Young, Jacob S.

Abstract IDH-wildtype diffuse astrocytic gliomas with lower-grade histological features alongside specific genomic alterations (e.g., TERT promoter mutation, EGFR amplification, gain Chr7/loss Chr10) are presently diagnosed as glioblastoma, IDH-wildtype (GBM) under WHO 2021 criteria. Previous analyses categorized these into “early/evolving” or “surgically undersampled” GBMs. However, it remains unclear whether these tumors share identical clinical and prognostic features with histologic GBM. Data from IDH-wt molecular GBMs across six institutions were aggregated. Astrocytic IDH-wt tumors of any grade that lacked necrosis or microvascular proliferation on initial histopathology yet exhibited molecular alterations consistent with WHO 2021 GBM diagnosis, were included. Recursive partitioning analysis (RPA) was used to categorize patients into risk groups based on overall survival (OS). Among the 264 patients included, the median age was 60 years (IQR: 51-67), with 162 (61%) being male. Additionally, 210 (80%) were diagnosed since 2016, and 216 (82%) received chemoradiation plus adjuvant temozolomide (GBM-SOC). The median follow-up period was 3.9 years (95% CI: 3.4, 4.6). Identified univariate risk factors for worse survival included older age, biopsy-only status, EGFR amplification, absence of initial adjuvant treatment, low post-operative KPS, and tumor histologic grade of 3. RPA divided patients into four distinct survival groups (p<0.0001). The “best” risk group comprised lower grade (<=2) tumors (n=58, median OS (mOS): 40 months (95% CI: 33, NA)). The “second best” group included Grade 3 patients receiving GBM-SOC without steroids during initial RT (n=139, mOS: 25 months (95% CI: 22, 28)). The “second worst” group encompassed Grade 3 patients who were on steroids during initial RT while receiving GBM-SOC (n=38, mOS: 15 months (95% CI: 13, 20)). The “worst” group contained Grade 3 tumors that had not undergone SOC (n=29, mOS: 9 months (95% CI: 4, 26)). These data show that histologic features and treatment are strong indicators of patient outcomes.

Abstract Current standard of care for IDH-wildtype glioblastoma (GBM) includes maximal safe resection, adjuvant radiation, and chemotherapy with the alkylating agent temozolomide. A subset of gliomas treated with temozolomide develop somatic hypermutation with a predominance of C>T transitions due to the alkylation effects on DNA. However, the frequency of occurrence, clinical ramifications, and predictive biomarkers for developing temozolomide-induced hypermutation (TMZ-HM) in GBM are unknown. Here we performed comprehensive histopathologic, genomic, and epigenomic evaluation of paired initial and recurrent GBM from 106 patients. Seven patients (7%) developed hypermutation at time of first recurrence, while an additional five patients (5%) developed hypermutation at a subsequent recurrence. Patients who developed TMZ-HM had a significantly longer interval between initial surgery and first recurrence (27.8 vs. 9.9 months, p<0.001). In contrast to IDH-mutant gliomas where TMZ-HM is associated with poor prognosis, those patients with IDH-wildtype GBM who developed TMZ-HM had significantly longer overall survival from both initial surgery (67.9 vs. 20.3 months, p<0.001) and from time of recurrence after development of hypermutation (30.9 vs. 9.5 months, p=0.001). There was no difference in oncogenic alteration frequency in initial GBM that subsequently developed TMZ-HM. However, 4 specific CpG sites out of 12 total interrogated sites in the promoter region of MGMT (a DNA repair enzyme) and 5 specific CpG sites in the promoter region of KCNQ1DN (a negative regulator of c-Myc) were significantly more hypermethylated in those GBM that developed TMZ-HM. We then generated a weighted risk score across these CpG sites that can be used to prospectively identify GBM likely to develop TMZ-HM associated with favorable survival. In summary, patients with GBM that develop TMZ-HM follow a more favorable clinical course, and specific MGMT and KCNQ1DN promoter hypermethylation patterns could serve as a biomarker to identify these patients who may potentially benefit from extended alkylating chemotherapy treatment.

Abstract Harnessing the neuroplastic potential of the human brain is being increasingly recognized as an important neuro-oncological paradigm to facilitate safe resection of brain tumors while preserving neurological function and quality of life. Interventional neurorehabilitation, employing both invasive and noninvasive neuromodulation techniques, represents an important emerging therapeutic strategy to induce or enhance neural plasticity to promote functional recovery in brain tumor patients. This study aimed to conduct a comprehensive review of interventional neurorehabilitation techniques for glioma patients. Methods In accordance with PRISMA guidelines, searches of Medline, Embase, Web of Science, APA PsycINFO, and Cochrane were undertaken from database inception to November 28, 2023. Studies reporting on neuromodulation applied to glioma patients were included. Results Seven studies reporting findings from 118 patients met the inclusion criteria. Three neuromodulation techniques were identified and included transcranial magnetic stimulation (TMS) reported in 5 out of 7 (71.4%) studies; transcranial direct current stimulation (tDCS); and continuous cortical electrical stimulation (cCES) using grid electrodes, reported in one study each. All studies applying noninvasive stimulation to ameliorate postoperative deficits demonstrated an improvement on at least one outcome measure. The 2 studies applying tDCS and cCES to induce plasticity reported evidence of functional reorganization. Conclusions There is emerging evidence of benefits of neuromodulation to improve postoperative outcome in glioma patients. In the current literature, noninvasive stimulation has shown to have a favorable safety profile. Large-scale, double-blind, sham-controlled trials are warranted to further investigate the effectiveness of these interventions for modulating different cognitive networks in patients undergoing glioma surgery.

Abstract Background Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07–0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37–0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.