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Background Vestibular schwannoma (VS) is the most common tumour of the cerebellopontine angle. Owing to complex anatomy and high rates of morbidity, surgical management of large tumours is challenging. We seek to explore the clinical landscape of VS to identify predictors of outcome and help guide surgical decision making. Methods We retrospectively reviewed charts of patients who underwent primary surgery for VS between 2005 and 2020 at a quaternary referral center in Toronto, Canada. Mined data includes patient demographics, clinical presentation, radiological features, and treatment details. Regression modelling was used to identify predictors of tumour control, postoperative morbidity, and correlates of progression free survival (PFS). Results Two hundred and five tumours with sufficient data were included in our study. Syndromic NF2, large tumours (>3cm), subtotal resection (vs gross total resection), presence of edema on preoperative MRI, and preoperative trigeminal symptoms were all predictors of postoperative progression/need for further treatment; the latter four were also associated with shorter progression free survival. Extent of resection (EOR), tumour size, and Koos grade were independently predictive of postoperative progression/secondary intervention in multivariate models; however, only EOR was independently predictive of progression-free survival. EOR, tumour size, and patient age are each independently predictive of facial nerve outcome. Conclusions We comprehensively explore the clinical landscape of surgically treated vestibular schwannoma and highlight important outcome predictors and disease subgroups. This may have important implications in risk stratifying these challenging cases.

Background Chordomas are rare malignant bone cancers of the skull-base and spine. Patient survival is variable and not reliably predicted using clinical factors or molecular features. This study identifies prognostic epigenetic chordoma subtypes that are detected noninvasively using plasma methylomes. Methods Methylation profiles of 68 chordoma surgical samples were obtained between 1996 and 2018 across three international centers along with matched plasma methylomes where available. Results Consensus clustering identified two stable tissue clusters with a disease-specific survival difference that was independent of clinical factors in a multivariate Cox analysis (HR = 14.2, 95%CI: 2.1–94.8, P = 0.0063). Immune-related pathways with genes hypomethylated at promoters and increased immune cell abundance were observed in the poor-performing “Immune-infiltrated” subtype. Cell-to-cell interaction plus extracellular matrix pathway hypomethylation and higher tumor purity were observed in the better-performing “Cellular” subtype. The findings were validated in additional DNA methylation and RNA sequencing datasets as well as with immunohistochemical staining. Plasma methylomes distinguished chordomas from other clinical differential diagnoses by applying fifty chordoma-versus-other binomial generalized linear models in random 20% testing sets (mean AUROC = 0.84, 95%CI: 0.52–1.00). Tissue-based and plasma-based methylation signals were highly correlated in both prognostic clusters. Additionally, leave-one-out models accurately classified all tumors into their correct cluster based on plasma methylation data. Conclusions Here, we show the first identification of prognostic epigenetic chordoma subtypes and first use of plasma methylome-based biomarkers to noninvasively diagnose and subtype chordomas. These results may transform patient management by allowing treatment aggressiveness to be balanced with patient risk according to prognosis.

Background Meningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management. Methods We evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms. Results We developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score. Conclusion We propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.

Meningiomas are the most common primary intracranial tumour in adults1. Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; however, they do not accurately reflect the clinical behaviour of all meningiomas2. Molecular classifications of meningioma that reliably reflect tumour behaviour and inform on therapies are required. Here we introduce four consensus molecular groups of meningioma by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance in a unified analysis. These molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of the newly defined molecular groups and uncovered highly abundant and group-specific protein targets that we validated using immunohistochemistry. Single-cell RNA sequencing revealed inter-individual variations in meningioma as well as variations in intrinsic expression programs in neoplastic cells that mirrored the biology of the molecular groups identified. Multi-omics datasets are integrated to generate a unified and clinically informed molecular classification of meningiomas.

BACKGROUND High-grade gliomas impose substantial morbidity and mortality due to rapid cancer progression and recurrence. Factors such as surgery, chemotherapy and radiotherapy remain the cornerstones for treatment of brain cancer and brain cancer research. The role of anesthetics on glioma progression is largely unknown. METHODS This multicenter retrospective cohort study compared patients who underwent high-grade glioma resection with minimal sedation (awake craniotomy) and those who underwent craniotomy with general anesthesia (GA). Various perioperative factors, intraoperative and postoperative complications, and adjuvant treatment regimens were recorded. The primary outcome was progression-free survival (PFS); secondary outcomes were overall survival (OS), postoperative pain score, and length of hospital stay. RESULTS A total of 891 patients were included; 79% received GA, and 21% underwent awake craniotomy. There was no difference in median PFS between awake craniotomy (0.54, 95% confidence interval [CI]: 0.45-0.65 y) and GA (0.53, 95% CI: 0.48-0.60 y) groups (hazard ratio 1.05; P

