Lack of Influence of Non-Overlapping Mutations in BRAF, NRAS, or NF1 on 12-Month Best Objective Response and Long-Term Survival after Checkpoint Inhibitor-Based Treatment for Metastatic Melanoma.

BACKGROUND: Non-overlapping somatic mutations in BRAF, NRAS, or NF1 genes occur in 85% of metastatic melanoma patients. It is not known whether these mutations affect immunotherapy outcome. MATERIALS AND METHODS: Next-Gen sequencing of 324 oncogenes was performed in 73 metastatic melanoma patients. A retrospective review of immunotherapy outcome was performed. RESULTS: BRAF fusions/internal rearrangements, BRAF V600E, NRAS, NF1 mutations, and triple-negative genotypes occurred in 6.9%, 30.1%, 17.8%, 32.9%, and 12.3% of patients, respectively. Median potential follow-up was 41.0 months. Patients with BRAF fusion/rearrangement had decreased progression-free and overall survival (p = 0.015). The other genotypes each had similar progression-free and overall survival. Patients who achieved a complete best objective response at 12 months (n = 36, 49.3%) were found to have significantly improved survival compared those who failed to achieve remissions (n = 37, 50.7%, p < 0.001). CONCLUSIONS: The most important determinant of long-term survival was achievement of a complete response by 12 months following immunotherapy. PR and SD were not a stable type of response and generally resulted in progression and death from melanoma. Rare patients with BRAF fusions or rearrangements had decreased progression-free and overall survival following initial immunotherapy. Other BRAF, NRAS, or NF1 mutations were not associated with significant differences in outcome.

Seasonal and sex differences in cell proliferation, neurogenesis, and cell death within the dentate gyrus of adult wild-caught meadow voles.

Past research indicates that female meadow voles (Microtus pennsylvanicus) show decreased neurogenesis within the hippocampus during the breeding season relative to the non-breeding season, whereas male voles show no such seasonal changes. We expanded upon these results by quantifying a variety of endogenous cell proliferation and neurogenesis markers in wild-caught voles. Adult male and female voles were captured in the summer (breeding season) or fall (non-breeding season), and blood samples and brain tissue were collected. Four cellular markers (pHisH3, Ki67, DCX, and pyknosis) were labeled and then quantified using either fluorescent or light microscopy. The volume of the cell layers within the dentate gyrus (hilus and granule cell layer) was significantly larger in males than in females. In both sexes, all the cellular markers decreased significantly in the dentate gyrus during the breeding season relative to the non-breeding season, indicating decreased cell proliferation, neurogenesis, and pyknosis. Only the pHisH3 marker showed a sex difference, with females having a greater density of this cell proliferation marker than males. During the breeding season relative to the non-breeding season, males and females showed the predicted significant increases in testosterone and estradiol, respectively. Overall, these results suggest higher levels of neuronal turn-over during the non-breeding season relative to the breeding season, possibly due to seasonal changes in sex steroids.