Choon-Hyuck Kwon

Living-donor liver transplantation associated with higher incidence of hepatocellular carcinoma recurrence than deceased-donor liver transplantation.

Background Living-donor liver transplantation (LDLT) is becoming an important tool in hepatocellular carcinoma (HCC) treatment. However, the oncologic outcome between LDLT and deceased-donor LT (DDLT) for HCC remains controversial. This study aims to compare the HCC recurrence rates after LDLT versus DDLT. Methods Two hundred sixteen patients (166 LDLTs and 50 DDLTs) who underwent LT for HCC within University of California-San Francisco criteria were retrospectively reviewed. LDLT patients were divided into two groups: small living-donor graft (LDG; graft-to-recipient body weight ratio<1.0, n=59) and nonsmall LDG (graft-to-recipient body weight ratio≥1.0, n=107). Patients were further stratified into low- and high-risk settings by the number of risk factors for recurrence. Results The recurrence-free survival was lower in LDLT compared with DDLT (88.6% and 80.7% vs. 96.0% and 94.0% at 1 and 5 years; P=0.045). There was no significant difference between two groups regarding the majority of clinical and tumor characteristics, with the exception of a higher proportion of microvascular invasion presence in LDLT. After the adjustment for microvascular invasion, LDLT was identified as an independent risk factor for recurrence. Moreover, recurrence-free survival between small and nonsmall LDG was not statistically significant. In low-risk setting (⩽1 risk factor), LDLT showed comparable outcome with DDLT. However, the risk of recurrence was higher in LDLT than DDLT in high-risk patients. Conclusion In conclusion, LDLT showed poorer outcome than DDLT. This should be considered to select optimal strategy for HCC.

Effect of intermittent hepatic inflow occlusion with the Pringle maneuver during donor hepatectomy in adult living donor liver transplantation with right hemiliver grafts: A prospective, randomized controlled study

To evaluate the effects of intermittent hepatic inflow occlusion (IHIO) during donor hepatectomy for living donor liver transplantation (LDLT) in recipients and donors, we performed a single‐center, open‐label, prospective, parallel, randomized controlled study. Adult donor‐recipient pairs undergoing LDLT with right hemiliver grafts were randomized into IHIO and control groups (1:1). In the IHIO group, IHIO was performed during donor hepatectomy. The primary endpoint was the peak serum alanine aminotransferase (ALT) concentration in the recipients within 5 days after the operation. Blood samples for measurements of interleukin‐6 (IL‐6), IL‐8, tumor necrosis factor α (TNF‐α), and hepatocyte growth factor (HGF) were taken from the donors and the recipients during the operation and postoperatively. Biopsy samples for measurements of caspase‐3 and malondialdehyde (MDA) were taken from the donors and the recipients. In all, 50 donor‐recipient pairs (ie, 25 pairs in each group) completed this study. The mean peak serum ALT levels within 5 days after the operation did not differ in the recipients between the 2 groups (P = 0.32) but were higher in the donors of the IHIO group (P = 0.002). There were no differences in the prothrombin times or total bilirubin levels in the recipients or donors between the 2 groups. The amount of blood loss during donor hepatectomy was significantly lower in the IHIO group versus the control group (P = 0.02). The mean hospital stay for donors was 19.3 ± 7.2 days in the control group and 15.8 ± 4.6 days in the IHIO group (P = 0.046). There were no in‐hospital deaths within 1 month and no cases of primary nonfunction or initially poor function in the 2 groups. The concentrations of IL‐6, IL‐8, TNF‐α, and HGF did not differ between the 2 groups, nor did the concentrations of caspase‐3 and MDA. In conclusion, although we found differences in postoperative peak serum ALT levels in donors, donor hepatectomy with IHIO for LDLT using a right hemiliver graft with a graft‐to‐recipient body weight ratio > 0.9% and <30% steatosis can be a tolerable procedure for donors and recipients. Liver Transpl 18:130–138, 2012.

