No abstract

Objective Liver is the major organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or as bile acids. Intracellular hydrolysis of lipoprotein-derived cholesteryl esters (CE) is essential to generate the free cholesterol (FC) required for this process. We earlier demonstrated that over-expression of human cholesteryl ester hydrolase (Gene symbol CES1) increased bile acid synthesis in human hepatocytes and enhanced reverse cholesterol transport in mice. The objective of the present study was to demonstrate that liver-specific deletion of its murine ortholog, Ces3, would decrease cholesterol elimination from the body and increase atherosclerosis. Approach and Results Liver-specific Ces3 knockout mice (Ces3-LKO) were generated and Ces3 deficiency did not affect the expression of genes involved in cholesterol homeostasis and FC or bile acid transport. The effects of Ces3 deficiency on the development of Western diet-induced atherosclerosis were examined in LDLR-/- mice. Despite similar plasma lipoprotein profiles, there was increased lesion development in LDLR-/-Ces3-LKO mice along with a significant decrease in bile acids content of the bile. Ces3 deficiency significantly reduced the flux of cholesterol from [3H]-CE labeled HDL to feces (as FC and bile acids) and decreased total fecal sterol elimination. Conclusions Our results demonstrate that hepatic Ces3 modulates the hydrolysis of lipoprotein-delivered CE and thereby regulates FC and bile acid secretion into the feces. Its deficiency, therefore, results in reduced cholesterol elimination from the body leading to significant increase in atherosclerosis. Collectively, these data establish the anti-atherogenic role of hepatic CE hydrolysis.

PURPOSE: The recent sorafenib versus radioembolization in advanced hepatocellular carcinoma (SARAH) and selective internal radiation therapy versus sorafenib in locally advanced hepatocellular carcinoma (SIRveNIB) trials showed no statistically significant difference in overall survival for randomization to selective internal radiotherapy (SIRT) versus sorafenib for locally advanced hepatocellular carcinoma, although SIRT was better tolerated. Given the high cost of both treatments, we investigated their comparative cost-effectiveness from a US healthcare sector perspective. PATIENTS AND METHODS: We constructed a state-transition microsimulation model to simulate patients allocated to SIRT versus sorafenib according to an intention-to-treat principle. Hazard rates of disease progression and death were based on pooled individual patient data generated from the SARAH and SIRveNIB trials’ Kaplan-Meier curves. Inputs for adverse events, treatment adherence, and quality of life utility weights were derived from trial data as well. Costs were based on Medicare reimbursement rates and literature. We performed probabilistic sensitivity analysis and estimated costs and quality-adjusted life years (QALYs) over a 5-year time horizon. We evaluated sensitivity to uncertainty of key model parameters. RESULTS: Costs were $78,859 v $58,397 (difference $20,462; 95% uncertainty interval $14,444 to 27,205) and QALYs were 0.88 v 0.87 (difference 0.02, −0.02 to 0.05) for sorafenib versus SIRT, respectively. The incremental cost-effectiveness ratio (ICER) of sorafenib was $1,280,224/QALY. The likelihood that sorafenib would be cost effective did not exceed 1%, assuming cost-effectiveness thresholds up to $200k/QALY. If the monthly price of sorafenib decreased from $16,390 to below $7,000, the ICER of sorafenib fell below $200k/QALY, and an ICER < $100k/QALY was reached if the monthly price fell below $6,600. CONCLUSION: Sorafenib is unlikely to provide a gain in quality-adjusted survival compared with SIRT at an acceptable cost for the US healthcare sector. Only if the current price decreased by more than 50% would sorafenib be considered economically attractive.

IMPORTANCE Prostate cancer is the most common malignant neoplasm among men and is the one with the highest positive surgical margin (PSM) rate. This high rate is due to the difficulty in balancing the risk of extraprostatic disease and excising periprostatic structures, which ultimately affects patients' quality of life. In the case of a PSM, the appropriateness of adjuvant radiation therapy (aRT) should be discussed. The financial burden of PSMs on health systems has not been investigated. OBJECTIVE To estimate the financial costs associated with a PSM during radical prostatectomy on the basis of the odds of undergoing aRT.