Background The therapeutic challenge of glioblastoma (GBM) has catalyzed the development of clinical trials to evaluate novel interventions. With increased understanding of GBM biology and technological advances, the neurosurgeon's role in neuro-oncology has evolved. Objective To evaluate the current landscape of procedure-based clinical trials for GBM to characterize this evolution, gain insight into past failures, and accordingly outline implications for future research and practice that may inform future studies. Methods The ClinicalTrials.gov database was searched for surgical/procedural trials in individuals with GBM. Demographics, specific intervention, trial phase, and main outcome measures were abstracted. Results A total of 224 of 2311 GBM trials (9.7%) were identified as procedural, with the majority being based in the United States (155/224, 69.2%), single-center (155/224, 69.2%), and not randomized (176/224, 78.6%). Primary and recurrent GBMs were evenly addressed. The leading interventions were local delivery of therapeutics (50.0%), surgical techniques (33.9%), such as image-guided surgery, and novel device applications (14.3%). Phase I designs predominated (82/224, 36.6%). The top primary outcome was safety/tolerability/feasibility (88/224, 39.3%), followed by survival (46/224, 20.5%). Approximately 17% of studies were terminated, withdrawn, or suspended. Fifty-two linked publications were identified, among which 42 were classified as having a positive result. Conclusion Procedural interventions comprised ∼10% of all registered GBM trials. Local delivery of therapeutics, use of surgical imaging techniques and novel device applications, predominantly through phase I designs, represent the evolved role of the neurosurgeon in neuro-oncology. Improved reporting of trial designs, outcomes, and results are needed to better inform the field and increase efficiency.

Introduction Meningioma is the most common primary brain tumor. Most meningiomas are benign; however, a subset of these tumors can be aggressive, presenting with early or multiple tumor recurrences that are refractory to neurosurgical resection and radiotherapy. There is no standard systemic therapy for these patients, and post-surgical management of these patients is usually complicated due to lack of accurate prediction for tumor progression. Methods In this review, we summarise the crucial immunosuppressive role of checkpoint regulators, including PD-1 and PD-L1 interacting in the tumor microenvironment, which has led to efforts aimed at targeting this axis. Results Since their discovery, checkpoint inhibitors have significantly improved the outcome in many types of cancers. Currently, targeted therapy for PD-1 and PD-L1 proteins are being tested in several ongoing clinical trials for brain tumors such as glioblastoma. More recently, there have been some reports implicating increased PD-L1 expression in high-grade (WHO grades II and III) meningiomas. Several clinical trials are underway to assess the efficacy of checkpoint inhibitors in the therapeutic management of patients with aggressive meningiomas. Here, we review the immune suppressive microenvironment in meningiomas, and then focus on clinical and pathological characterization and tumor heterogeneity with respect to PD-L1 expression as well as challenges associated with the assessment of PD-L1 expression in meningioma. Conclusion We conclude with a brief review of ongoing clinical trials using checkpoint inhibitors for the treatment of high-grade and refractory meningiomas.

Surgery is the main treatment option for the management of craniopharyngiomas. Transcranial microsurgical approaches, such as pterional and subfrontal approaches, have constituted the classic operative strategy for resection of these tumors. However, the development of endoscopic endonasal approaches has revolutionized the treatment of craniopharyngiomas in the last 15 years, and endoscopic resection is favored for most craniopharyngiomas. In this article, we discuss our experience with the management of craniopharyngiomas and review the current results of the surgical treatment of those tumors, including discussion of goals of surgery, complications, recurrences, and the role of adjuvant treatment.

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often painful neuronal tumors called schwannomas (SWNs). While germline mutations in SMARCB1 or LZTR1, plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q have been identified in a subset of patients, little is known about the epigenomic and genomic alterations that drive SWNTS-related SWNs (SWNTS-SWNs) in a majority of the cases. We performed multiplatform genomic analysis and established the molecular signature of SWNTS-SWNs. We show that SWNTS-SWNs harbor distinct genomic features relative to the histologically identical non-syndromic sporadic SWNs (NS-SWNS). We demonstrate the existence of four distinct DNA methylation subgroups of SWNTS-SWNs that are associated with specific transcriptional programs and tumor location. We show several novel recurrent non-22q deletions and structural rearrangements. We detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, with predominance in LZTR1-mutant tumors. In addition, we identified specific genetic, epigenetic, and actionable transcriptional programs associated with painful SWNTS-SWNs including PIGF, VEGF, MEK, and MTOR pathways, which may be harnessed for management of this syndrome.

Background Endoscopic endonasal approaches (EEAs) have been adopted as an alternative to standard transcranial approaches for olfactory groove meningiomas (OGMs). However, the relative cost-effectiveness remains controversial. Methods Cost-utility analysis from a societal perspective comparing EEA vs transcranial approaches for OGM was used in this study. Surgical treatment was modeled using decision analysis, and a Markov model was adopted over a 20-year horizon. Parameters were obtained from literature review. Costs were expressed in 2017 Canadian dollars. Results In the base case, EEA was cost-effective compared with transcranial surgery with an incremental cost-effectiveness ratio of $33 523 ($30 475 USD)/QALY. There was a 55% likelihood that EEA was cost-effective at a willingness-to-pay of $50 000/QALY. EEA remained cost-effective at a cerebrospinal fluid leak rate below 60%, gross total resection rate above 25%, and base cost less than $66 174 ($60 158 USD). Conclusion EEA may be a cost-effective alternative to transcranial approaches for selected OGM.

