Cancer is the leading cause of death after liver transplantation (LT). This multicenter case–control nested study aimed to evaluate the effect of maintenance immunosuppression on post‐LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus‐based immunosuppression. After 13 922 person/years follow‐up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post‐LT malignancy were older age (HR = 1.06 [95% CI 1.05–1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14–1.99]), smoking habit (HR = 1.96 [95% CI 1.42–2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19–1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression‐related predictor of post‐LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non‐melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT.
Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra-and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10 nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 mM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenibtreated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.
present our experience in liver transplantation in a series of 22 patients with unresectable bilateral hepatic metastases of neuroendocrine tumors and with previous resection of the primary tumor. Methods: We retrospectively reviewed the medical records of 22 patients (12 men and 10 women), with a mean age of 49,7 years, who underwent liver transplantation due to bilateral neuroendocrine liver metastases with previous resection of the primary tumour during 21 years. The most frequent location of the primary tumor was the pancreas in 13 patients (2 carcinoid, 3 gastrinoma, 1 glucagonoma and 8 non-functioning tumors). The remaining 9 tumors were located in the small bowel (7) and in the lung (2). Results: Only 1 patient died due to technical complications related to the transplant, representing a mortality rate for the entire group of 4,5 %. After a median follow-up of 11 years (range: 1 month-21 years), two patients died due to tumoral recurrence at 15 and 17 months. The survival rate at 3 and 5 years was 86% and 57%, respectively. Conclusions: In our series, the results the liver transplantation in the management of unresectable neuroendocrine liver metastases indicate that careful patient selection is required. The key to obtaining good results is individualization of the indication for this procedure.
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