Background: TERT promoter mutation (TPM) is an established biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival (PFS). TERT expression, however, has also been observed even in tumours with wildtype TERT promoters (TP-WT). This study aimed to examine TERT expression and clinical outcomes in meningiomas. Methods: TERT expression, TPM status, and TERT promoter methylation of a multi-institutional cohort of meningiomas (n=1241) was assessed through nulk RNA sequencing (n=604), Sanger sequencing of the promoter (n=1095), and methylation profiling (n=1218). 380 Toronto meningiomas were used for discovery, and 861 external institution samples were compiled as a validation cohort. Results: Both TPMs and TERTpromoter methylation were associated with increased TERT expression and may represent independent mechanisms of TERT reactivation. TERT expression was detected in 30.4% of meningiomas that lacked TPMs, was associated with higher WHO grades, and corresponded to shorter PFS, independent of grade and even among TP-WT tumours. TERT expression was associated with a shorter PFS equivalent to those of TERT-negative meningiomas of one higher grade. Conclusions: Our findings highlight the prognostic significance of TERT expression in meningiomas, even in the absence of TPMs. Its presence may identify patients who may progress earlier and should be considered in risk stratification models.

Background: Primary melanocytic neoplasms of the central nervous system (PMN-CNS) are rare lesions of variable aggressiveness originating from leptomeningeal melanocytes. They present as either circumscribed or diffuse lesions within the CNS. Given the limited number of reported cases, survival and recurrence outcomes are poorly understood. Methods: A retrospective chart review of all local adult (≥18 years) cases of PMN-CNS in British Columbia, Canada (1993-present). Results: We identified 11 cases, median age at diagnosis was 60 years (IQR: 45-64), 72% female. Tumor location included cerebrum (54.5%), spine (36.4%) and multifocal (9.1%). Four cases (36%) had confirmed GNAQ/GNA11 mutations and six cases (54.5%) were negative for BRAF V600E mutations. Operative outcomes were: gross total resection (27.3%), subtotal resection (63.6%) and biopsy-only (9.1%). Surgery was followed by adjuvant fractionated radiotherapy in 10 (91%) cases. Seven cases (63.6%) received adjuvant chemotherapy and/or immunotherapy, specifically ipilimumab and nivolumab (n=6) and temozolomide (n=1). Radiographic recurrence was observed in 7 (63.6%) cases at a median 11 (IQR: 3.5-14) months postoperatively. Median survival was 24 months (IQR: 4-103). Conclusions: Findins from this case series will assist in prognostication for PMN-CNS. Further multicenter international case series are needed to better understand these very rare neoplasms.

Background: The WHO grade of meningioma was updated in 2021 to include homozygous deletions of CDKN2A/B and TERT promotor mutations. Previous work including the recent cIMPACT-NOW statement have discussed the potential value of including chromosomal copy number alterations to help refine the current grading system. Methods: Chromosomal copy number profiles were inferred from from 1964 meningiomas using DNA methylation. Regularized Cox regresssion was used to identify CNAs independenly associated with post-surgical and post-RT PFS. Outcomes were stratified by WHO grade and novel CNAs to assess their potential value in WHO critiera. Results: Patients with WHO grade 1 tumours and chromosome 1p loss had similar outcomes to those with WHO grade 2 tumours (median PFS 5.83 [95% CI 4.36-Inf] vs 4.48 [4.09-5.18] years). Those with chromosome 1p loss and 1q gain had similar outcomes to those with WHO grade 3 cases regardless of initial grade (median PFS 2.23 [1.28-Inf] years WHO grade 1, 1.90 [1.23-2.25] years WHO grade 2, compared to 2.27 [1.68-3.05] years in WHO grade 3 cases overall). Conclusions: We advocate for chromosome 1p loss being added as a criterion for a CNS WHO grade of 2 meningioma and addition of 1q gain as a criterion for a CNS WHO grade of 3.