Management of clinically aggressive meningiomas is a considerable challenge. PD-L1 induced immune suppression has increasingly gained attention in clinical management of cancer; however, to date, the clinical significance and regulatory mechanisms of PD-L1 in meningioma is not yet fully characterized. We sought to characterize PD-L1 expression in meningioma and elucidate its regulatory mechanisms. Immunohistochemical staining of PD-L1 expression in meningiomas showed 43% positivity in both tumor and immune cells and we observed intra and inter tumoral heterogeneity. Univariate and multivariate analyses confirmed that PD-L1 protein expression is an independent prognostic marker for worse recurrence free survival in meningioma. Furthermore, our transcriptomic analysis revealed a strong association between PD-L1 expression and that of NFKB2 and carbonic anhydrase 9 (CA9). We also demonstrated that both of these markers, when co-expressed with PD-L1, predict tumor progression. Our studies on several meningioma cell lines cultured in hypoxic conditions validated the association of CA9 and PD-L1 expression. Here we show the clinical significance of PD-L1 in meningioma as a marker that can predict tumor recurrence. We also show an association PD-L1 expression with NFKB2 expression and its induction under hypoxic conditions. These findings may open new avenues of molecular investigation in pathogenesis of meningioma.

The WHO Classification of Tumors of Soft Tissue and Bone divides rhabdomyosarcoma (RMS) into alveolar, embryonal, pleomorphic, and spindle cell/sclerosing types. Advances in molecular diagnostics have allowed for further refinement of RMS classification including the identification of new subtypes. Very rare RMS with epithelioid and spindle cell morphology, female predominance, marked osseous predilection, ALK expression, EWSR1/FUS-TFCP2 gene fusions, and highly aggressive clinical behavior have recently been recognized with only 23 cases reported in the English language literature. Herein, we report two additional cases with detailed clinicopathologic description and molecular confirmation. In brief, two young women presented each with a primary bone tumor-one with a frontal bone tumor and another with an osseous pelvic tumor. Both tumors showed epithelioid to spindle cell morphology, ALK expression, and EWSR1/FUS-TFCP2 gene fusions. Both patients died of disease less than 17 months from diagnosis despite administration of multiple lines of aggressive treatment. In addition, we review the literature and discuss differential diagnostic and potential treatment considerations.

Purpose To quantitatively compare the recurrence pattern of glioblastoma (IDH-wild type) versus grade 4 IDH-mutant astrocytoma (herein referred to as wtIDH and mutIDH, respectively) following primary chemoradiation. Methods Twenty-two wtIDH and 22 mutIDH patients matched by sex, extent of resection, and corpus callosum involvement were enrolled. The recurrent gross tumor volume (rGTV) was compared with both the gross tumor volume (GTV) and clinical target volume (CTV) from radiotherapy planning. Failure patterns were quantified by the incidence and volume of the rGTV outside the GTV and CTV, and positional differences of the rGTV centroid from the GTV and CTV. Results The GTV was smaller in wtIDH compared to the mutIDH group (mean±SD: 46.5±26.0 cm3 v. 72.2±45.4 cm3, p=0.026). The rGTV was 10.7±26.9 cm3 and 46.9±55.0 cm3 smaller than the GTV for the same groups (p=0.018). The rGTV extended outside the GTV in 22 (100%) and 15 (68%) (p=0.009) of wtIDH and mutIDH patients, respectively; however, the volume of rGTV outside the GTV was not significantly different (12.4±16.1 cm3 vs. 8.4±14.2 cm3, p=0.443). The rGTV metrics extending outside the CTV was not different between the groups. The rGTV centroid was within 5.7 mm of the closest GTV edge for 21 (95%) and 22 (100%) of wtIDH and mutIDH patients, respectively. Conclusion The rGTV extended beyond the GTV less often in mutIDH patients, suggesting limited margin radiotherapy could be beneficial in this group. The results support the study of small margin adaptive radiotherapy per the ongoing UNITED MR-Linac 5 mm CTV trial (NCT04726397).

Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allelespecific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer. info:eu-repo/semantics/publishedVersion

Background Glioblastoma (GBM) has a median age of diagnosis of 64 years old and the incidence increases with age. An increasing number of elderly patients are being diagnosed with GBM and undergoing surgery. These patients often present with multiple medical comorbidities and have significantly worse outcomes compared to adult patients. The goal of this study was to determine clinical predictors of survival in elderly patients undergoing surgery for GBM. Methods Our brain tumor database was reviewed for all patients 65 years of age and older that underwent surgery for newly diagnosed GBM over a 14-year period from 2005 to 2018. Patient characteristics, comorbidities, complications, and treatment were collected. A total of 150 patients were included, and subdivided into two age categories; 65–74 years old and 75 years or older. Results The median OS for all patients was 9.4 months. Neither the presence nor number of medical comorbidities were associated with decreased survival (P = .9 and P = .1, respectively). Postoperative complications were associated with worse survival for all patients (HR = 2.34, P = .01) and occurred in patients in the older age category and patients with longer lengths of stay (P < .0001). Conclusions The presence of medical comorbidities is not a reason to exclude patients with GBM from surgical consideration. Excluding EOR and adjuvant treatment, postoperative complication is the most significant predictor of survival in elderly patients. Postoperative complications are associated with a longer LOS and are more common in patients 75 years of age and older.

