Retrospective analysis of LTx pts receiving de novo ADVAGRAF (ADV; n=505) or tacrolimus immediate release (BD; n=4299) in the ELTR over 3 years. Factors influencing graft/pt survival were identified using uni- and multivariate regression (p<0.05). Differences between ADV/Tac BD were assessed by KM analysis. Comparable baseline demographics. Overall graft/pt survival: 73% and 77%. Univariate analysis identified non-ADV as a significant risk factor for poor graft/pt survival (p=0.0004, p=0.006). Significance was confirmed by multivariate analysis for graft survival (table). KM analysis demonstrated significantly improved graft/pt survival with ADV vs Tac BD over 3 years (graft: 82% vs 73%, p=0.0004; pt: 83% vs 76%, p=0.006).Table: No Caption available.A large observational study from the ELTR identified significant improvements in graft/pt survival with ADV vs Tac BD in de novo LTx over 3 years. DISCLOSURES:Adam, R.: Other, Astellas, Astellas supports ELTR. Karam, V.: Other, Astellas, Astellas supports ELTR. Delvart, V.: Other, Astellas, Astellas supports ELTR. Trunecka, P.: Other, Astellas, Advisory boards & received consultancy agreements, Pfizer, Speaker honorarium. Samuel, D.: Other, Astellas, Consultant fees and Astellas supports ELTR, Novartis, Consultant fees, Roche, Consultant fees. Bechstein, W.: Other, Astellas, Honoraria and served on advisory boards. Klempnauer, J.: Other, Astellas, Support, Novartis, Support, Roche, Support, Genzyme, Support, BMS, Support. Colledan, M.: Other, Novartis, Honorarium for advisory board. Muiesan, P.: Other, Novartis, One off honorarium for participating at ad board.

Crigler-Najjar syndrome type I (CNS) is caused by a deficiency of uridine diphosphate glucuronosyltransferase. Patients are at risk of fatal brain injury due to unconjugated hyperbilirubinemia. Treatment consists of 10 - 12h phototherapy daily. Most patients undergo liver transplantation as phototherapy becomes less effective and constitutes a significant impairment in quality of life. A 13-year-old boy and an 11-year-old girl with CNS were evaluated at our center. Both patients required 8 - 12h of phototherapy daily to maintain s-bilirubin below 450 μmol/liter. Hepatocytes were isolated under good manufacturing practices from liver tissue obtained from deceased organ donors. Fresh ABO compatible hepatocytes were infused through a portal catheter. Before infusion patients underwent liver resection of segments 2 and 3 to induce liver regeneration and proliferation of transplanted hepatocytes. Immunosuppression consisted of basiliximab, tacrolimus and steroids. The girl received 5.3 x 109 viable hepatocytes at one occasion and the boy received two infusions from different donors three months apart with 2.2 and 9 x 109 viable hepatocytes. In both patients s-bilirubin increased initially after the first procedure. Thereafter s-bilirubin decreased continuously in both patients to 50% of pre-transplant levels for more than 6 months. Bile analysis showed presence of bilirubin diglucuronides in both patients after transplantation. The boy experienced a sudden increase of serum bilirubin to pre-transplant levels 6 months after the first infusion associated with a severe scabies infection. Despite intensified phototherapy s-bilirubin did not improve. Due to the scabies infection and an incorrect assumption that the cells were rejected immunosuppression was stopped. After cessation of immunosuppressive therapy the patient presented with fever, abdominal pain and elevated transaminases followed by increasing high-level donor specific antibodies indicating viable hepatocytes at time of cessation. These studies confirm that hepatocyte transplantation can be a useful treatment for CNS. Preconditioning patients with liver resection prior to cell transplantation is safe and might improve donor hepatocyte engraftment. To our knowledge this is the first report of antibody-mediated rejection in clinical hepatocyte transplantation.

Background: The DLTR was created in 1999. It holds data on recipients of explanted metabolically disturbed livers. Results: By Dec 2012, 1085 domino liver transplantations (DLT) in 1065 patients were reported from 62 hospitals in 21 countries. Male/female ratio is 74% and 26%, respectively, with a mean recipient age at time of transplantation of 55.5±9.2 yrs (range 1.9 - 73.9 yrs, median 56.7 yrs). Overall, the frequency of retransplantation in DLT recipients was 7%. The vast majority of livers used for DLT come from familial transthyretin amyloidotic (FAP) afflicted donors (99%), but there is also the use of livers with metabolic disorders such as Hyperoxalosis, Maple Syrup Urine Disease and Hypercholesterolemia. Altogether, main diagnoses in DLT recipients were HCC (39%), alcoholic cirrhosis (20%) and HCV (16%), but in the last 5-year period HCV decreased to 12% while alcoholic cirrhosis increased to 26%. The percentage of HCC remains the same. Survival was similar in FAP liver donors and non-donor FAP patients. In the whole material, DLT recipients with malignancy had inferior survival compared to non-malignant recipients, a difference that disappeared when analyzing the last 5 years. Tumor recurrence and septicemia caused the majority of deaths (39%). Surprisingly, significantly better graft survival was seen in recipients of non-Val30Met mutated livers compared to Val30Met mutated livers (5-yr survival 73% and 66%, respectively, p<0.05). The DLTR contains eight patients retransplanted 7-11 years after DLT because of FAP symptoms. Conclusion: By careful recipient selection and done by experienced teams DLT is of value and can significantly contribute in relieving organ shortage. Short-term outcome in DLT recipients is excellent. Long-term survival must also be deemed good bearing in mind the dismal prognosis in these patients without transplantation. The comparable survival in DLT recipients with and without malignancies in recent years may be due to better DLT recipient selection criteria. The risk of transmitting de novo amyloidosis with the grafted liver is real and cannot be neglected. This report is presented on behalf of all reporting members of the DLTR.

