Combined BRAF, MEK, and heat-shock protein 90 inhibition in advanced BRAF V600-mutant melanoma.

BACKGROUND: Resistance to BRAF and MEK inhibitors in BRAF V600-mutant melanoma is common. Multiple resistance mechanisms involve heat-shock protein 90 (HSP90) clients, and a phase 1 study of vemurafenib with the HSP90 inhibitor XL888 in patients with advanced melanoma showed activity equivalent to that of BRAF and MEK inhibitors. METHODS: Vemurafenib (960 mg orally twice daily) and cobimetinib (60 mg orally once daily for 21 of 28 days) with escalating dose cohorts of XL888 (30, 45, 60, or 90 mg orally twice weekly) was investigated in a phase 1 trial of advanced melanoma, with a modified Ji dose-escalation design. RESULTS: Twenty-five patients were enrolled. After two dose-limiting toxicities (DLTs) (rash and acute kidney injury) in the first cohort, lower doses of vemurafenib (720 mg) and cobimetinib (40 mg) were investigated with the same XL888 doses. Three DLTs (rash) were observed in 12 patients in the XL888 60-mg cohort, and this was determined as the maximum tolerated dose. Objective responses were observed in 19 patients (76%), and the median progression-free survival was 7.6 months, with a 5-year progression-free survival rate of 20%. The median overall survival was 41.7 months, with a 5-year overall survival rate of 37%. Single-cell RNA sequencing was performed on baseline and on-treatment biopsies; treatment was associated with increased immune cell influx (CD4-positive and CD8-positive T cells) and decreased melanoma cells. CONCLUSIONS: Combined vemurafenib and cobimetinib plus XL888 had significant toxicity, requiring frequent dose reductions, which may have contributed to the relatively low progression-free survival despite a high tumor response rate. Given overlapping toxicities, caution must be used when combining HSP90 inhibitors with BRAF and MEK inhibitors.

Intraoperative Automated Radiographic Visualization Tool Allows for Higher Accuracy of Cam Lesion Resection When Used by Novice Surgeons for Arthroscopic Femoroplasty: Lowering the Learning Curve.

PURPOSE: To compare the accuracy of conventional fluoroscopy versus an intraoperative radiographic visualization tool in assisting a novice and experienced hip arthroscopist in comprehensive cam correction to a desired alpha angle (AA). METHODS: A cadaveric study was performed using 28 hemi-pelvises with cam-type deformity (AA > 55˚) measured on anteroposterior, lateral, and Dunn-view radiographs. Two fellowship-trained hip arthroscopists each performed 14 arthroscopic femoroplasties. The specimens were randomly assigned: 14 of the procedures were performed by the experienced surgeon, with 7 using the automated radiographic visualization tool (Guided Femoroplasty) and 7 using routine fluoroscopy (Control). The same number of hips was assigned to the novice surgeon, completing 7 femoroplasties with and without the visualization tool. Each hip was imaged before and after femoroplasty in 6 different positions using intraoperative fluoroscopy to evaluate head-neck offset. Femoroplasty AAs were compared between groups with and without visualization tool use, as well as between surgeons. One-way analysis of variance analysis was performed to evaluate the consistency of cam resection. RESULTS: For the experienced hip arthroscopist, comparison of Guide Femoroplasty and Control groups resulted in similar accuracy when compared to the controls, with post-femoroplasty AA averages ranging from 41.4° ± 3.8˚ to 44.8° ± 2.8˚ (P = .511) and 40.2° ± 5.3˚ to 45.6° ± 2.2˚ (P = .225), respectively. For the novice hip arthroscopist, the Guided Femoroplasty group had higher accuracy, with post-femoroplasty AA averages ranging from 42.8° ± 2.6˚ to 46.1° ± 7.2˚(P = .689) with and 39.8° ± 3.1˚ to 51.9° ± 8.1˚ (P = .001) without the visualization tool. Comparison of procedure time did not show any statistically significant difference between the use of the radiographic visualization tool and controls for either surgeon (P > .05 for all). CONCLUSIONS: Femoroplasty with and without the use of automated radiographic visualization tool results in accurate cam resection when used by both the experienced and novice surgeon. However, higher accuracy was observed when resecting to a desired AA performed by a novice surgeon using the visualization tool. Additionally, use of the visualization tool did not result in longer procedure times for either surgeon. CLINICAL RELEVANCE: The impact of incomplete cam resections and over-resection on patient outcomes in the literature has led to the recent development of automated intraoperative radiographic visualization tools that allow for assistance of cam resection accuracy for the treatment of femoroacetabular impingement syndrome. This cadaveric study demonstrates that femoroplasty with the use of an intraoperative automated radiographic visualization tool may result in more accurate cam resections.