Background: Meningiomas exhibit considerable heterogeneity. We previously identified four distinct molecular groups (immunogenic, NF2-wildtype, hypermetabolic, proliferative) which address much of this heterogeneity. Despite their utility, the stochasticity of clustering methods and the requirement of multi-omics data limits the potential for classifying cases in the clinical setting. Methods: Using an international cohort of 1698 meningiomas, we constructed and validated a machine learning-based molecular classifier using DNA methylation alone. Original and newly-predicted molecular groups were compared using DNA methylation, RNA sequencing, whole exome sequencing, and clinical outcomes. Results: Group-specific outcomes in the validation cohort were nearly identical to those originally described, with median PFS of 7.4 (4.9-Inf) years in hypermetabolic tumors and 2.5 (2.3-5.3) years in proliferative tumors (not reached in the other groups). Predicted NF2-wildtype cases had no NF2 mutations, and 51.4% had others mutations previously described in this group. RNA pathway analysis revealed upregulation of immune-related pathways in the immunogenic group, metabolic pathways in the hypermetabolic group and cell-cycle programs in the proliferative group. Bulk deconvolution similarly revealed enrichment of macrophages in immunogenic tumours and neoplastic cells in hypermetabolic/proliferative tumours. Conclusions: Our DNA methylation-based classifier faithfully recapitulates the biology and outcomes of the original molecular groups allowing for their widespread clinical implementation.

Background: Telemedicine evaluation for treatment of acute stroke patients with IV thrombolysis has been shown to be beneficial. Its usefulness for the evaluation of patients transferred from a primary stroke centre (PSC) to a comprehensive stroke centre (CSC) for endovascular thrombectomy (EVT) is less well defined. Methods: We retrospectively analyzed the Canadian OPTIMISE registry which included data from 20 comprehensive stroke centers across Canada between January 1, 2018, and December 31, 2022 to compare treatment metrics and early outcomes between two groups: patients evaluated by telemedicine (TM) and patients evaluated in person (non-TM) at the PSC prior to CSC transfer. Results: We included 3317 patients who were transferred from a PSC to a CSC for: 888 TM and 2429 non-TM. There were no major differences in baseline characteristics, including intravenous thrombolysis administration, though the TM group included more men. TM patients had longer onset-to-puncture times (441 vs 403 minutes, p<0.001) and higher symptomatic intracerebral hemorrhage (sICH) rates (7.4% vs 3.7%, p<0.001), but CSC door-to-puncture times and successful recanalization rates did not differ. Conclusions: Patients transferred to a CSC for EVT first evaluated by TM had similar characteristics to those evaluated in person at the PSC, but longer onset-to-puncture times and higher sICH rates.

Background: Primary central nervous system lymphoma (PCNSL) is highly sensitive to corticosteroid induced cell arrest, apoptosis and shrinkage. However, the precise impact of preoperative corticosteroid on accuracy of PCNSL diagnosis using tissue obtained from open or stereotactic biopsies remains debated. Methods: We conducted a systematic review and meta-analysis to determine the effect of preoperative corticosteroids on non-diagnostic biopsy rates for PCNSL in immunocompetent adults. Subgroup analyses explored whether non-diagnostic rates varied based on biopsy type. Results: Nineteen studies, comprising 1226 patients (55% male; mean age: 60.3 years), of which 679 (55.4%) received corticosteroids prior to biopsy were included. Overall, patients pretreated with corticosteroids were two times more likely to have a non-diagnostic biopsy compared to patients that were corticosteroid-naïve prior to biopsy (RR = 2.1 [95% CI: 1.1-4.1]). In the subgroup analysis limited to stereotactic biopsies, patient pretreated with corticosteroids were three times more likely to have a non-diagnostic biopsy (RR = 3.0 [95% CI: 1.2-7.5]). Whereas, in the open biopsy subgroup, there was no significant difference in non-diagnostic rates. Conclusions: Corticosteroids should be withheld, if clinically safe, prior to stereotactic biopsies in cases of suspected PCNSL. If corticosteroids are administered preoperatively, an open biopsy should be considered instead of stereotactic biopsy.

Background: Intracranial epidermoid cysts (IEC) are benign congenital intracranial lesions that rarely undergo malignant transformation. We report a case of IEC evolving into squamous cell carcinoma (SCC) 1-year post-resection. Further, we conducted a systematic review on cases of early malignant transformations of IECs. Methods: MEDLINE, EMBASE, and Scopus were searched from inception until December 2023 for studies reporting malignant transformations of IECs within 2 years of diagnosis. Results: A 48-year-old female underwent surgical resection of a cerebellopontine angle (CPA) IEC in May 2022. She re-presented in July 2023 with headaches, nausea, vomiting, right facial weakness, and rapid cyst progression. Repeat surgical resection revealed a high-grade SCC. Our systematic review identified 19 (10 females, 9 males) additional IEC cases undergoing malignant transformation within 2 years. The mean age at presentation was 57.6 years, most common location was CPA (n=13, 68.4%) and mean time between IEC to malignant transformation was 10.6 months. Eighteen (94.7%) cases transformed to SCC, of which 2 had leptomeningeal carcinomatosis, and 1 transformed to glioblastoma. Conclusions: While malignant transformations of IECs are rare, regular postoperative follow-up is crucial for early malignancy detection and treatment initiation. Further study is warranted to evaluate factors contributing to accelerated malignant progression of IECs.

