Blood Salvage and Autotransfusion With Single Leukoreduction Does Not Increase the Risk of Tumor Recurrence After Liver Transplantation for Advanced Hepatocellular Carcinoma.

OBJECTIVE: The aim of this study was to determine whether autotransfusion of salvaged blood with single leukoreduction is associated with post-transplant tumor recurrence in patients with advanced hepatocellular carcinoma (HCC). BACKGROUND: Previous studies have consistently demonstrated the safety of autotransfusion of salvaged and leukoreduced blood during liver transplantation for HCC. However, the effects of this technique remained unknown for advanced HCC. METHODS: Of 349 patients who underwent living donor liver transplantation for advanced HCC: 74 of 129 without autotransfusion were matched with 74 of 220 with autotransfusion using propensity score based on tumor biology, allogeneic transfusion, and others. Survival analysis was performed with death as a competing risk event. The primary outcome was HCC recurrence. RESULTS: Recipients in autotransfusion group received 811 (497-1247) mL of salvaged blood with single leukoreduction. In the matched cohort, cumulative overall recurrence probability at 1/2/5 years after transplantation was 24.6%/ 38.3%/39.7% for nonautotransfusion group and 16.2%/23.1%/32.5% for autotransfusion group. There were no significant differences between the 2 groups in overall recurrence [hazard ratio (HR) = 0.72 (0.43-1.21)], intrahepatic recurrence [HR = 0.70 (0.35-1.40)], and extrahepatic recurrence [HR = 0.82 (0.46-1.47)]. Also, there were no significant differences in overall death [HR = 0.57 (0.29-1.12)], HCC-related death [HR = 0.59 (0.29-1.20)], and HCC-unrelated death [HR = 0.48 (0.09-2.65)]. CONCLUSIONS: When allogeneic transfusion was matched, autotransfusion was not significantly related to HCC recurrence, with more favorable probabilities for autotransfusion, in patients with advanced HCC. Thus, blood salvage and autotransfusion could be safely used with single leukoreduction, without double-filtered leukoreduction, during liver transplantation for HCC with potential benefits from avoiding allogeneic red blood cell transfusion.

Safety of the Use of Blood Salvage and Autotransfusion During Liver Transplantation for Hepatocellular Carcinoma.

OBJECTIVE: To determine whether autotransfusion of red blood cells (RBCs) salvaged during liver transplantation is associated with the recurrence of hepatocellular carcinoma (HCC). BACKGROUND: Blood salvage is widely used during liver transplantation to reinfuse salvaged autologous RBCs and reduce allogeneic transfusion. However, the reintroduction of cancer cells via autotransfusion is a major concern in HCC patients. METHODS: Among 397 patients who underwent living-donor liver transplantation for HCC, 97 of 114 recipients without intraoperative autotransfusion were matched with 222 of 283 recipients with intraoperative autotransfusion with unfixed matching ratio using the propensity score based on age, sex, allogeneic transfusion, immunosuppression, tumor biology, and others. Competing risks Cox regression was used to compare HCC recurrence risk of the 2 paired groups. RESULTS: Recipients in autotransfusion group received 1177 ±â€Š1318 mL of salvaged RBCs during surgery. A leukocyte depletion filter was used for all autotransfused RBCs. Cumulative HCC recurrence rate at 1, 2, and 5 years after transplantation were 10.4% (5.3%-17.6%), 19.1% (11.6%-28.0%), and 24.1% (15.2%-34.0%) for nonautotransfusion group and 10.8% (7.2%-15.4%), 14.9% (10.5%-20.0%), and 20.3% (14.9%-26.4%) for autotransfusion group, respectively. Autotransfusion versus nonautotransfusion group was not significantly different in overall recurrence [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.47-1.53, P = 0.579] and intrahepatic recurrence (HR 0.75, 95% CI 0.36-1.56) or extrahepatic recurrence (HR 1.00, 95% CI 0.49-2.04). CONCLUSIONS: We found no evidence of a significant impact of autotransfusion on posttransplant HCC recurrence. Thus, salvaged and filtered RBCs could be used in HCC patients undergoing liver transplantation with potential benefits from avoiding allogeneic RBCs transfusion and its complications.

Actionable gene expression-based patient stratification for molecular targeted therapy in hepatocellular carcinoma.

