High trough levels of everolimus combined to sorafenib improve patients survival after hepatocellular carcinoma recurrence in liver transplant recipients.

Recurrence of hepatocellular carcinoma (HCC) following liver transplantation (LT) occurs in 10%-20% of patients transplanted for HCC. The treatment of HCC recurrence after LT remains a challenge. Consecutive patients who underwent LT for HCC between 2005 and 2015 at our center were recruited. Characteristics of patients with recurrence, modalities of treatment and outcome were collected retrospectively. Patient survival was analyzed according to HCC recurrence therapeutic strategy. Among 306 transplanted patients, 43 patients (14.1%) developed recurrence with a median survival time after recurrence of 10.9 months (95%CI: 6.6-18.6). Survival of patients treated with Sorafenib (SOR) and everolimus (EVL) (n = 19) was significantly better than that of the group treated with other strategies (n = 24) (P = 0.001). Multivariable analysis demonstrated that SOR plus EVL therapy and absence of dissemination at diagnosis of recurrence were independent predictive factors of prolonged survival after recurrence. Among the patients who treated with EVL, survival of patients with controlled EVL blood trough levels ≥5 ng/ml was significantly better compared to those with EVL trough levels <5 ng/ml (P = 0.021). Combination therapy of sorafenib and everolimus was an independent predictor for better survival after HCC recurrence. Patients with controlled everolimus trough level ≥5 ng/ml might get the best survival benefit.

Common variants in the lipoprotein lipase gene, but not those in the insulin receptor substrate-1, the beta3-adrenergic receptor, and the intestinal fatty acid binding protein-2 genes, influence the lipid phenotypic expression in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a common, atherogenic lipid disorder characterized by a variable phenotypic expression of hyperlipidemia. Variations in genes regulating fatty acid metabolism must be considered in the search for factors affecting the lipid phenotypic expression of FCHL. Therefore, we have evaluated the association of the common variants in the lipoprotein lipase (LPL) (D9N, N291S, and S447X), insulin receptor substrate-1 (IRS-1) (G972R), fatty acid binding protein-2 (FABP-2) (A54T), and beta3-adrenergic receptor (beta3-AR) (W64R) genes with lipid and lipoprotein levels in 30 Italian FCHL families (195 individuals). The transmission disequilibriun test (TDT) was used to evaluate the association between these variants and the FCHL trait. No significant differences were observed in the frequencies of the common LPL variants between affected and nonaffected FCHL family members. A significantly lower frequency of the LPL447X allele was noted only when members of the FCHL families were compared with normolipemic controls (.06 v.142, respectively; P <.01) suggesting a reduced representation of this LPL variant in FCHL families. The frequencies of variants in the IRS-1, FABP-2, and beta3-AR genes were not significantly different between affected and nonaffected FCHL family members and normolipemic controls. The TDT did not demonstrate any significant association of these gene variants with the FCHL trait. FCHL individuals carrying the LPL N291S gene showed higher plasma lipids and apolipoprotein B (apoB) levels compared with affected noncarriers. Only a marginal effect of the LPL D9N and S447X variants on lipid levels in FCHL individuals was observed. Conversely, the variants in the IRS-1, FABP2, and beta3-AR genes did not show any major influence on lipid and lipoprotein levels in FCHL family members. In conclusion, these results confirmed that none of the investigated genes were major loci for FCHL. Nevertheless, variations in genes affecting the removal rate of triglycerides (TG) from plasma, such as the LPL gene, significantly influence the lipid phenotypic expression of FCHL. Conversely, genetic variants in the IRS-1, FABP-2, and the beta3-AR gene appear not to have a major role as modifier genes in FCHL.