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Objective: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial)., Summary and Background Data: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data., Patients and Methods: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence., Results: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245)., Conclusions: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients., Clinical Trial Registration: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.

Background: We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC)., Methods: In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint., Results: Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874)., Conclusions: Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Background: The authors studied the impact of neutrophil activation, detected in experimental models, on reperfusion injury in clinical renal transplantation., Methods: Forty-five patients from a larger trial comparing three immunosuppressive protocols were recruited: perioperative antithymocyte globulin (ATG) with low initial cyclosporine A (CsA) triple therapy (group A, n=15); two-dose basiliximab with low initial CsA triple therapy (group B, n=16); and conventional triple therapy (group C, n=14). Blood samples were obtained preoperatively, before reperfusion, and at 1 and 5 min after reperfusion. During reperfusion, samples were collected from the iliac artery and the graft vein for calculation of transrenal differences (Delta) of study parameters. Leukocyte differential counts, plasma lactoferrin concentration, and neutrophil CD11b and L-selectin expressions were assessed. Graft blood flow was measured at 2 and 30 min after reperfusion., Results: ATG induced neutrophil activation already before reperfusion. Thus, group A was excluded, but groups B and C were pooled for analysis of reperfusion-induced neutrophil activation. At 1 min after reperfusion, lactoferrin concentration was higher in graft vein than iliac artery, yielding Delta=15 microg/L (P<0.05). Concomitantly, Delta neutrophil count correlated with both Delta L-selectin expression (R=0.49, P=0.012) and graft blood flow at 2 min (R=0.51, P=0.007). At 5 min after reperfusion, 0.17 (-1.0-0.24)x10 cells/L neutrophils were sequestered in the graft (P<0.001). This sequestration correlated with graft blood flow at 30 min (R=0.53, P=0.005) and was stronger in patients with delayed graft function (DGF) (Delta = -0.38 [-1.45 to -0.2]) than those without (Delta = -0.12 [-0.41-0.24], P<0.001). In multiple regression analysis, sequestration was the most important parameter associated with DGF., Conclusions: Neutrophils are activated and sequestered in the reperfused graft during clinical renal transplantation. Neutrophil sequestration is a powerful independent factor explaining the incidence of DGF.