Aim of the study Hepatobiliary scintigraphy can detect post-liver transplantation (LTx) structural complications and provide information of graft function. Hepatic extraction fraction (HEF) is a measurement of the hepatic extraction efficiency and hepatic extraction rate. In this study, we compared the HEF with biochemical and histological parameters between the LTx patients receiving cyclosporin A (CSA) or tacrolimus (TAC). Methods Thirty-nine adult patients who underwent LTx due to HCV cirrhosis between March 2007 and May 2011 were evaluated. All patients underwent a three-month follow-up that included hepatobiliary scintigraphy and blood biochemistry tests (s-bilirubin, ALT, AST, ALP, and gamma-GT). The same tests were repeated at the one-year follow-up; in addition s-creatinine, Iohexol clearance and a liver biopsy were performed. These clinical parameters were compared between the two groups, TAC (n=15), and CSA (n=24). Results The average HEF was significantly lower in the CSA group compared to the TAC group both at 3-month and 1-year after transplantation (p<0.001). The liver biochemistry tests, average donor and recipient age, average cold ischemia time, and Iohexol clearance were comparable between the two groups. Histology showed that the TAC group had more inflammation than the CSA group. Moreover, three patients who converted from CSA to TAC for liver unrelated side effects between 3.7 and 6.3 months postoperatively all increased their HEF values (27 to 90%, 42 to 100%, and 13 to 26%). Conclusion CSA treated patients presented a lower HEF value on hepatobiliary scintigraphy in spite of comparable liver function by traditional measurements indicating a false decrease on HEF values by CSA. Our finding has significant clinical implications as it indicates that the assessment of the liver graft function may be misled due to the falsely low HEF values in CSA treated patients with otherwise good liver function.

CTL are crucial in the defense against viral infections. In the course of investigating peripheral blood and intrahepatic CD8 T cells in patients with chronic hepatitis C virus (HCV) infection, we observed a significant population of CD8 T cells expressing the FcγRIIIA (CD16) receptor. This observation led us to characterize these cells with respect to their phenotype and function in a cohort of patients with chronic HCV infection as well as in healthy blood donors. On average, 10% of peripheral blood CD8 T cells from HCV-infected patients expressed CD16 compared with only a few percent in healthy donors. CD16+ CD8 T cells displayed a late-stage effector phenotype with high levels of perforin. These cells exhibited a restricted TCR profile suggesting underlying clonal expansion. Stimulation of CD16 on CD8 T cells evoked a vigorous response similar to that of CD16 stimulation in NK cells. Our data suggest that CD8 T cells, during chronic HCV infection in humans, continue to differentiate beyond defined stages of terminal effector cells, acquiring CD16 and NK cell-like functional properties.

From September 1990 to January 1992, 545 liver transplant patients were randomised to treatment with either FK506 and prednisolone or a conventional cyclosporin-based immunosuppressive regimen (CBIR). Eight European centres participated in the study. Adverse events were reported as defined by each centre. Hyperglycaemia was reported as an adverse event in 30.7% of patients receiving FK 506 compared with 20.5% in the CBIR group (P < 0.01). Diabetes mellitus was reported in 17.2% of patients treated with FK 506 and 9.5% of CBIR-treated patients (P < 0.05). Treatment with insulin was required in 12.0% of patients in the DK 506 treatment group and in 5% in the CBIR group at 6 months. Initially, higher doses of FK 506 were used. During the study, the protocol was changed to allow a lower dose of FK 506. When the early and late cohorts of patients were compared, the incidence of diabetes mellitus fell from 23.9% to 10.5% in FK 506-treated patients but remained relatively constant in the CBIR group (10.4% to 8.7%). The median cumulative doses of i.v. and p.o. corticosteroids were significantly greater in the CBIR group. Thus, in the overall series, the incidence of diabetes mellitus was significantly greater in the FK 506 group as compared with the CBIR group. However, when a lower FK 506 dose was used during the second half of the study, the difference in the incidence of diabetes mellitus disappeared.

Studies in the USA and Japan have shown that tacrolimus (FK506) is a potent immunosuppressant. To compare the efficacy and safety of tacrolimus-based and conventional cyclosporin-based immunosuppressive regimens we recruited 545 liver transplant recipients from eight European centres into a randomised open trial.Analysis of the data at 12 months post-transplant showed that tacrolimus was associated with a significant reduction in acute, refractory acute, and chronic rejection episodes. The rates were, for acute rejection, tacrolimus 40.5% vs 49.8% cyclosporin (p=0.040; absolute difference 9.3% [95% Cl 0.9-17.8%]). For refractory acute and chronic rejections the comparisons were 0.8% vs 5.3% (p=0.005) and 1.5% vs 5.3% (p=0.032). These results were seen despite significantly lower corticosteroid usage. The incidence of infection was also lower in patients receiving tacrolimus. Patient and graft survival rates were not significantly different (tacrolimus 82.9% and 77.5%; cyclosporin 77.5% and 72.6%).Safety data were comparable-the most serious events being renal impairment, disturbances of glucose metabolism, and neurological complications-but these events were more common in the tacrolimus group. In this trial tacrolimus had advantages over cyclosporin in respect of lower rejection rates, even though less concurrent immunosuppression was administered.