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.

Background Brain metastases which require resection are treated with surgery followed by whole brain radiation therapy or postoperative cavity boost stereotactic radiosurgery (POCBS). Recently a novel strategy using neoadjuvant stereotactic radiosurgery (NaSRS) followed by resection was reported, demonstrating lower rates of postoperative leptomeningeal dissemination (LMD) and symptomatic radiation toxicity compared to a comparative cohort of patients treated with postoperative SRS. Objective To determine if the rate of symptomatic radiation toxicity at 1 yr in patients who receive NaSRS differs significantly from historical rates for patients treated with POCBS. Methods This is a multi-center, non-randomized, open phase II clinical trial. A total of 30 patients with up to 10 brain metastases, at least 1 of which is appropriate for surgical resection, will be enrolled for over 4 yr. All enrolled patients will be assigned to receive NaSRS followed by surgery. Expected outcome This study will clarify whether symptomatic radiation toxicity caused by NaSRS is significantly decreased compared to historical rates associated with POCBS. Secondary endpoints will include 1-yr local control (LC) of the treated lesion, 1-yr rates of LMD, median survival and 2-yr rates of progression-free and overall survival. Tertiary analyses will include correlation between LC and radiation toxicity with pretreatment clinical factors, serum markers, radiomic features, and molecular assessments of the resected tumors. Discussion This prospective study will determine the toxicity associated with NaSRS and provide additional quantitative metrics of efficacy for future comparative trials.

Purpose Brain metastases (BrM) are common in patients with epidermal growth factor receptor (EGFRm) mutant non-small cell lung cancer (NSCLC). We sought to determine the rate of neurologic death (ND) in this population. Methods and Materials We analyzed data from 198 patients who received a diagnosis of BrM from EGFRm NSCLC between 2004 and 2016, comparing patients whose initial treatment for BrM was stereotactic radiosurgery with or without tyrosine kinase inhibitors (TKI), whole brain radiation therapy (WBRT) with or without TKI, or TKI alone. The incidence of ND was determined using a competing risks analysis. Univariate and multivariate analyses were used to identify clinical variables associated with this outcome. Results The percentage of patients who initially received stereotactic radiosurgery, whole brain radiation therapy, or TKI alone was 22%, 61%, and 17%, respectively. Median overall survival in these subgroups was 31.1, 14.6, and 24.6 months, respectively (P = .0016). The 5-year incidence of ND among all patients was 40% and did not significantly vary according to treatment group. In a multivariable model, only leptomeningeal disease at any point in a patient’s disease course significantly correlated with ND (hazard ratio 4.75, P Conclusions Among our cohort of patients with BrM from EGFRm NSCLC, the incidence of ND was significantly higher than suggested by previous reports. BrM should be considered a driver of mortality in many patients with EGFRm NSCLC, and treatments providing better control of BrM, lower neurocognitive side effects, and maintenance of quality of life are needed.

Von Hippel-Lindau disease (VHL) is a heritable condition caused by pathogenic variants in VHL and is characterized by benign and malignant lesions in the central nervous system (CNS) and abdominal viscera. Due to its variable expressivity, existing efforts to collate VHL patient data do not adequately capture all VHL manifestations. We developed a comprehensive and standardized VHL database in the web-based application, REDCap, that thoroughly captures all VHL manifestation data. As an initial trial, information from 86 VHL patients from the University Health Network/Hospital for Sick Children was populated into the database. Analysis of this cohort showed missense variants occurring with the greatest frequency, with all variants localizing to the α- or β-domains of VHL. The most prevalent manifestations were central nervous system (CNS), renal, and retinal neoplasms, which were associated with frameshift variants and large deletions. We observed greater age-related penetrance for CNS hemangioblastomas with truncating variants compared to missense, while the reverse was true for pheochromocytomas. We demonstrate the utility of a comprehensive VHL database, which supports the standardized collection of clinical and genetic data specific to this patient population. Importantly, we expect that its web-based design will facilitate broader international collaboration and lead to a better understanding of VHL.

The invasive capacity of GBM is one of the key tumoral features associated with treatment resistance, recurrence, and poor overall survival. The molecular machinery underlying GBM invasiveness comprises an intricate network of signaling pathways and interactions with the extracellular matrix and host cells. Among them, PI3k/Akt, Wnt, Hedgehog, and NFkB play a crucial role in the cellular processes related to invasion. A better understanding of these pathways could potentially help in developing new therapeutic approaches with better outcomes. Nevertheless, despite significant advances made over the last decade on these molecular and cellular mechanisms, they have not been translated into the clinical practice. Moreover, targeting the infiltrative tumor and its significance regarding outcome is still a major clinical challenge. For instance, the pre- and intraoperative methods used to identify the infiltrative tumor are limited when trying to accurately define the tumor boundaries and the burden of tumor cells in the infiltrated parenchyma. Besides, the impact of treating the infiltrative tumor remains unclear. Here we aim to highlight the molecular and clinical hallmarks of invasion in GBM.

