Microsimulation Model for Evaluating the Cost-Effectiveness of Surveillance in BAP1 Pathogenic Variant Carriers.

PURPOSE: Pathogenic BAP1 germline variants cause a tumor-predisposition syndrome (BAP1-TPDS) linked to uveal melanoma, mesothelioma, cutaneous melanoma, and renal cell carcinoma. Surveillance of carriers of pathogenic BAP1 variants provides an opportunity for early tumor detection; however, there are no evidence-based guidelines for management of BAP1-TPDS, nor health economic evaluation; this study aims to provide this evidence. METHODS: We created a Markov microsimulation health state transition model of BAP1 germline carriers to predict if active surveillance for the four main tumors influences survival and improves associated economic costs with a time horizon of 100 years from the perspective of the healthcare system (N = 10,000). Model inputs were derived from data published by the BAP1 Interest Group Consortium and other studies. Management and healthcare costs were extracted from Australian costing schedules (final figures converted to US dollars [USD]), and outcomes compared for individuals receiving surveillance with those in a nonsurveillance arm. Robustness was evaluated on 10,000 iterations of a 100-sample random sampling of the model output. RESULTS: On average, surveillance of BAP1 carriers increased survival by 4.9 years at an additional cost of $6,197 USD for the healthcare system including surveillance costs ($1,265 USD per life year gained). The nonsurveillance arm had more diagnosed late tumors (62.8% v 10.7%) and a higher rate of BAP1-related deaths (50.2% v 35.4%; a 29.5% increase). The model was cost-effective under all sensitivity analyses. Our secondary robustness analysis estimated that 99.86% of 100-sample iterations were cost-effective and 19.67% of these were cost-saving. CONCLUSION: It is recommended that carriers of BAP1 germline variants are identified and undertake active surveillance, as this model suggests that this could improve survival and be cost-effective for the healthcare system.

The cost-effectiveness of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus: An economic evaluation using data from the DECLARE-TIMI 58 trial.

AIM: To undertake a cost-effectiveness analysis of dapagliflozin in treating high-risk patients with type 2 diabetes mellitus (T2DM), using both directly observed events in the DECLARE-TIMI 58 trial and surrogate risk factors to predict endpoints not captured within the trial. METHODS: An established T2DM model was adapted to integrate survival curves derived from the DECLARE-TIMI 58 trial, and extrapolated over a lifetime for all-cause mortality, hospitalization for heart failure, stroke, myocardial infarction, hospitalization for unstable angina, and end-stage kidney disease. The economic analysis considered the overall DECLARE trial population, as well as reported patient subgroups. Total and incremental costs, life-years and quality-adjusted life-years associated with dapagliflozin versus placebo were estimated from the perspective of the UK healthcare payer. RESULTS: In the UK setting, treatment with dapagliflozin compared to placebo was estimated to be dominant, with an expected increase in quality-adjusted life-years from 10.43 to 10.48 (+0.06) and a reduction in lifetime total costs from £39 451 to £36 899 (-£2552). Across all patient subgroups, dapagliflozin was estimated to be dominant, with the greatest absolute benefit in the prior heart failure subgroup (incremental lifetime costs -£4150 and quality-adjusted life-years +0.11). CONCLUSIONS: The results of this study demonstrate that dapagliflozin compared to placebo appears to be cost-effective, when considering evidence reported from the DECLARE-TIMI 58 trial, at established UK willingness-to-pay thresholds. The findings highlight the potential of dapagliflozin to have a meaningful impact in reducing the economic burden of T2DM and its associated complications across a broad T2DM population.

Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours.

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).

Tumour procurement, DNA extraction, coverage analysis and optimisation of mutation-detection algorithms for human melanoma genomes.

Whole genome sequencing (WGS) of cancer patients' tumours offers the most comprehensive method of identifying both novel and known clinically-actionable genomic targets. However, the practicalities of performing WGS on clinical samples are poorly defined.This study was designed to test sample preparation, sequencing specifications and bioinformatic algorithms for their effect on accuracy and cost-efficiency in a large WGS analysis of human melanoma samples.WGS was performed on melanoma cell lines (n = 15) and melanoma fresh frozen tumours (n = 222). The appropriate level of coverage and the optimal mutation detection algorithm for the project pipeline were determined.An incremental increase in sequencing coverage from 36X to 132X in melanoma tissue samples and 30X to 103X for cell lines only resulted in a small increase (1-2%) in the number of mutations detected, and the quality scores of the additional mutations indicated a low probability that the mutations were real. The results suggest that 60X coverage for melanoma tissue and 40X for melanoma cell lines empower the detection of 98-99% of informative single nucleotide variants (SNVs), a sensitivity level at which clinical decision making or landscape research projects can be carried out with a high degree of confidence in the results. Likewise the bioinformatic mutation analysis methodology strongly influenced the number and quality of SNVs detected. Detecting mutations in the blood genomes separate to the tumour genomes generated 41% more SNVs than if the blood and melanoma tissue genomes were analysed simultaneously. Therefore, simultaneous analysis should be employed on matched melanoma tissue and blood genomes to reduce errors in mutation detection.This study provided valuable insights into the accuracy of SNV with WGS at various coverage levels in human clinical cancer specimens. Additionally, we investigated the accuracy of the publicly available mutation detection algorithms to detect cancer specific SNVs which will aid researchers and clinicians in study design and implementation of WGS for the identification of somatic mutations in other cancers.

Efficacy and safety of angiotensin receptor blockade are not modified by aspirin in patients with chronic heart failure: a cohort study from the Candesartan in Heart failure--Assessment of Reduction in Mortality and morbidity (CHARM) programme.

AIMS: It is unknown whether there is an interaction between aspirin and angiotensin receptor blockers on outcomes in patients with heart failure (HF). METHODS AND RESULTS: The efficacy and safety of candesartan vs. placebo was assessed in 7599 patients with symptomatic HF and reduced or preserved left ventricular ejection fraction enrolled in the CHARM programme according to baseline aspirin use. Patients were randomized to candesartan or matching placebo and were followed for a median of 38 months. Aspirin was used in 4246 (55.9%) of patients at baseline. When compared with placebo, candesartan use was associated with lower event rates for cardiovascular (CV) death or HF hospitalization (primary outcome) in both the aspirin group (28 vs. 31.9%, HR 0.81, 95% CI 0.72-0.90) and non-aspirin group (33 vs. 38%, HR 0.81, 95% CI 0.72-0.91). Baseline aspirin use did not modify the effectiveness of candesartan in reducing the risk of CV death or HF hospitalization in CHARM overall (P = 0.64) or in the CHARM individual trials. In addition, there was no significant interaction between aspirin therapy and candesartan in terms of discontinuation of study drug due to adverse reactions (P = 0.72). CONCLUSION: There appears to be no significant modification of the benefit of candesartan on CV mortality and morbidity outcomes or safety by concomitant use of aspirin in patients with chronic HF.