GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma

Summary: Uveal melanoma (UM) is characterized by mutually exclusive activating mutations in GNAQ, GNA11, CYSLTR2, and PLCB4, four genes in a linear pathway to activation of PLCβ in almost all tumors and loss of BAP1 in the aggressive subset. We generated mice with melanocyte-specific expression of GNA11Q209L with and without homozygous Bap1 loss. The GNA11Q209L mice recapitulated human Gq-associated melanomas, and they developed pigmented neoplastic lesions from melanocytes of the skin and non-cutaneous organs, including the eye and leptomeninges, as well as at atypical sites, including the lymph nodes and lungs. The addition of Bap1 loss increased tumor proliferation and cutaneous melanoma size. Integrative transcriptome analysis of human and murine melanomas identified RasGRP3 to be specifically expressed in GNAQ/GNA11-driven melanomas. In human UM cell lines and murine models, RasGRP3 is specifically required for GNAQ/GNA11-driven Ras activation and tumorigenesis. This implicates RasGRP3 as a critical node and a potential target in UM. : Moore et al. generate a preclinical mouse model of melanoma that recapitulates features of aggressive uveal melanoma. By comparing murine and human melanomas, they identify a dependency on RasGRP3 in uveal melanoma. Keywords: uveal melanoma, RASGRP3, BAP1, GNAQ, GNA11, genetically engineered mouse model, melanoma, BRAF, leptomeningeal melanocytom

Trials of providing information to general practitioners: a systematic review

ObjectiveTo determine if providing general practitioners (GPs) with costing information can change their clinical behaviour and reduce medical costs.Data sourcesMEDLINE, CINAHL, Health Plan and EMBASE and citations in review articles were searched for studies published between 1980 and 1996.Study selectionStudies were included if they provided costing information to GPs with the aim of decreasing costs by changing behaviour, included an objective measure of GP performance or clinical care, and used a randomised or quasi-randomised controlled design, crossover design or a controlled time series.Data extractionData extracted included study design, intervention used and measure of GP performance/clinical care (including test ordering, drug prescribing, hospital and primary care visits and costs).Data synthesisSix studies met the inclusion criteria. Computerised feedback on drug costs increased generic prescribing, and "academic detailing" decreased inappropriate prescribing of target drugs. Providing costing information also decreased ordering of diagnostic tests. "Gatekeeper" physicians reduced use of hospital and specialist services. Only two studies found the changes were sustained for nine months or longer and only one evaluated health outcomes.ConclusionThe provision of costing information can change GP behaviour in all service areas. Sustainability of these changes and linking of cost savings to health outcomes have not been well studied

Improving Physicians' Knowledge of the Costs of Common Medications and Willingness to Consider Costs When Prescribing

OBJECTIVES: To determine the effectiveness of an educational intervention designed to improve physicians' knowledge of drug costs and foster willingness to consider costs when prescribing. DESIGN: Pre- and post-intervention evaluation, using physicians as their own controls. SETTING: Four teaching hospitals, affiliated with 2 residency programs, in New York City and northern New Jersey. PARTICIPANTS: One hundred forty-six internal medicine house officers and attendings evaluated the intervention (71% response rate). Of these, 109 had also participated in a pre-intervention survey. INTERVENTION: An interactive teaching conference and distribution of a pocket guide, which listed the average wholesale prices of over 100 medications commonly used in primary care MEASUREMENTS AND MAIN RESULTS: We administered a written survey, before and 6 months after the intervention. Changes in attitudes and knowledge were assessed, using physicians as their own controls, with Wilcoxon matched-pairs signed-rank tests. Eighty-five percent of respondents reported receiving the pocket guide and 46% reported attending 1 of the teaching conferences. Of those who received the pocket guide, nearly two thirds (62%) reported using it once a month or more, and more than half (54%) rated it as moderately or very useful. Compared to their baseline responses, physicians after the intervention were more likely to ask patients about their out-of-pocket drug costs (22% before vs 27% after; P < .01) and less likely to feel unaware of drug costs (78% before vs 72% after; P = .02). After the intervention, physicians also reported more concern about the cost of drugs when prescribing for patients with Medicare (58% before vs 72% after; P < .01) or no insurance (90% before vs 98% after; P < .01). Knowledge of the costs of 33 drugs was more accurate after the intervention than before (P < .05). CONCLUSION: Our brief educational intervention led to modest improvements in physicians' knowledge of medication costs and their willingness to consider costs when prescribing. Future research could incorporate more high-intensity strategies, such as outreach visits, and target specific prescribing behaviors