Purpose: Isocitrate dehydrogenase (IDH) mutations are common in low-grade gliomas and the IDH mutation status is now integrated into the WHO classification of gliomas. IDH mutations lead to preferential accumulation of the R- relative to the S-enantiomer of 2-hydroxyglutarate (2-HG). We investigated the utility of tissue total 2-HG, R-2-HG, and the R-2-HG/S-2-HG ratio (rRS) as diagnostic and prognostic biomarkers for IDH mutations in gliomas. Experimental Design: Glioma tissue and blood samples from 87 patients were analyzed with HPLC-MS/MS coupled with a CHIROBIOTIC column to quantify both enantiomers of 2-HG. ROC analysis was conducted to evaluate the sensitivity and specificity of 2-HG, R-2-HG, and rRS. The feasibility of real-time determination of IDH status was evaluated in 11 patients intraoperatively. The prognostic value of rRS was evaluated using the Kaplan–Meier method. Results: The rRS in glioma tissues clearly distinguished patients with IDH-mutant versus wild-type tumors (P < 0.001). Sensitivity and specificity using an rRS cut-off value of 32.26 were 97% and 100%, respectively. None of total 2-HG, R-2-HG, or rRS was elevated in serum samples. Among patients with IDH-mutant tumors, tissue rRS stratifies overall survival. The duration of tissue analysis is approximately 60 minutes. Conclusions: Our study demonstrates that rRS is a reliable biomarker of IDH mutation status. This technique can be used to determine IDH mutation status intraoperatively, and to guide treatment decisions based on IDH mutation status in real time. Finally, rRS values may provide additional prognostic information and further validation is required.

Background Meningiomas represent one of the most common brain tumors and exhibit a clinically heterogeneous behavior, sometimes difficult to predict with classic histopathologic features. While emerging molecular profiling efforts have linked specific genomic drivers to distinct clinical patterns, the proteomic landscape of meningiomas remains largely unexplored. Methods We utilize liquid chromatography tandem mass spectrometry with an Orbitrap mass analyzer to quantify global protein abundances of a clinically well-annotated formalin-fixed paraffin embedded (FFPE) cohort (n = 61) of meningiomas spanning all World Health Organization (WHO) grades and various degrees of clinical aggressiveness. Results In total, we quantify 3042 unique proteins comparing patterns across different clinical parameters. Unsupervised clustering analysis highlighted distinct proteomic (n = 106 proteins, Welch’s t-test, P < 0.01) and pathway-level (eg, Notch and PI3K/AKT/mTOR) differences between convexity and skull base meningiomas. Supervised comparative analyses of different pathological grades revealed distinct patterns between benign (grade I) and atypical/malignant (grades II‒III) meningiomas with specific oncogenes enriched in higher grade lesions. Independent of WHO grade, clinically aggressive meningiomas that rapidly recurred (3 cm maximum tumor diameter) and those with previous radiation exposure revealed perturbed pro-proliferative (eg, epidermal growth factor receptor) and metabolic as well as inflammatory response pathways (mitochondrial activity, interferon), respectively. Conclusions Our proteomic study demonstrates that meningiomas of different grades and clinical parameters present distinct proteomic profiles. These proteomic variations offer potential future utility in helping better predict patient outcome and in nominating novel therapeutic targets for personalized care.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.

During the last two decades evolution of the endoscopic endonasal approaches (EEA) has offered the option of minimally invasive techniques in the management of esthesioneuroblastomas (ENB), either as endoscope assisted cranial resection or as pure endoscopic procedures. This study presents the use of pure EEA in the management of ENB in our center, along with a literature review. We retrospectively reviewed the clinical, radiology and pathology records of patients with ENB treated during the period July 2006 to January 2016. During the above period, ten patients with ENB were treated using pure EEA. The mean age was 47.5 years. The gender distribution was: eight males, two females. The most common presenting symptoms were nasal obstruction and discharge or epistaxis (8/10). The mean duration of symptoms was 1.5 years. All patients had preoperative confirmation of ENB by biopsy. Five patients received neoadjuvant radiation and four underwent postoperative radiation. One patient did not receive any radiotherapy and no patient received chemotherapy. Gross total resection was achieved in all patients and intraoperative microscopically negative surgical margins achieved in 9/10 (90%). No major intraoperative complications occurred. The most common postoperative complication was nasal infection. Cerebrospinal fluid leak was noted in one patient. During the follow-up period of 6–120 months (mean 74.8) two cases of neck lymph node recurrence were observed. No deaths due to the disease occurred during the follow-up period. Pure EEA offer excellent results in the management of ENB. Neoadjuvant radiation treatment is promising although more studies need to establish its role.