Intratumoral delivery of IL-18 naked DNA induces T-cell activation and Th1 response in a mouse hepatic cancer model

BackgroundThe novel cytokine, interleukin (IL)-18, is a strong interferon-γ inducer and costimulatory factor in Th1 cell activation. IL-18 triggers IFN-γ production and enhances cytolytic activity in both T and NK cells. However, the exact mechanism of antitumor action of IL-18 remains to be clarified. To determine the effects of IL-18 plasmid DNA on hepatic cancer in mice, CT26 murine colon adenocarcinoma cells were established in mouse liver.MethodsPlasmid vectors encoding IL-18 were transferred directly into the liver 7 days after tumor injection to restrict IL-18 expression within the tumor site. The IL-18 protein level was increased in the liver 4 days after plasmid injection, and a marked antitumoral effect was observed at day 7. Antitumor effects were evaluated by measuring tumor regression, immune cell population, and IFN-γ production.ResultsThe IL-18 plasmid controlled the growth of hepatic tumors and proliferation of splenic immune cells. Moreover, treatment of CT26 tumors with the IL-18 plasmid significantly enhanced the population of the effector T and NK cells in the spleen and peripheral blood. In spleen, the population of CD4+CD62Low cells was augmented in response to IL-18 on day 7. These results are consistent with the increase in CD4+ T cells secreting IFN-γ, but not CD8+ T cells. The marked reduction of tumor growth in tumor-bearing mice was associated with the maintenance of IFN-γ production in spleen in response to IL-18. These antitumoral effects were maintained until 14 days after plasmid injection.ConclusionOur results suggest that direct plasmid DNA transfer of IL-18 with no accompanying reagents to augment transfection efficiency may be useful in tumor immunotherapy.

Mycophenolate mofetil promotes down-regulation of expanded B cells and production of TNF-α in an experimental murine model of colitis

In this study, we used a murine intestinal inflammation model that mimics immunologic characteristics of human Crohns disease (CD) to investigate the anti-inflammatory effects of mycophenolate mofetil (MMF) on intestinal injury and tissue inflammation. When these colitic mice were pretreated with MMF, we observed a significant decrease in mortality rates and body weight loss as well as an improvement in both wasting and histopathologic signs of colonic inflammation, relative to untreated colitic mice. To determine the mechanisms of action of MMF, we compared various immunological characteristics of the untreated and MMF-pretreated colitic mice. MMF-pretreated colitic mice showed an 18% decrease in the proportion of CD19+ B cells compared with untreated colitic mice 3 days. As a result, MMF pretreatment increases proportion of apoptotic T and B cells, especially CD19+ B cells. Also, down-regulation of Th1 cytokines (TNF-alpha, IFN-gamma) and augmentation of CD4+CD45RB(low) regulatory T (Treg) cells were observed in MMF-pretreated colitic mice compared with untreated colitic mice. Furthermore, mycophenolic acid (MPA) reduced TNF-alpha-stimulated NF-kappaB activation in HT-29 colon epithelial cells. Also, MMF-pretreated colitic mice significantly reduced expression of MD-1 compared with untreated colitic mice on B cells and dendritic cells (DCs). These studies show that MMF pretreatment can improve experimental colitis by down-regulation of expanded B cells population through apoptosis and augmentation of Treg cells. Through these mechanisms, MMF might also be an effective agent for the treatment of other diseases characterized by mucosal inflammation.