Background: Meningiomas are the most common intracranial tumor with surgery, dural margin treatment, and radiotherapy as cornerstones of therapy. Response to treatment continues to be highly heterogeneous even across tumors of the same grade. Methods: Using a cohort of 2490 meningiomas in addition to 100 cases from the prospective RTOG-0539 phase II clinical trial, we define molecular biomarkers of response across multiple different, recently defined molecular classifications and use propensity score matching to mimic a randomized controlled trial to evaluate the role of extent of resection, dural marginal resection, and adjuvant radiotherapy on clinical outcome. Results: Gross tumor resection led to improved progression-free-survival (PFS) across all molecular groups (MG) and improved overall survival in proliferative meningiomas (HR 0.52, 95%CI 0.30-0.93). Dural margin treatment (Simpson grade 1/2) improved PFS versus complete tumor removal alone (Simpson 3). MG reliably predicted response to radiotherapy, including in the RTOG-0539 cohort. A molecular model developed using clinical trial cases discriminated response to radiotherapy better than standard of care grading in multiple cohorts (ΔAUC 0.12, 95%CI 0.10-0.14). Conclusions: We elucidate biological and molecular classifications of meningioma that influence response to surgery and radiotherapy in addition to introducing a novel molecular-based prediction model of response to radiation to guide treatment decisions.

Background: Meningiomas have significant heterogeneity between patients, making prognostication challenging. For this study, we prospectively validate the prognostic capabilities of a DNA methylation-based predictor and multiomic molecular groups (MG) of meningiomas. Methods: DNA methylation profiles were generated using the Illumina EPICarray. MG were assigned as previously published. Performance of our methylation-based predictor and MG were compared with WHO grade using generalized boosted regression modeling by generating time-dependent receiver operating characteristic (ROC) curves and computing area under the ROC curves (AUCs) along with their 95% confidence interval using bootstrap resampling. Results: 295 meningiomas treated from 2018-2021 were included. Methylation-defined high-risk meningiomas had significantly poorer PFS and OS compared to low-risk cases (p<0.0001). Methylation risk increased with higher WHO grade and MG. Higher methylome risk (HR 4.89, 95%CI 2.02-11.82) and proliferative MG (HR 4.11, 95%CI 1.29-13.06) were associated with significantly worse PFS independent of WHO grade, extent of resection, and adjuvant RT. Both methylome-risk and MG classification predicted 3- and 5-year PFS and OS more accurately than WHO grade alone (ΔAUC=0.10-0.23). 42 cases were prescribed adjuvant RT prospectively although RT did not significantly improve PFS in high-risk cases (p=0.41). Conclusions: Molecular profiling outperforms conventional WHO grading for prognostication in an independent, prospectively collected cohort of meningiomas.

Background: Meningiomas are the most common intracranial tumor, graded from 1 (benign) to 3 (malignant). The aim of this study was to identify clinical features associated with overall survival (OS), progression-free survival (PFS) and functional status for malignant meningiomas. Methods: Demographic, clinical and histopathological data from grade 3 intracranial meningioma cases were identified in the clinical databases from seven sites in North America and Europe from 1991-2022. Summary statistics and Kaplan-Meier OS and PFS curves were generated. Results: We identified 108 patients, with a median age 65 years (IQR: 52, 72) and 53.7% were female. Median OS was 109 months (95% CIs: 88, 227), and 5-year OS rate was 65% (95% CIs: 56, 76). Median PFS was 38 months (95% CIs: 24, 56) and 5-year PFS rate was 37% (95% CIs: 28, 49). OS and PFS were significantly lower in patients aged ≥65 years. Median preoperative KPS score was 80 (IQR: 70, 90), postoperatively KPS was 90 (IQR: 70, 98) and 1-year follow-up KPS was 70 (IQR: 50, 80). Conclusions: This study provides robust survival, recurrence and functional data for grade 3 meningiomas in North America and Europe over a 30-year period.