One of the most prominent features of glioblastoma (GBM) is hyper-vascularization. Bone marrow-derived macrophages are actively recruited to the tumor and referred to as glioma-associated macrophages (GAMs) which are thought to provide a critical role in tumor neo-vascularization. However, the mechanisms by which GAMs regulate endothelial cells (ECs) in the process of tumor vascularization and response to anti-angiogenic therapy (AATx) is not well-understood. Here we show that GBM cells secrete IL-8 and CCL2 which stimulate GAMs to produce TNFα. Subsequently, TNFα induces a distinct gene expression signature of activated ECs including VCAM-1, ICAM-1, CXCL5, and CXCL10. Inhibition of TNFα blocks GAM-induced EC activation both in vitro and in vivo and improve survival in mouse glioma models. Importantly we show that high TNFα expression predicts worse response to Bevacizumab in GBM patients. We further demonstrated in mouse model that treatment with B20.4.1.1, the mouse analog of Bevacizumab, increased macrophage recruitment to the tumor area and correlated with upregulated TNFα expression in GAMs and increased EC activation, which may be responsible for the failure of AATx in GBMs. These results suggest TNFα is a novel therapeutic that may reverse resistance to AATx. Future clinical studies should be aimed at inhibiting TNFα as a concurrent therapy in GBMs. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01163-0.

On July 24, 2020, a workshop sponsored by the National Brain Tumor Society was held on innovating brain tumor clinical trials based on lessons learned from the COVID-19 experience. Various stakeholders from the brain tumor community participated including the US Food and Drug Administration (FDA), academic and community clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and representatives from the Society for Neuro-Oncology and the National Cancer Institute. This report summarizes the workshop and proposes ways to incorporate lessons learned from COVID-19 to brain tumor clinical trials including the increased use of telemedicine and decentralized trial models as opportunities for practical innovation with potential long-term impact on clinical trial design and implementation.

To evaluate the relationships between calibration dose rate, calculated biologically effective dose (BED), and clinical factors and tumor control after stereotactic radiosurgery (SRS) for acoustic neuroma.We performed a retrospective study of all patients with acoustic neuromas treated with frame-based cobalt-60 SRS at a single institution between 2005 and 2019. The calibration dose rate and cobalt-60 half-life were used to calculate the nominal dose rate during treatment. An SRS-specific monoexponential model accounting for treatment time per lesion was used to estimate BED.The study included 607 patients with 612 acoustic neuromas. Median follow-up was 5.0 years. There was no association between dose rate or BED with local failure (LF), radiologic edema, or symptomatic edema. Cystic tumors (adjusted hazard ratio 0.26, P = 0.028) were associated with lower LF, while use of SRS as salvage treatment for growing tumors (adjusted hazard ratio 4.9, P0.0001) was associated with higher LF. LF occurred more frequently in larger-diameter tumors, while radiologic or symptomatic edema occurred more frequently in larger-volume tumors.Radiosurgery dose rate and BED were not associated with tumor control or radiologic or symptomatic edema. Salvage SRS and larger tumors were associated with a higher LF rate, while cystic tumors were associated with a lower LF rate. Patients with larger tumors should be counseled appropriately about potential side effects and when to seek follow-up care.

Background: The purpose of our study was to characterize clinical features among brain metastasis (BM) patients who were long term survivors (LTS). Methods: We reviewed a registry of BM patients referred to our multidisciplinary BM clinic between 2006 and 2014 and identified 97 who lived &ge, 3 years following BM diagnosis. The clinical and treatment characteristics were obtained from a prospectively maintained database, and additional information was obtained through review of electronic medical records and radiologic images. Survival analyses were performed using the Kaplan-Meier method. Results: Median follow up for LTS was 67 months (range 36&ndash, 181). Median age was 54 years, 65% had single BM, 39% had stable extracranial disease at the time of BM treatment, and brain was the first site of metastasis in 76%. Targetable mutations were present in 39% of patients and 66% received treatment with targeted-, hormonal-, or immuno-therapy. Brain surgery at the time of diagnosis was performed in 40% and stereotactic radiosurgery (SRS) or whole brain radiotherapy (alone or combination) in 52% and 56%, respectively. Following initial BM treatment, 5-year intracranial disease-free survival was 39%, and the cumulative incidence of symptomatic radio-necrosis was 16%. Five and ten-year overall survival was 72% and 26%, respectively. Conclusion: Most LTS were younger than 60 years old and had a single BM. Many received treatment with surgery or targeted, immune, or hormonal therapy.

Background Anaplastic pleomorphic xanthoastrocytoma (APXA) is a rare subtype of CNS astrocytoma. They are generally treated as high-grade gliomas; however, uncertainty exists regarding the optimal therapy. Here, we report on 3 pediatric cases of APXA. Methods Our institutional database was queried for cases of APXA and 3 cases were identified. Surgical samples were processed for methylation profiling and chromosomal microarray analysis. Methylation data were uploaded to the online CNS tumor classifier to determine methylation-based diagnoses to determine copy number variations (CNVs). Results Two patients were male, 1 female, and all were aged 12 years at diagnosis. All underwent a gross total resection (GTR) and were diagnosed with an APXA. Immunohistochemical analysis demonstrated that 2 cases were BRAF V600E positive. Methylation-based tumor classification supported the APXA diagnosis in all cases. CNV analyses revealed homozygous CKDN2A deletions in all and chromosome 9p loss in 2 cases. All patients received radiation therapy (54 Gy in 30 fractions) with concurrent temozolomide. Two patients received maintenance chemotherapy with temozolomide and lomustine for 6 cycles as per the Children’s Oncology Group ACNS0423. The third patient recurred and went on to receive a second GTR and 6 cycles of lomustine, vincristine, and procarbazine. All are alive with no evidence of disease >4 years post-treatment completion (overall survival = 100%, event free survival = 67%). Conclusions The natural history and optimal treatment of this rare pediatric tumor are not well understood. This case series supports the use of adjuvant chemoradiotherapy in the treatment of APXA. The genetic landscape may be informative for optimizing treatment and prognosis.

