Bush, Nancy Ann Oberheim

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.

Abstract BACKGROUND The prognostic importance of maximal resection of contrast enhancing and non-contrast enhancing disease has been established. Nonetheless, glioblastomas exist within the framework of complex neural circuitry serving cognition, movement, and behavior consequential leading to neurological impairments. The prognostic importance of neurological impairments on survival remains poorly understood. METHODS This is a retrospective, single cohort study from UCSF including 316 eligible patients diagnosed over 20 years with 9.6 years of follow-up. All patients underwent surgical resection for newly diagnosed glioblastoma for whom survival, molecular, preoperative and postoperative MRI images, and clinical data were available. All patients had chemoradiation treated IDH-wild-type glioblastoma with available preoperative and 1-month post-surgical resection neurological outcomes. We employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS). RESULTS Preoperative neurological impairments were present in 75.6% (n= 239) and new post resection impairments were identified in 37.3% (n=117). Univariate analysis confirmed that new postoperative cognitive impairment [HR 7.91, 95% CI 2.47-25.33] and hemiplegia [HR 3.38, 95% CI 0.83-13.67] (not hemiparesis) impact OS. Risk stratified grouping by RPA demonstrated that gross total resection of contrast enhancing tumor in patients with no new postoperative neurological impairments confers the longest OS (median OS 27.1 months 95%CI 21.5-33.7). Patients with any residual tumor volume after surgery but no new neurological deficits experience a similar survival to younger patients (under 65) with 1 or more new postoperative neurological deficits (median OS 16.6 months 95%CI 15.2-19.2). Shortest OS is identified in patients with any volume of residual tumor plus 1 or more new postoperative neurological deficits and age over 65 (median OS 11.4 months, 95%CI 9.3-13.5). CONCLUSIONS This study confirms that new postoperative neurological impairments impact overall survival in patients with chemoradiation treated IDH-wild-type glioblastoma.