Enhancement of the immunosuppressive effect of human adipose tissue-derived mesenchymal stromal cells through HLA-G1 expression

BACKGROUND AIMS Mesenchymal stromal cells (MSC) from several tissues have immunomodulatory properties that involve various immunosuppressive molecules. An example is human leukocyte antigen (HLA)-G, a non-classical major histocompatibility complex (MHC) class I molecule that induces tolerance via interactions with inhibitory receptors present on major immune effector cells. Recently, the molecular mechanisms that regulate MSC-mediated immunosuppression have come under investigation. Our goal was to determine whether HLA-G plays a crucial role in immunosuppression and whether human adipose tissure (hAT) MSC can be used as a tool for biologic immunosuppression with HLA-G in transplantation. METHODS MSC were characterized by fluorescence-activated cell sorting (FACS) analysis, reverse transcriptase (RT)-polymerase chain reaction (PCR) and staining for differentiation. The immunogenicity and immunomodulatory effects of MSC were monitored by peripheral blood mononuclear cell (PBMC) proliferation assay with or without phytohemagglutinin (PHA) stimulation. Stable expression of HLA-G1 in MSC was done using a lentiviral system. Results. MSC from different tissues had similar morphology, immunophenotypic characters and differentiation potential. We also found that the immunosuppressive effect of MSC was monitored along with their endogenous HLA-G mRNA and protein levels. Stable expression of HLA-G1 appeared to enhance the immunosuppressive effect of hAT MSC, and the function of HLA-G1 was significantly decreased by HLA-G antagonistic antibody in PBMC proliferation assays. CONCLUSIONS Although the HLA-G molecule is not the sole factor for MSC-mediated immunosuppression, our data provide evidence that HLA-G plays an important role in immunosuppression and that hAT MSC can be used as a tool for biologic immunosuppression during transplantation procedures.

Effect of nicotinamide on early graft failure following intraportal islet transplantation

Intraportal islet transplantation (IPIT) may potentially cure Type 1 diabetes mellitus; however, graft failure in the early post-transplantation period presents a major obstacle. In this study, we tested the ability of nicotinamide to prevent early islet destruction in a syngeneic mouse model. Mice (C57BL/6) with chemically-induced diabetes received intraportal transplants of syngeneic islet tissue in various doses. Islets were cultured for 24 h in medium with or without 10 mM nicotinamide supplementation. Following IPIT, islet function was confirmed by an intraperitoneal glucose tolerance test (IPGTT) and hepatectomy. The effects of nicotinamide were evaluated by blood glucose concentration, serum monocyte chemoattractant protein-1 (MCP-1) concentration, and immunohistology at 3 h and 24 h after IPIT. Among the various islet doses, an infusion of 300 syngeneic islets treated with nicotinamide exhibited the greatest differences in glucose tolerance between recipients of treated and untreated (i.e., control) islets. One day after 300 islet equivalent (IEQ) transplantation, islets treated with nicotinamide were better granulated than the untreated islets (P = 0.01), and the recipients displayed a slight decrease in serum MCP-1 concentration, as compared to controls. After 15 days, recipients of nicotinamide-pretreated islets showed higher levels of graft function (as measured by IPGTT) than controls. The pretreatment also prolonged graft survival (> 100 days) and function; these were confirmed by partial hepatectomy, which led to the recurrence of diabetes. Pretreatment of islet grafts with nicotinamide may prevent their deterioration on the early period following IPIT in a syngeneic mouse model.

Optimal Tailored Screening Protocol after Living Donor Liver Transplantation for Hepatocellular Carcinoma

The indication for hepatocellular carcinoma (HCC) is expanding in living donor liver transplantation (LDLT). Early detection and effective management of recurrence has become an important issue in LDLT for HCC. This study aimed to find an optimal screening protocol in terms of screening interval and screening tools by analyzing recurrence pattern after LDLT for HCC. A total of 205 LDLT patients in two centers from February 1999 to October 2010 was reviewed. Recurrence appeared in 55 cases. Six risk factors for recurrence were identified: preoperative alpha-fetoprotein >400, Edmonson grade 3 or 4, tumor size >7 cm, tumor number ≥7, minimal tumor necrosis in the transarterial chemoembolization group and positive micro-vascular invasion. Four groups with different ranges of index scores showed different recurrence-free survival and median time to recurrence. Group I showed low and late recurrence. Groups II and III showed linearly increased rate of recurrence until 18 months. Group IV showed very early recurrence within 6 months. Across the groups, extra-hepatic recurrence developed in more than 40% of cases and multi-organ recurrence rate was 20%. The screening interval should be different based on the risk of recurrence. Screening should include work-up for extra-hepatic recurrence as well as intra-hepatic recurrence. Graphical Abstract

