Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system (CNS) progression is frequently an end-stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. Additionally, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Key Points Question Can cell-free DNA analysis of cerebrospinal fluid provide additional diagnostic utility beyond cytologic assessment? Findings In this diagnostic study of 43 cerebrospinal fluid samples from 22 patients with leptomeningeal disease confirmed by cytologic assessment who did not have parenchymal tumors abutting their cerebrospinal fluid, tumor-derived cell-free DNA was detected in the cerebrospinal fluid of 40 (93%) samples, whereas 31 (72%) of the samples were positive for malignant neoplasm as determined by cytologic analysis, a significant difference. Meaning These findings suggest that cerebrospinal fluid cell-free DNA analysis may be more sensitive than cytologic analysis for diagnosing leptomeningeal disease.

Wilhelm Uhthoff, known for his contributions to both neurology and neuro-ophthalmology, was a German ophthalmologist who specialized in neurologic disorders. The eponym “Uhthoff’s phenomenon” was first used to describe the reversible, transient blurring of vision in patients with multiple sclerosis during exercise. Subsequently, it was discovered that this neurologic sign not only was triggered by physical exertion but also by other homeostatic disruptions such as hot baths, menstruation, and high external temperatures. Here, we take a look at the life and career of Wilhelm Uhthoff and discuss the basis behind this phenomenon.