Background Recent international sequencing efforts have allowed for the molecular taxonomy of lower-grade gliomas (LGG). We sought to analyze The Cancer Genome Atlas (TCGA, 2015) gene expression datasets on molecularly defined oligodendrogliomas (IDH-mutated and 1p/19q-codeleted) patients treated with adjuvant radiation or those observed to discover prognostic markers and pathways. Methods mRNA expression and clinical information of patients with oligodendroglioma were taken from the TCGA “Brain Lower Grade Glioma” provisional dataset. Transcription factor network reconstruction and analysis were performed using the R packages “RTN” and “RTNsurvival.” Elastic net regularization and survival modeling were performed using the “biospear,” “plsRCox,” “survival” packages. Results From our cohort of 137 patients, 65 received adjuvant radiation and 72 were observed. In the cohort that received adjuvant radiotherapy, a transcription factor activity signature, that correlated with hypoxia, was associated with shorter disease-free survival (DFS) (median = 45 months vs 108 months, P < .001). This increased risk was not seen in patients who were observed (P = .2). Within the observation cohort, a transcription factor activity signature was generated that was associated with poor DFS (median = 72 months. vs 143 months., P < .01). Conclusions We identified a transcription factor activity signature associated with poor prognosis in patients with molecular oligodendroglioma treated with adjuvant radiotherapy. These patients would be potential candidates for treatment intensification. A second signature was generated for patients who were more likely to progress on observation. This potentially identifies a cohort who would benefit from upfront adjuvant radiotherapy.

BACKGROUND A Phase 2 multi-center study was conducted to evaluate the replication-competent oncolytic adenovirus, DNX-2401 (tasadenoturev), in combination with the anti-PD-1 antibody, pembrolizumab, in subjects with recurrent glioblastoma. METHODS Subjects ≥ 18 years with glioblastoma at first or second recurrence were treated with a single intratumoral injection of 5e8-5e10 vp DNX-2401 at the time of biopsy, followed by 200 mg pembrolizumab infusions every 3 weeks until progression or toxicity. RESULTS Forty-nine subjects were enrolled at first (79.6%) or second (20.4%) recurrence after prior surgery (89.8%), radiotherapy (100%), and temozolomide (100%). Forty-eight of 49 (98%) were treated with 5e8 vp (n=3), 5e9 vp (n=3), or 5e10 vp (n=42) DNX-2401 and pembrolizumab. Median treatment duration was 7 cycles (range 1–35) with one subject remaining on treatment (cycle 31). Adverse events were primarily mild to moderate, consistent with underlying disease, and manageable. Headache, brain edema, and fatigue are the most common events reported as related to the treatment regimen. Of subjects treated with full dose DNX-2401 and pembrolizumab (n=42), 5 subjects (11.9%) had confirmed responses, including 2 durable ongoing complete responses and 3 partial responses. One subject remains tumor free > 12 months after completing the planned 24 months of pembrolizumab. Median overall survival was 12.5 months; OS-12 and OS-18 were 54.5% and 20.8%, respectively. Four subjects, all of which have survived more than 21 months, continue to be followed for survival. CONCLUSIONS DNX-2401 plus pembrolizumab provides encouraging activity and is safe in patients with recurrent glioblastoma. A global, randomized, controlled Phase 3 study is planned.

Schwannomatosis (SWNTS) is a genetic cancer predisposition syndrome that manifests as multiple and often, painful neuronal tumors called schwannomas (SWNs). Very little is known about the epigenomic and genomic alterations in SWNTS related SWNs (SWNTS-SWNs) other than germline mutations in SMARCB1 and LZTR1 plus somatic mutations in NF2 and loss of heterozygosity in chromosome 22q. Herein, we have comprehensively established the specific molecular signatures of SWNTS-SWNs. We found that tumor anatomic location was associated with pain and distinct DNA methylation and transcriptional signatures. DNA sequencing revealed several novel non-22q deletions, specifically in LZTR1-mutant cases. Whole-genome sequencing identified novel recurrent structural rearrangements. Further, chromosomal aberrations in SWNTS-SWNs were accompanied by increased transcription of mismatch repair genes. Our transcriptome analysis detected the SH3PXD2A-HTRA1 gene fusion in SWNTS-SWNs, more commonly in LZTR1-mutant tumors. In addition, we identified the specific genetic, epigenetic, and transcriptional hallmarks of painful SWNs that may be harnessed to develop new treatments for this debilitating syndrome.