Intraoperative abortion of adult living donor liver transplantation: 15 cases from 1,179 cases in 20 years of experience in a single center

Purpose This study aimed to report intraoperative abortion of adult living donor liver transplantation (LDLT). Methods From June 1997 to December 2016, 1,179 adult LDLT cases were performed. 15 cases (1.3%) of intraoperative abortions in LDLT were described. Results Among 15 cases, 5 intraoperative abortions were donor-related, and remaining 10 cases were recipient-related. All donor-related abortions were due to unexpected steatohepatitis. Among remaining 10 recipient-related intraoperative abortions, unexpected extension of hepatocellular carcinoma was related in 5 cases. Two cases of intraoperative abortions were related to bowel inflammation, and 2 cases were associated with severe adhesion related to previous treatment. One recipient with severe pulmonary hypertension was also aborted. Conclusion Complete prevention of aborted LDLT is still not feasible. In this regard, further efforts to minimize intraoperative abortion are required.

Immunosuppression status of liver transplant recipients with hepatitis C affects biopsy-proven acute rejection

Background/Aims The relationship between patient survival and biopsy-proven acute rejection (BPAR) in liver transplant recipients with hepatitis C remains unclear. The aims of this study were to compare the characteristics of patients with and without BPAR and to identify risk factors for BPAR. Methods We retrospectively reviewed the records of 169 HCV-RNA-positive patients who underwent LT at three centers. Results BPAR occurred in 39 (23.1%) of the HCV-RNA-positive recipients after LT. The 1-, 3-, and 5-year survival rates were 92.1%, 90.3%, and 88.5%, respectively, in patients without BPAR, and 75.7%, 63.4%, and 58.9% in patients with BPAR (P<0.001). Multivariate analyses showed that BPAR was associated with the non-use of basiliximab and tacrolimus and the use of cyclosporin in LT recipients with HCV RNA-positive. Conclusion The results of the present study suggest that the immunosuppression status of HCV-RNA-positive LT recipients should be carefully determined in order to prevent BPAR and to improve patient survival.

Different Etiologies and Prognostic Factors after Liver Transplantation for Fulminant Hepatic Failure in Korea: 1605

Background: Recently, much effort was put into improvement of the liver waiting list allocation system. Still obviously, none of the newly developed scores is significantly beneficent in compare to MELD score. The new LiMAx test might have a potential to improve the prediction of mortality by patients with liver cirrhosis. Methods: A prospective observational single center study has been conducted in our department. In the on-going study 400 patients with different stages of cirrhosis are to be included and followed at 6, 12 and 24 months. Standard clinical parameters, biochemical blood tests as well as the LiMAx test were performed by inclusion. The end points are: death or liver transplantation. T-test comparison between the groups, as well as a multivariate logistic Regression was performed. Results: Up to now 240 patients are included in the study. After excluding patients who became liver transplantation 148 and 96 patients reached 6 and 12 months follow up respectively. 54% of the patients suffer of alcohol cirrhosis, 20% was HCV positive. The Child-B stadium was observed in 41%, Child-C in 27% of cases. The 6 and 12 month mortality was 13.5 and 31.3% respectively. The patients who died at 6 and 12 month had significantly lower LiMAx value (91 and 99 μg/kg/h) than those who survived (132 and 147μg/kg/h, p=.008). LiMAx value, creatinineand sodium serum level were the only significant parameters in the multivariate regression analysis including also other laboratory parameters like total bilirubin or coagulation factors. Conclusions: The LiMAx test might predict a liver dependent death by patients with liver cirrhosis. Final results of the study are needed to estimate the exact value of LiMAx test in evaluation of patient with liver cirrhosis. 1605