Overcoming differential tumor penetration of BRAF inhibitors using computationally guided combination therapy.

BRAF-targeted kinase inhibitors (KIs) are used to treat malignancies including BRAF-mutant non-small cell lung cancer, colorectal cancer, anaplastic thyroid cancer, and, most prominently, melanoma. However, KI selection criteria in patients remain unclear, as are pharmacokinetic/pharmacodynamic (PK/PD) mechanisms that may limit context-dependent efficacy and differentiate related drugs. To address this issue, we imaged mouse models of BRAF-mutant cancers, fluorescent KI tracers, and unlabeled drug to calibrate in silico spatial PK/PD models. Results indicated that drug lipophilicity, plasma clearance, faster target dissociation, and, in particular, high albumin binding could limit dabrafenib action in visceral metastases compared to other KIs. This correlated with retrospective clinical observations. Computational modeling identified a timed strategy for combining dabrafenib and encorafenib to better sustain BRAF inhibition, which showed enhanced efficacy in mice. This study thus offers principles of spatial drug action that may help guide drug development, KI selection, and combination.

Prospective Analysis of Radiology Resource Utilization and Outcomes for Participation in Oncology Multidisciplinary Conferences.

RATIONALE AND OBJECTIVES: Radiology participation is necessary in oncology multidisciplinary conferences (MDCs), but the resources required to do so are often unaccounted for. In this prospective study we provide an analysis of resource utilization as a function of outcomes for all MDCs covered by an entire radiology section and provide a time-based cost estimate. MATERIALS AND METHODS: Following institutional review board approval, prospective data on all MDCs covered by abdominal radiologists at a single tertiary care academic center were obtained over nine weeks. A predefined questionnaire was used by a single observer who attended every imaging review and recorded the total time spent by the radiologists and several outcome measures. The total time recorded was used to provide a time-based cost estimate using a national salary survey. RESULTS: Six radiologists participated in a total of 57 MDCs, with 577 cases reviewed and discussed. 181 (31%) cases were performed at outside facilities requiring full reinterpretation. Clinically significant revisions to original reports were recorded in 107 (18.5%) cases. Radiologist input directly resulted in alteration of cancer staging in 65 (11%) patients and specific recommendations for follow-up diagnostic workup in 280 (48%) of cases. The mean total time devoted by the staff radiologist per week to MDCs was 18.7 hours/week, nearly a half of full-time effort, or 8% of total effort per radiologist. The total annual projected cost of radiology coverage for each weekly MDC was $26,920. CONCLUSION: Section-wide radiologist participation in MDCs directly resulted in change in clinical management in nearly half of reviewed cases. This was achieved at a notable time cost, highlighting the need for efficient integration of radiology MDC participation into radiologist workflow and compensation models.