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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.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Glioma/genética , Glioma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Histonas/genética , Resultado del Tratamiento , Epigénesis Genética , MutaciónRESUMEN
BACKGROUND: For patients undergoing surgery at an Ambulatory Surgical Center, recent changes to Centers for Medicare and Medicaid Services policy allow for the omission of a 30-day preoperative History and Physical (H&P). Preoperative H&Ps for low-risk surgery may contribute to health care waste and lead to unnecessary preoperative testing and treatment cascades. METHODS: In this qualitative study, we conducted 30 semi-structured interviews with surgeons who frequently perform low-risk surgeries. We aimed to evaluate surgeon perspectives on the continued use of the 30-day preoperative H&P and specifically the potential risks and benefits associated with the elimination of a preoperative H&P requirement from institutional practice. We used an interpretive description approach to generate a thematic description. RESULTS: Most participants felt that the 30-day preoperative H&P was low value and frequently described it as "unnecessary," "redundant," or "just checking a box." Many viewed the 30-day requirement as arbitrary and felt that new H&P findings were rare and unlikely to influence surgical care. The participants who favored the preoperative H&P felt it was a safeguard to ensure "nothing was missed" and were less likely to be burdened by the requirement than participants who felt it was low value. CONCLUSIONS: Surgeons performing low-risk procedures question the utility and value of conducting a preoperative H&P within 30 days of surgery. De-implementation of the 30-day preoperative H&P for low-risk patients may increase convenience for patients and providers. Furthermore, it may improve value in surgery by increasing access to services for patients with greater need for preoperative assessment.
Asunto(s)
Medicare , Cirujanos , Anciano , Humanos , Examen Físico , Investigación Cualitativa , Riesgo , Estados UnidosRESUMEN
The original version of this review article unfortunately contained a mistake in the author group section.
RESUMEN
PURPOSE OF REVIEW: H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system created a specific category of "Diffuse Midline Glioma, H3K27M-mutant". Here we outline the latest pre-clinical data and ongoing current clinical trials that target H3K27M, as well as explore diagnosis and treatment monitoring by serial liquid biopsy. RECENT FINDINGS: Multiple epigenetic compounds have demonstrated efficacy and on-target effects in pre-clinical models. The imipridone ONC201 and the IDO1 inhibitor indoximod have demonstrated early clinical activity against H3K27M-mutant gliomas. Liquid biopsy of cerebrospinal fluid has shown promise for clinical use in H3K27M-mutant tumors for diagnosis and monitoring treatment response. While H3K27M has elicited a widespread platform of pre-clinical therapies with promise, much progress still needs to be made to improve outcomes for diffuse midline glioma patients. We present current treatment and monitoring techniques as well as novel approaches in identifying and targeting H3K27M-mutant gliomas.
