living-related liver transplantation for primary biliary cirrhosis. PATIENTS AND METHODS: Between January 1996 and October 2000, 105 patients underwent living-related liver transplantation at the University of Tokyo Hospital. Eighteen of these patients with primary biliary cirrhosis were the subjects of this study. The risk scores in the conventional and updated Mayo models ranged from 5.9 to 11.6 and 6.9 to 13.7, respectively. RESULTS: The graft weight ranged from 330 to 533 g, corresponding to 33 to 55% of the recipient's standard liver volume. Two patients died of pneumonia, 1 died due to sepsis, and the remaining 15 patients survived. The risk scores for the conventional and updated Mayo models correlated well with the duration of hospitalization (P=0.01, R=0.67 for both). The scores of the dead patients by the two models were more than 10 and 12, respectively. The postoperative courses of all of the donors were uneventful. CONCLUSIONS: The risk score in the Mayo model adequately reflected the outcome of the patients. To achieve the best possible outcome, further therapeutic tactics are necessary for patients with conventional or updated Mayo risk scores of more than 10 or 12, respectively.

Adult↗

PubMed2001

Methioninase cancer gene therapy with selenomethionine as suicide prodrug substrate.

In this study, we report a novel approach to gene-directed enzyme prodrug therapy for cancer. This gene therapy strategy exploits the toxic pro-oxidant property of methylselenol, which is released from selenomethionine (SeMET) by cancer cells with the adenoviral-delivered methionine alpha,gamma-lyase (MET) gene cloned from Pseudomonas putida. In MET-transduced tumor cells, the cytotoxicity of SeMET is increased up to 1000-fold compared with nontransduced cells. A strong bystander effect occurred because of methylselenol release from MET gene-transduced cells and uptake by surrounding tumor cells. Methylselenol damaged the mitochondria via oxidative stress and caused cytochrome c release into the cytosol, thereby activating the caspase cascade and apoptosis. Adenoviral MET-gene/SeMET treatment also inhibited tumor growth in rodents and significantly prolonged their survival. Recombinant adenovirus-encoding MET gene-SeMET treatment thereby offers a new paradigm for cancer gene therapy.

Adenoviridae↗

PubMed2001

Requirement of ceramide for adhesion of Helicobacter pylori to glycosphingolipids.

Direct adhesion of Helicobacter pylori to immobilized glycosphingolipids (GSLs) was compared to that of their corresponding oligosaccharide-conjugated neoglycoconjugates in order to clarify the roles of the carbohydrate and lipid portions of GSLs in H. pylori adhesion. These bacteria were found to adhere to sulfatide, GM3, GalCer and LacCer, but not to ceramide, sphingomyelin, or polyacrylamides conjugated with beta-galactose, lactose, 3'-sialyllactose or 3'-sulfo-beta-galactose. Furthermore, neoglycolipids or bovine serum albumin derivatives with corresponding oligosaccharides were unable to serve as the ligands. H. pylori adhesion to GalCer with alpha-hydroxyl fatty acid was much stronger than GalCer with the non-hydroxyl fatty acid. These results suggest that H. pylori recognize the conformation of GSL with alpha-hydroxyl fatty acid on solid phase.

Bacterial Adhesion↗

PubMed2001

A comparison of gene expression in murine cardiac allografts and isografts by means DNA microarray analysis.

BACKGROUND: Acute rejection of allografts remains a significant problem in clinical transplantation, and the fundamental mechanism underlying this rejection are as yet only poorly elucidated. Recently, DNA microarrays have come into use for the study of gene expression profiles, and we have taken advantage of this new technology to investigate acute rejection. We compared mRNA profiles in murine cardiac allografts with isografts using DNA microarrays with probe sets corresponding to more than 11,000 mice genes. METHODS: We screened for gene expression changes in murine cardiac allografts between fully incompatible mice strains (BALB/c H2d to C3H/He H2k) using a DNA microarray. The heart was heterotopically transplanted. Allografts (BALB/c to C3H/He) were removed on days 1, 3, and 5. As a control, isografts (C3H/He to C3H/He) harvested on days 1, 3, and 5 and native hearts of both strain mice (C3H/He and BALB/c) were obtained. RESULTS: On day 5, interferon-gamma (IFN-gamma) and many IFN-gamma-inducible genes were profoundly induced in the allograft relative to isograft. Monokine induced by IFN-gamma was most profoundly induced followed by inducibly expressed GTPase and Lmp-2. IFN-gamma was also profoundly induced. The induction was detectable from day 3. In contrast, genes regulated by other cytokines exhibited only modest changes. CONCLUSION: IFN-gamma-inducible genes are specifically up-regulated in murine cardiac allografts, suggesting that signaling mediated by IFN-gamma may play an important role in the late phase of acute rejection in vivo.

Animals↗

PubMed2001

Frequent beta-catenin aberration in human hepatocellular carcinoma.

Recently, mutations in the beta-catenin gene in hepatocellular carcinoma (HCC) have been reported: approximately 20% of HCCs had activating mutations at the glycogen synthase kinase 3beta phosphorylation sites within the exon 3 of the beta-catenin gene. However, changes in the level of the beta-catenin protein in HCC have not been well studied. We examined, by Western blotting, the expression level of the beta-catenin protein in cancerous tissues in comparison with that in adjacent non-cancerous tissues obtained from 32 cases of HCC with hepatitis C. An increase in the beta-catenin protein level in cancerous tissue compared to that in adjacent non-cancerous tissue was found in 15 (46.9%) of 32 cases of HCC. Mutation in exon 3 of the beta-catenin gene was found in six (18.8%) of the 32 cases, in five of which the beta-catenin protein level was increased. In total, beta-catenin aberration was found in 16 (50.0%) of 32 cases of HCC. It should be noted that beta-catenin aberration was also found in early HCC although it was observed chiefly in advanced HCCs. These results indicate that beta-catenin aberration is a frequent event in the development of HCC and may facilitate the development of HCC in the course of chronic hepatitis.

