Glutathione S-Transferase T1 Mismatch Is a Risk Factor for Chronic Ductopenic Rejection of Liver Allografts.

The underlying causes of chronic rejection (CR) after liver transplantation (LT) are not completely known. The main aim of this study was to explore the involvement of the minor histocompatibility antigen glutathione S-transferase T1 (GSTT1) in CR. We retrospectively studied 611 patients who underwent LTs at University Hospital Virgen del Rocío between 2003 and 2016 with a median follow-up of 7.4 ± 4.2 years. The GSTT1 genotype was determined by polymerase chain reaction. We defined GSTT1 mismatch as a specific donor/recipient combination in which a recipient who was homozygous for the deletion allele received a transplant from a positive donor. The prevalence of CR in our whole cohort was 11.6% (71/611), and the prevalence in the GSTT1-mismatched group was 18.8% (16/85) versus 10.5% (55/526) in the GSTT1-matched group. In the cyclosporine A (CsA) group, the prevalence was 26.3% (26/99), much higher than the 8.8% (45/512) observed in the tacrolimus (Tac) group. For statistical analysis, the patients were distributed into 2 groups: group 1, regarded as GSTT1 mismatched, which included the donor (D)+/recipient (R)- allelic combination; and group 2, regarded as GSTT1 matched, which included the other allelic combinations of D+/R+, D-/R-, and D-/R+. All relevant clinical information was collected, and a diagnosis of CR was always confirmed by liver biopsy. GSTT1 mismatch (hazard ratio [HR], 1.99; 95% confidence interval [CI], 1.08-3.66; P = 0.03) and use of CsA/Tac (P < 0.001) were independent risk factors for CR. CR increased the risk of mortality (HR, 2; 95% CI, 1.2-3.6; P = 0.01). Out of the 71 CR patients, 12 (16.9%) needed retransplantation. In conclusion, the GSTT1 D+/R- allelic mismatch is an independent risk factor for CR. A long follow-up of LT patients is recommended because the incidence of CR in adults seems to be underestimated.

Impact of Early Initiated Everolimus on the Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

BACKGROUND: Many centers implement everolimus-based immunosuppression in liver transplant patients with hepatocellular carcinoma. We aimed to explore the potential impact of early initiated everolimus on tumor recurrence after liver transplantation. METHODS: This study included 192 patients with hepatocellular carcinoma undergoing liver transplantation among who 64 individuals were prospectively enrolled (2012-2015) and received early initiated everolimus (ie, started between postoperative day 15 to 21), whereas the remaining 128 patients acted as historical controls without everolimus. Propensity score matching was performed to ensure comparability. Multivariate Cox regression and competing risks analysis were used to control for potential confounders. RESULTS: Patients with and without everolimus were comparable in terms of number of nodules (P = 0.37), total tumor diameter (P = 0.44), Milan criteria fulfillment (P = 0.56), and histological differentiation (P = 0.61), but there were increased microvascular invasion rates in the everolimus group (26.5% vs 13.3%; P = 0.026). Tumor recurrence rates were similar with and without everolimus (10.9% vs 9.9% at 36 months respectively; P = 0.18). After controlling for microvascular invasion among other potential confounders, everolimus had no significant impact on tumor recurrence, neither in the multivariate Cox regression (relative risk = 3.23; P = 0.09), nor in the competing risks analysis for tumor recurrence-death (relative risk = 1.02; P = 0.94). Patients receiving everolimus had reduced tacrolimus trough concentrations and lower serum creatinine within the first 18 months postliver transplantation. CONCLUSION: Everolimus may not be universally prescribed to prevent tumor recurrence in liver transplant patients with hepatocellular carcinoma. Future randomized trials should be focused on patients with histological features of increased tumor aggressiveness, in whom the potential benefit would be higher.

Conversion from calcineurin inhibitors to mTOR inhibitors stabilizes diabetic and hypertensive nephropathy after liver transplant.

AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors (mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclosporine. METHODS: The study included 86 liver graft recipients immunosuppressed with mTORi treatment after orthotopic liver transplantation (OLT), including all liver recipients with worsening renal function before conversion to mTORi (n = 55 patients) and recipients with normal renal function who converted to mTORi for other reasons (n = 31 patients). We identified patients with diabetes mellitus (n = 28), arterial hypertension (n = 27), proteinuria (n = 27) and all three factors (n = 8) (some patients have hypertension and diabetes and no proteinuria). The primary endpoint was evolution in renal function defined as the development in plasma creatinine as a function of diabetes mellitus (DM), hypertension (HT) or proteinuria. We required elevated serum creatinine for at least two weeks to define renal dysfunction. RESULTS: Only patients that converted because of renal failure with plasma creatinine levels > 1.5 mg/dL showed an improvement of renal function (2.14 to 1.77 mg/dL) (P = 0.02). Patients with DM showed no improvement of serum creatinine levels (1.31 mg/dL to 1.37 mg/dL) compared with non DM patients (1.31 mg/dL to 1.15 mg/dL) (P = 0.01), HT patients (1.48 mg/dL to 1.5 mg/dL) with non HT patients (1.21mg/dL to 1.08 mg/dL) and patients with proteinuria (1.44 mg/dL to 1.41 mg/dL) and no proteinuria (1.31 mg/dL to 1.11 mg/dL). CONCLUSION: In OLT recipients with diabetes or hypertensive nephropathy, conversion to mTORi does not improve renal function but stabilizes plasma levels of creatinine. Proteinuria is not a contraindication to conversion to mTORi; it also stabilizes renal function. Conversion to mTORi should only be avoided in patients with diabetes, hypertension and proteinuria.

Improving outcomes in pancreatic cancer: key points in perioperative management.

This review focused in the perioperative management of patients with pancreatic cancer in order to improve the outcome of the disease. We consider that the most controversial points in pancreatic cancer management are jaundice management, vascular resection and neo-adjuvant therapy. Preoperative biliary drainage is recommended only in patients with severe jaundice, as it can lead to infectious cholangitis, pancreatitis and delay in resection, which can lead to tumor progression. The development of a phase III clinical trial is mandatory to clarify the role of neo-adjuvant radiochemotherapy in pancreatic adenocarcinoma. Venous resection does not adversely affect postoperative mortality and morbidity, therefore, the need for venous resection should not be a contraindication to surgical resection in selected patients. The data on arterial resection alone, or combined with vascular resection at the time of pancreatectomy are more heterogeneous, thus, patient age and comorbidity should be evaluated before a decision on operability is made. In patients undergoing R0 resection, arterial resection can also be performed.