BACKGROUND: The effectiveness of molecular targeted agents is modest in hepatocellular carcinoma (HCC). Efficacy of molecular targeted therapies has been better in cancer patients with high expression of actionable molecules defined as cognate target molecules. However, patient stratification based on the actionable molecules dictating the effectiveness of targeted drugs has remained understudied in HCC. EXPERIMENTAL DESIGN & RESULTS: Paired tumor and non-tumoral tissues derived from a total of 130 HCC patients were studied. Real-time RT-PCR was used to analyze the mRNA expression of actionable molecules in the tissues. mRNA levels of EGFR, VEGFR2, PDGFRß, FGFR1, and mTOR were up-regulated in tumors compared to non-tumors in 35.4, 42.3, 61.5, 24.6, and 50.0% of patients, respectively. Up-regulation of EGFR was observed at early stage and tended to gradually decrease toward late stages (BCLC stage A: 41.9%; B: 30.8%; C: 17.6%). Frequency of VEGFR2 expression in tumors at stage C was lower than that in the other stages (BCLC stage A: 45.9%; B: 41.0%; C: 29.4%). PDGFRß and mTOR were observed to be up-regulated in more than 50% of tumors in all the stages whereas FGFR1 was up-regulated in only about 20% of HCC irrespective of stages. A cluster analysis of actionable gene expression revealed that HCC can be categorized into different subtypes that predict the effectiveness of molecular targeted agents and combination therapies in clinical trials. Analysis of in vitro sensitivity to sorafenib demonstrated that HCC cells with up-regulation of PDGFRß and c-Raf mRNA are more susceptible to sorafenib treatment in a dose and time-dependent manner than cells with low expression of the genes. CONCLUSIONS: mRNA expression analysis of actionable molecules could provide the rationale for new companion diagnostics-based therapeutic strategies in the treatment of HCC.

The different etiology of fulminant hepatic failure (FHF) in Korea and prognostic factors in patients undergoing liver transplantation for FHF.

BACKGROUND: The prognosis of fulminant hepatic failure (FHF) depends on the etiology and reversibility. In this study, we identified the etiological difference of FHF in Korea and analyzed the prognostic factors after liver transplantation (LT) for FHF. METHODS: We retrospectively reviewed 42 patients with FHF who underwent LT from April 1999 to April 2011 at Samsung Medical Center, Seoul, Korea. The patients were categorized into two groups according to the short-term result of LT, and perioperative profiles were compared to identify the short-term poor prognostic factors. RESULTS: Unlike Western countries, there was no paracetamol-related FHF but herbal/folk medicines were the most frequent causes of FHF (26.2%). HAV-related FHF increased significantly and comprised the main portion of FHF with Herbal/folk medicines after 2005. Encephalopathy grade, onset time, pre-transplantation need of renal replacement, and ventilator treatment were significantly different between groups in univariate analysis. In multivariate analysis, pre-transplantation renal replacement treatment and hepatic encephalopathy grade IV were the independent prognostic factors after LT. CONCLUSIONS: The etiologies of FHF in Korea were different compared with Western reports. The requirement of renal replacement treatment and hepatic encephalopathy grade IV were identified as independent poor prognostic factors after LT for FHF in this study.

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.

Hepatocyte transplantation for glycogen storage disease type Ib.

Glycogen storage disease type I (GSD-I) is a group of autosomal recessive disorders with an incidence of 1 in 100,000. The two major subtypes are GSD-Ia, caused by a deficiency of glucose-6-phosphatase (G6Pase), and GSD-Ib, caused by a deficiency of glucose-6-phosphate transporter (G6PT). We report that a substantial improvement was achieved following several infusions of hepatocytes in a patient with GSD-Ib. Hepatocytes were isolated from the unused cadaveric whole livers of two donors. At the first transplantation, approximately 2 x 10(9) cells (2% of the estimated recipient's total hepatocytes) were infused. Seven days later 1 x 10(9) (1% of liver mass) cryopreserved hepatocytes from the same donor were infused, and an additional 3 x 10(9) (3% of liver mass) cells from the second donor were infused 1 month after the second transplantation. After the hepatocyte transplantation, the patient showed no hypoglycemic symptoms despite the discontinuation of cornstarch meals. Liver biopsies on posttransplantation days 20 and 250 showed a normal level of glucose-6-phosphatase activity in presolubilization assay that was very low before transplantation. This was the first and successful clinical hepatocyte transplantation in Korea. In this study, hepatocyte transplantation allowed a normal diet in a patient with GSD-Ib, with substantial improvement in their quality of life. Hepatocyte transplantation might be an alternative to liver transplantation and dietary therapy in GSD-Ib.