Tolerance and efficacy of BRAF plus MEK inhibition in patients with melanoma who previously have received programmed cell death protein 1-based therapy.

BACKGROUND: Combined BRAF and MEK inhibition (BRAF-MEK) is a standard therapy for patients with BRAF V600-mutant melanoma, but to the authors' knowledge, the tolerance, adverse event (AE) profile, and efficacy have not been well defined in the post-programmed cell death protein 1 (PD-1) setting. METHODS: Patients with BRAF V600-mutant melanoma who received combined BRAF-MEK after prior PD-1-based therapy were assembled from 4 tertiary care centers in the United States and Australia. Dose modification was defined as a treatment break, dose reduction, or intermittent dosing. Rates of hospitalization and discontinuation due to AEs were collected, and overall survival (OS) was calculated using Kaplan-Meier methods from the time of the initiation of BRAF-MEK therapy. RESULTS: A total of 78 patients were identified as having received a BRAF-MEK regimen at a median of 34 days after the last dose of PD-1-based therapy. The majority of patients (86%) received the combination of dabrafenib and trametinib. Approximately 80% of patients had American Joint Committee on Cancer M1c or M1d disease. Sixty-five regimens (83%) had ≥1 dose modification. The median time to the first dose modification was 14 days; 86% occurred within 90 days and 71% involved pyrexia. Dose modifications were more common in patients receiving BRAF-MEK <90 days after the last dose of PD-1 and who were not receiving steroids. Of the dose modifications, 25 (31%) led to an AE-related hospitalization. Among 55 BRAF-naive patients, the median time receiving BRAF-MEK therapy was 5.8 months and the median OS was 15.6 months. CONCLUSIONS: The majority of patients receiving BRAF-MEK inhibition after PD-1 therapy require dose interruptions, and a significant minority require hospitalization for AEs. In this higher risk population, the median time receiving therapy and OS may be inferior to those presented in published phase 3 trials.

Point-of-Care Ultrasonography Integration in Undergraduate Medical Education: A Student-Driven Approach.

BACKGROUND: The importance of medical ultrasonography (US) is well established, but given an already dense curriculum, integration of US into preclinical training can be difficult. Although there is no clear consensus on the best practice for integrating US into medical school curricula, growing student interest in US training demands investigation of potential solutions. OBJECTIVE: To investigate whether US integration through peer-assisted learning (PAL) and extracurricular activities during preclinical training is perceived to be valuable by student participants. METHODS: First- and second-year students at the West Virginia School of Osteopathic Medicine (WVSOM) were invited via email to attend 4 monthly PAL extracurricular US sessions on the following point-of-care US topics: (1) basic lung examination to assess pleural sliding, (2) extended focused assessment with sonography for trauma, (3) right upper quadrant biliary examination, and (4) US-guided central venous catheter placement. A brief survey using Likert-style questions inquired about participants' level of agreement with whether the given session was appropriately complex, increased comfort with US, was informative and interactive, and improved confidence in identifying anatomic structures (sessions 2 and 3 only). A final question asked participants whether they would attend more extracurricular US sessions. RESULTS: Fifty-eight students (36 unique students) attended the peer-led sessions. Of the 58 students, 50 responded to the survey for a response rate of 86.2%. Responses were overwhelmingly positive. All respondents strongly agreed or agreed that these sessions improved their confidence in identifying anatomic structures using US, and 49 (98%) strongly agreed or agreed that they would attend more US sessions. CONCLUSION: Respondents strongly endorsed the peer-led US sessions, which has facilitated the formal integration of an elective US course at WVSOM. The peer-led sessions introduced at WVSOM could provide the framework and motivation for similar courses at osteopathic medical schools across the country.

Oxidized HDL, Adipokines, and Endothelial Dysfunction: A Potential Biomarker Profile for Cardiovascular Risk in Women with Obesity.

OBJECTIVE: High BMI predicts adverse cardiovascular outcomes and positively correlates with increased levels of adipokines. The relationship among BMI, IL-6, TNFα, adiponectin, and oxidized high-density lipoprotein (Ox-HDL) with circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) has not been well studied. Elevated CEC levels have been described in both humans and mice with obesity and diabetes. Ox-HDL has been shown to be a potent driver of adipogenesis in vivo and in vitro. In this study, elevated BMI was examined in 2 groups of women studied in Brooklyn, New York, and Huntington, West Virginia, respectively. METHODS: Twenty-six females with obesity and five lean controls without overt cardiovascular disease were enrolled, 13 from Huntington and 13 from Brooklyn. Cytokine levels, EPCs, and CECs were determined. RESULTS: Females with obesity had elevated levels of leptin, IL-6, and Ox-HDL, increased CEC levels, and decreased EPC and adiponectin levels (all P < 0.01). The Ox-HDL levels were higher in women from Brooklyn versus Huntington (P < 0.01), possibly from higher TNFα levels in Brooklyn or higher adiponectin levels in Huntington. Seventy-five percent of the variance in Ox-HDL levels could be predicted in this population (P < 0.01). CONCLUSIONS: This study reveals a unique inflammatory biomarker profile in females with obesity.

MRI radiomic features are associated with survival in melanoma brain metastases treated with immune checkpoint inhibitors.

BACKGROUND: Melanoma brain metastases historically portend a dismal prognosis, but recent advances in immune checkpoint inhibitors (ICIs) have been associated with durable responses in some patients. There are no validated imaging biomarkers associated with outcomes in patients with melanoma brain metastases receiving ICIs. We hypothesized that radiomic analysis of magnetic resonance images (MRIs) could identify higher-order features associated with survival. METHODS: Between 2010 and 2019, we retrospectively reviewed patients with melanoma brain metastases who received ICI. After volumes of interest were drawn, several texture and edge descriptors, including first-order, Haralick, Gabor, Sobel, and Laplacian of Gaussian (LoG) features were extracted. Progression was determined using Response Assessment in Neuro-Oncology Brain Metastases. Univariate Cox regression was performed for each radiomic feature with adjustment for multiple comparisons followed by Lasso regression and multivariate analysis. RESULTS: Eighty-eight patients with 196 total brain metastases were identified. Median age was 63.5 years (range, 19-91 y). Ninety percent of patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and 35% had elevated lactate dehydrogenase. Sixty-three patients (72%) received ipilimumab, 11 patients (13%) received programmed cell death protein 1 blockade, and 14 patients (16%) received nivolumab plus ipilimumab. Multiple features were associated with increased overall survival (OS), and LoG edge features best explained the variation in outcome (hazard ratio: 0.68, P = 0.001). In multivariate analysis, a similar trend with LoG was seen, but no longer significant with OS. Findings were confirmed in an independent cohort. CONCLUSION: Higher-order MRI radiomic features in patients with melanoma brain metastases receiving ICI were associated with a trend toward improved OS.