In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6-month study (with an additional 6 months of follow-up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI-related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard-exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 ± 10.2 mL/minute; controls, 2.3 ± 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post-transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy-proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus-treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI-related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post-transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation. Liver Transpl 15:1262–1269, 2009. © 2009 AASLD.

Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination. The reversal of dysfunction occurs after washout for some, although not all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA sequencing and expression quantitative trait loci (eQTL) analysis identify specific pathways underlying β cell failure and recovery. Comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β cell lipoglucotoxicity show shared gene expression signatures. The identification of mechanisms associated with human β cell dysfunction and recovery and their overlap with T2D islet traits provide insights into T2D pathogenesis, fostering the development of improved β cell-targeted therapeutic strategies.

PURPOSE: To retrospectively evaluate the clinical outcome of patients with hepatocellular carcinoma (HCC) who exceeded the Milan criteria, who underwent transarterial chemoembolization (TACE) before orthotopic liver transplantation (OLT), to determine the value of computed tomography (CT)-based tumor response to TACE as a preoperative selection criterion for OLT.\ud \ud \ud \ud MATERIALS AND METHODS: The study included 33 patients with HCC who exceeded the Milan criteria and underwent OLT after TACE. Informed written consent was obtained before TACE and OLT. Institutional review board approval was not required. Tumor response to TACE was evaluated at 1 month with CT according to amended Response Evaluation Criteria in Solid Tumours (RECIST) guidelines. In the explanted liver, degree of tumor necrosis (> or = 90%, 50%-89%, or < 50%), residual tumor stage and grade, and presence of microvascular invasion were assessed. Follow-up after OLT ranged from 1 to 143 months.\ud \ud \ud \ud RESULTS: After TACE, CT showed complete tumor response (CR) in 18 (55%) patients. On the explanted liver, tumor necrosis was rated 90% or greater in 20 (61%) patients, with a good correlation with CT. Microvascular invasion was observed in nine (27%) of 33 patients; none of them were reported to have a CR at CT. The 5-year cumulative survival rate after OLT was 72.5%; it was significantly (P = .003) higher in patients with a CR (94.4%) compared with patients with a partial response (PR) (45.4%) and stable disease (50%). The 5-year cumulative recurrence-free rate after OLT was 74.4%; it was not affected by the tumor nodule size and number, whereas it was significantly (P = .008) higher in patients with a CR (94.4%) compared with patients with a PR (46.7%) and stable disease (50%).\ud \ud \ud \ud CONCLUSION: In patients with HCC who exceeded the Milan criteria, a CR after TACE, on the basis of amended RECIST guidelines, is associated with excellent posttransplantation outcomes. Therefore, 1-month response to TACE assessed at CT may represent a valid selection criterion for OLT