A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma

Peer reviewe

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma : A Randomized, Multicenter, Open-Label Phase 3 Trial

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.Peer reviewe

Abdominal Wall Morbidity Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Background: Incisional hernia formation has been reported as high as 20% within 1 year following midline laparotomy. Since hyperthermic intraperitoneal chemotherapy is likely to impair wound healing, we sought to investigate the incidence of incisional hernia formation and abdominal wall rupture following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Methods: Consecutive patients with radiographic evidence of peritoneal metastases were scheduled for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at the Comprehensive Cancer Center, University Hospital Tuebingen, Germany. Clinical data were retrospectively analyzed. Results: Between May 2005 and May 2014, 271 patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Within follow-up, 19 (7%) incisional hernias and 11 (4%) abdominal wall ruptures were observed. Age ⩾70 years, cardio-pulmonary comorbidity, the presence of pseudomyxoma peritonei or mesothelioma, and postoperative abdominal wall rupture were detected as risk factors for hernia formation. However, Cox multivariate analysis only confirmed the presence of pseudomyxoma peritonei or mesothelioma and postoperative abdominal wall rupture as independent risk factors. Conclusion: Our data do not suggest that cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is necessarily associated with a higher incidence of incisional hernia formation. However, patients suffering from pseudomyxoma peritonei or mesothelioma and patients with postoperative abdominal wall rupture seem to be at risk for developing incisional herniation. </jats:sec

Glucose-raising polymorphisms in the human clock gene Cryptochrome 2 (<em>CRY2</em>) affect hepatic lipid content.

Circadian rhythms govern vital functions. Their disruption provokes metabolic imbalance favouring obesity and type-2 diabetes. The aim of the study was to assess the role of clock genes in human prediabetes. To this end, genotype-phenotype associations of 121 common single nucleotide polymorphisms (SNPs) tagging ARNTL, ARNTL2, CLOCK, CRY1, CRY2, PER1, PER2, PER3, and TIMELESS were assessed in a study population of 1,715 non-diabetic individuals metabolically phenotyped by 5-point oral glucose tolerance tests. In subgroups, hyperinsulinaemic-euglycaemic clamps, intravenous glucose tolerance tests, and magnetic resonance imaging/spectroscopy were performed. None of the tested SNPs was associated with body fat content, insulin sensitivity, or insulin secretion. Four CRY2 SNPs were associated with fasting glycaemia, as reported earlier. Importantly, carriers of these SNPs&#39; minor alleles revealed elevated fasting glycaemia and, concomitantly, reduced liver fat content. In human liver tissue samples, CRY2 mRNA expression was directly associated with hepatic triglyceride content. Our data may point to CRY2 as a novel switch in hepatic fuel metabolism promoting triglyceride storage and, concomitantly, limiting glucose production. The anti-steatotic effects of the glucose-raising CRY2 alleles may explain why these alleles do not increase type-2 diabetes risk