Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle–related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. Significance: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

Neuropsychiatric systemic lupus erythematosus is associated with a high mortality rate, and knowledge of the underlying mechanisms, postulated neuroimmune interfaces, and complications of this dise... Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multiple immunologic abnormalities and has the potential to involve the central nervous system (CNS). The preval...

Comprehensive knowledge of major revisions in the fifth edition of the World Health Organization classification of central nervous system tumors, including the molecular, clinical, and imaging feat... The World Health Organization (WHO) published the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5) in 2021, as an update of the WHO central nervous system ...

BACKGROUND AND PURPOSE: Hypophysitis is one of the well-known adverse effects of immune checkpoint inhibitors. Immune checkpoint inhibitor–induced hypophysitis frequently causes irreversible hypopituitarism, which requires long-term hormone replacement. Despite the high frequency and clinical significance, characteristic MR imaging findings of immune checkpoint inhibitor–induced hypophysitis have not been established. In the present study, we aimed to review and extract the MR imaging features of immune checkpoint inhibitor–induced hypophysitis. MATERIALS AND METHODS: This retrospective international multicenter study comprised 20 patients with melanoma who were being treated with immune checkpoint inhibitors and clinically diagnosed with immune checkpoint inhibitor–induced hypophysitis. Three radiologists evaluated the following MR imaging findings: enlargement of the pituitary gland and stalk; homogeneity of enhancement of the pituitary gland; presence/absence of a well-defined poorly enhanced area and, if present, its location, shape, and signal intensity in T2WI; and enhancement pattern in contrast-enhanced dynamic MR imaging. Clinical symptoms and hormone levels were also recorded. RESULTS: Enlargement of the pituitary gland and stalk was observed in 12 and 20 patients, respectively. Nineteen patients showed poorly enhanced lesions (geographic hypoenhancing lesions) in the anterior lobe, and 11 of these lesions showed hypointensity on T2WI. Thyrotropin deficiency and corticotropin deficiency were observed in 19/20 and 12/17 patients, respectively, which persisted in 12/19 and 10/12 patients, respectively, throughout the study period. CONCLUSIONS: Pituitary geographic hypoenhancing lesions in the anterior lobe of the pituitary gland are characteristic and frequent MR imaging findings of immune checkpoint inhibitor–induced hypophysitis. They reflect fibrosis and are useful in distinguishing immune checkpoint inhibitor–induced hypophysitis from other types of hypophysitis/tumors.