Background: In 2016, the WHO Classification of Brain Tumors included brain invasion as a standalone diagnostic criterion for grade 2 meningioma diagnosis. In this study we explored the impact of this change on the incidence and distribution of meningioma grades. Methods: All cases of meningiomas diagnosed from 2007-2020 at a tertiary care hospital were identified. The distribution of meningioma grades before (WHO 2007) and after (WHO 2016) the introduction of the 2016 WHO criteria were compared. Each case in the 2007 cohort was re-graded according to the 2016 criteria to determine the intra-class correlation (ICC) between grading criteria. Results: Of 814 cases, 532 (65.4%) were in the 2007 WHO cohort and 282 (34.6%) were in the 2016 WHO cohort. There were no differences in the distribution of meningioma grades between cohorts (p=0.11). Upon re-grading, 21 cases (3.9%) were changed. ICC between original and revised grade was 0.92 (95% CIs: 0.91-0.93). Amongst Grade 2 meningiomas with brain invasion, 75.8% had three or more atypical histologic features or an elevated mitotic index. Conclusions: Brain invasion alone has minimal impact on the incidence or distribution of specific meningioma grade tumors, likely due to cosegregation of grade elevating features.

Background: The coronavirus disease 2019 (COVID-19) pandemic has led the implementation of institutional infection control protocols. This study will determine the effects of these protocols on outcomes of acute ischemic stroke (AIS) patients treated with endovascular therapy (EVT). Methods: Uninterrupted time series analysis of the impact of COVID-19 safety protocols on AIS patients undergoing EVT. We analyze data from prospectively collected quality improvement databases at 6 centers from March 11, 2019 to March 10, 2021. The primary outcome is 90-day modified Rankin Score (mRS). The secondary outcomes are angiographic time metrics. Results: Preliminary analysis of one stroke center included 214 EVT patients (n=150 pre-pandemic). Baseline characteristics were comparable between the two periods. Time metrics “last seen normal to puncture” (305.7 vs 407.2 min; p=0.05) and “hospital arrival to puncture” (80.4 vs 121.2 min; p=0.04) were significantly longer during pandemic compared to pre-pandemic. We found no significant difference in 90-day mRS (2.0 vs 2.2; p=0.506) or successful EVT rate (89.6% vs 90%; p=0.93). Conclusions: Our results indicate an increase in key time metrics of EVT in AIS during pandemic, likely related to infection control measures. Despite the delays, we found no difference in clinical outcomes between the two periods.

Background: The coronavirus disease 2019 (COVID-19) pandemic has led an implementation of institutional infection control protocols. This study will determine the effects of these protocols on outcomes of acute ischemic stroke (AIS) patients treated with endovascular therapy (EVT). Methods: Uninterrupted time series analysis of the impact of COVID-19 safety protocols on AIS patients undergoing EVT. We analyze data from prospectively collected quality improvement databases at 9 centers from March 11, 2019 to March 10, 2021. The primary outcome is 90-day modified Rankin Score (mRS). The secondary outcomes are angiographic time metrics. Results: Preliminary analysis of one stroke center included 214 EVT patients (n=144 pre-pandemic). Baseline characteristics were comparable between the two periods. Time metrics “last seen normal to puncture” (305.7 vs 407.2 min; p=0.05) and “hospital arrival to puncture” (80.4 vs 121.2 min; p=0.04) were significantly longer during pandemic compared to pre-pandemic. We found no significant difference in 90-day mRS (2.0 vs 2.2; p=0.506) or successful EVT rate (89.6% vs 90%; p=0.93). Conclusions: Our results indicate an increase in key time metrics of EVT in AIS during the pandemic, likely related to infection control measures. Despite the delays, we found no difference in clinical outcomes between the two periods.

Deep learning, a subset of artificial intelligence, has shown great potential in several recent applications to pathology. These have mainly involved the use of classifiers to diagnose disease, while generative modelling techniques have been less frequently used. Generative adversarial networks (GANs) are a type of deep learning model that has been used to synthesize realistic images in a range of domains, both general purpose and medical. In the GAN framework, a generator network is trained to synthesize fake images, while a dueling discriminator network aims to distinguish between the fake images and a set of real training images. As GAN training progresses, the generator network ideally learns the important features of a dataset, allowing it to create images that the discriminator cannot distinguish from the real ones. We report on our use of GANs to synthesize high resolution, realistic histopathology images of gliomas. The well- known Progressive GAN framework was trained on a set of image patches extracted from digital slides in the Cancer Genome Atlas repository, and was able to generate fake images that were visually indistinguishable from the real training images. Generative modelling in pathology has numerous potential applications, including dataset augmentation for training deep learning classifiers, image processing, and expanding educational material.