Journal Article↗

PubMed2001

Congestion of right liver graft in living donor liver transplantation.

BACKGROUND: Left liver graft from a small donor will not meet the metabolic demands of a larger adult recipient. One solution to this problem is to use a right liver graft without a middle hepatic vein (MHV). However, the need for drainage from the MHV tributaries has not yet been described. METHODS: Five right liver grafts without a MHV were transplanted in patients including two hepatitis B virus-cirrhosis, two fulminant hepatic failure and one secondary biliary cirrhosis. The graft weight ranged from 650 to 1,000 g, corresponding to 48 to 83% of the standard liver volume of the recipients. RESULTS: Two of five recipients were complicated with severe congestion of the right median sector immediately after reperfusion, followed by prolonged massive ascites and severe liver dysfunction. One of the patients died of sepsis with progressive hepatic dysfunction 20 days after the operation. CONCLUSIONS: Preservation and reconstruction of the MHV tributaries is recommended to prevent congestion of the right liver graft without MHV.

Body Weight↗

PubMed2001

Randomized comparison of ultrasonic vs clamp transection of the liver.

HYPOTHESIS: Hepatic parenchymal transection is a technical priority in liver surgery. The use of an ultrasonic dissector for hepatectomy may result in less blood loss than conventional clamp crushing. DESIGN: Randomized controlled trial. SETTING: University teaching hospital. PATIENTS: The 132 patients scheduled to undergo partial hepatectomies were randomly assigned to receive hepatic transection by ultrasonic dissector or by clamp crushing (66 patients by each method). INTERVENTIONS: All resections were performed with inflow occlusion and were guided ultrasonographically. Hepatectomies were graded according to a predefined system based on 6 criteria (blood loss, transection time, technical error, surgical margin, landmark appearance, and postoperative morbidity), each with 3 scores (lower scores indicating higher quality). MAIN OUTCOME MEASURES: Blood loss and hepatectomy grade. RESULTS: No difference was found between the ultrasonic and clamp groups in median blood loss (515 mL [range, 15-2527 mL] vs 452 mL [range, 17-1912 mL]; P =.63), transection time (61 minutes [range, 16-177 minutes] vs 54 minutes [range, 7-205 minutes]; P =.58), or transection speed (1.1 cm(2)/min [range, 0.4-4.0 cm(2)/min] vs 1.0 cm(2)/min [range, 0.4-3.0 cm(2)/min]; P =.90). Ultrasonic dissection caused more frequent histologically proven tumor exposure at the surgical margin (9 vs 3 patients; P =.09), incomplete appearance of landmark hepatic veins on the cut surface after anatomical resection (12 vs 4 patients; P =.03), and postoperative morbidity (20 vs 14 patients; P =.32) than did clamp crushing. The hepatectomies with clamp crushing had significantly higher grades than those with ultrasonic dissection (P =.05), as indicated by the lower median sum score (4.0 [range, 0-12] vs 5.0 [range, 0-19]; 95% confidence interval for difference, -2.0 to 0; P =.03). The transection method independently influenced hepatectomy grade (adjusted odds ratio = 3.06; 95% confidence interval, 1.35-6.92; P =.01). CONCLUSIONS: Ultrasonic dissection offers no reduction in blood loss compared with clamp crushing for transection of the liver. Clamp crushing results in a higher quality of hepatectomy and is therefore the option of choice.

Adult↗

PubMed2001

Increase in the concentration of carbon 18 monounsaturated fatty acids in the liver with hepatitis C: analysis in transgenic mice and humans.

Steatosis is one of the histologic characteristics of chronic hepatitis C and is well reproduced in a transgenic mouse model for hepatocellular carcinoma (HCC) in which the core protein of hepatitis C virus (HCV) plays a pivotal role in inducing steatosis and HCC. In the present study, the lipid composition in the liver of the HCV core gene transgenic mice as well as in those of chronic hepatitis C patients was determined. The concentration of carbon 18 monounsaturated (C18:1) fatty acids, such as oleic and vaccenic acids, which are known to increase membrane fluidity leading to higher cell division rates, significantly increased in the livers of transgenic mice compared to nontransgenic control mice. The concentration of C18:1 fatty acids also significantly increased in the livers of chronic hepatitis C patients compared to subjects without HCV infection. These results suggest that HCV may affect a specific pathway in the lipid metabolism and cause steatosis in the liver.

Animals↗

PubMed2001

Reversible hepatofugal portal flow after liver transplantation using a small-for-size graft from a living donor.

We describe a case of reversible hepatofugal portal flow 1 week after transplantation of a small-for-size liver graft from a living donor. A transient increase in intrahepatic portal vascular resistance was the suspected cause. The portal venous flow normalized after residual collateral channels had been interrupted surgically. The patient was discharged on the 90th postoperative day. Liver transplant clinicians should be aware that hepatofugal flow can occur with small-for-size liver grafts, despite sufficient portal venous flow immediately after transplantation.

Female↗

PubMed2001

Potter type III cystic disease and pancreatic malignancies.

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Abnormalities, Multiple↗