The latest medical research on Oncology

Glioblastoma is the most common and aggressive primary brain tumor. Large scale sequencing initiatives have cataloged its mutational landscape in hopes of elucidating mechanisms driving this deadly disease. However, a major bottleneck in harnessing this data for new therapies is deciphering "driver" and "passenger" events amongst the vast volume of information.

We utilized an autochthonous, in vivo screening approach to identify driver, EGFR variants. RNA-Seq identified unique molecular signatures of mouse gliomas across these variants, which only differ by a single amino acid change. In particular, we identified alterations to lipid metabolism, which we further validated through an unbiased lipidomics screen.

Our screen identified A289I as the most potent EGFR variant, which has previously not been characterized. One of the mechanisms through with A289I promotes gliomagenesis is to alter cellular triacylglycerides through MTTP. Knockout of Mttp in mouse gliomas, reduces gliomagenesis in multiple models.

EGFR variants that differ by a single amino acid residue differentially promote gliomagenesis. Among the identified mechanism that drive glioma growth include lipid metabolism through MTTP. Understanding triacylglyceride accumulation may present a prospective therapeutic pathway for this deadly disease.

Craniopharyngioma (CP) in adults is a rare benign tumor associated with many morbidities, with limited contemporary studies to define treatment, and follow-up guidelines.

A single-center retrospective study was conducted on patients aged ≥18-years from 2006-2018 with CP and who were treated with proton therapy (PT). Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS), local recurrence-free survival (LRFS), and toxicity were characterized using Kaplan-Meier and Cox regression analyses.

Ninety-one patients met the criteria, with a median age of 37-years (range 18-82y). PT was conducted after tumor resection in 88 patients (97%), in 64 patients (70.3%) as an adjuvant strategy and 27 (29.7%) after recurrent disease. Three patients received exclusive PT. A median MRI follow-up of 39 months revealed 35.2% complete response, 49.5% partial response, and 9.9% stable disease. Five patients developed local recurrence (LR). Pattern of failure study showed that these five LR were within the GTV volume. The 5-year LRFS was 92.0% [CI95%:84.90-99.60]. All the patients were alive at the end of the follow-up. Patients requiring treatment adaptation during PT tend to have a higher risk of LR (p=0.084). Endocrinopathy was the most frequent grade≥2 late toxicity. Among patients who were symptom-free before the start of treatment, none developed hearing toxicity but four (9.8%) developed visual disorders and 10 (11.3%) symptomatic memory impairment. Patients with large tumors had a higher risk of developing symptomatic memory impairment (p=0.029).

Adults with CP treated with PT have favorable survival outcomes, with acceptable late toxicity. Prospective quality-of-life and neurocognitive studies are needed to define late adverse effects better.

Molecularly-defined diffuse glioma types - including IDH-wildtype glioblastoma, IDH-mutant astrocytoma, IDH-mutant 1p/19q-codeleted oligodendroglioma, and H3 K27M-mutant diffuse midline glioma - were incorporated into U.S. cancer registry reporting for individuals with brain tumors beginning in 2018. We leveraged these new data to estimate the national-level overall survival (OS) patterns associated with glioma integrated diagnoses.

Individuals diagnosed with diffuse gliomas in 2018 and had brain molecular marker data were identified within the U.S. National Cancer Database. OS was estimated using Kaplan Meier methods and stratified by WHO CNS grade, age, sex, tumor size, treatment, extent of resection, and MGMT promoter methylation. Additionally, the effects of WHO CNS grade were examined among individuals with IDH-wildtype astrocytic gliomas.

8,651 individuals were identified. One-year OS was 53.7% for WHO grade 4 IDH-wildtype glioblastomas; 98.0%, 92.4%, and 76.3% for WHO grade 2, 3, and 4 IDH-mutant astrocytomas, respectively; 97.9% and 94.4% for WHO grade 2 and 3 IDH-mutant 1p/19q-codeleted oligodendrogliomas, respectively; and 55.9% for H3 K27M-mutant diffuse midline gliomas. Among IDH-wildtype glioblastomas, median OS was 17.1 months and 12.4 months for methylated and unmethylated MGMT promoters. Additionally, IDH-wildtype diffuse astrocytic gliomas reported as WHO grade 2 or 3 demonstrated longer OS compared to grade 4 tumors (both p<0.001).

Our findings provide the initial national OS estimates for molecularly-defined diffuse gliomas in the U.S. and illustrate the importance of incorporating such data into cancer registry reporting.