BACKGROUND The survival benefit of surgery for recurrent GBM in the current literature is variable, and often attributed to improvements in surgical technique over time. Studies examining outcomes over prolonged periods are lacking. The primary objective of our study was to determine if surgery for recurrent GBM confers a survival benefit compared to patients not undergoing repeat surgery. The secondary objective of our study was to investigate the effect of known prognostic factors on survival for patients undergoing repeat surgery for GBM. METHODS We analyzed our brain tumour biobank database from 1992 to 2018 for all adult patients that underwent repeat surgery for primary recurrent GBM. This cohort was compared to publicly available data from The Cancer Genome Atlas (TCGA). Survival and prognostic factors were compared within and between groups using Kaplan-Meier survival curves and Cox proportional hazards models. RESULTS A total of 676 patients were included (surgery cohort = 91, non-surgery cohort = 585). The surgery group had a lower age at diagnosis (50.6 vs 58.2 years old, p = < 0.001) and higher Karnofsky Performance Status (KPS) (81.4 vs 77.5, p = 0.002) at diagnosis than the non-surgery group. Other known prognostic factors including IDH status and MGMT methylation status were balanced between groups. Overall median survival was higher in the surgery group than the non-surgery group (30.6 months vs 13.9 months, p = < 0.0001). Within the surgery group, prognostic factors including age, sex, KPS, IDH status, MGMT status, extent of resection by surgeon, tumour location, and time to recurrence were not associated with additional survival benefit. CONCLUSIONS Patients that undergo surgery for recurrent GBM are of younger age and lower KPS at time of initial diagnosis. In patients that undergo repeat surgery, known patient and tumour prognostic factors are not associated with additional survival benefit.

Background Since the COVID-19 pandemic began, thousands of medical procedures and appointments have been canceled or delayed. The long-term effects of these drastic measures on brain tumor patients and caregivers are unknown. The purpose of this study is to better understand how COVID-19 has affected this vulnerable population on a global scale. Methods An online 79-question survey was developed by the International Brain Tumour Alliance, in conjunction with the SNO COVID-19 Task Force. The survey was sent to more than 120 brain tumor charities and not-for-profits worldwide and disseminated to pediatric and adult brain tumor patients and caregivers. Responses were collected from April to May 2020 and subdivided by patient versus caregiver and by geographical region. Results In total, 1989 participants completed the survey from 33 countries, including 1459 patients and 530 caregivers. There were no significant differences in COVID-19 testing rates (P = .662) or positive cases for brain tumor patients between regions (P = .1068). Caregivers were significantly more anxious than patients (P ≤ .0001). Patients from the Americas were most likely to have lost their jobs due to the pandemic, practiced self-isolation, and received telehealth services (P ≤ .0001). Patients from Europe experienced the most treatment delays (P = .0031). Healthcare providers, brain tumor charities, and not-for-profits were ranked as the most trusted sources of information. Conclusions As a result of COVID-19, brain tumor patients and caregivers have experienced significant stress and anxiety. We must continue to provide accessible high-quality care, information, and support in the age of COVID-19.

Purpose/Objective(s) The incidence of intracranial meningiomas increases with age. The standard of care treatment is complete surgical excision, followed by radiation therapy (RT) if indicated. However, six weeks of RT can be challenging for elderly or frail patients. The purpose of this study was to determine if short course RT is safe and effective in elderly patients with meningioma. Materials/Methods We performed a retrospective analysis of patients with meningioma treated with short course beam RT (5-15 fractions) at a single institution. Seventeen patients (94%) received 4005 cGy over 15 fractions and one patient (6%) received 2500 cGy over five fractions. Study endpoints were treatment toxicity (edema), progression-free (PFS) and overall survival (OS). Results Eighteen patients with histologically proven (n = 12) or radiologically presumed meningioma (n = 6, presumed grade I) were identified. Median age at treatment was 85 years (66-95 years). There were eight, eight and two patients with grade I, II and III tumours, respectively. Eight patients (44%) had radiologic edema prior to RT. Six (33%) required dexamethasone treatment during RT and the dose was increased during RT for two patients. Fourteen patients had reduced or no edema post-RT and 13 patients had stable or improving symptoms post-RT. Six patients had disease progression (five in-field, one out-of-field). Median PFS was 3.3 and 0.9 years for grade I and II/III tumours, respectively (p = 0.014). Median OS was 3.3 and 2.5 years for grade I and II/III tumours, respectively (p = 0.12). Conclusion Short course RT for elderly patients with meningioma is well-tolerated and can offer disease control for some patients, particularly those with grade I tumours.

Background There is scarce data on the quality of life of people with neurofibromatosis type 1 (NF1) and type 2 (NF2) in Canada. Methods A cross-sectional study of adults with NF1 and NF2 attending a tertiary center. Patients completed generic measures (SF-36, EQ-5D-5L, and PROMIS pain interference) and disease-specific questionnaires (PedsQL NF1 module and the NFTI-QOL for NF2). We compared generic scores between NF1 and NF2 individuals and used regression models to assess factors associated with quality of life. Results Hundred and eighty-four participants were enrolled. Mean age was 33 years in NF1 and 40 years in NF2. NF1 and NF2 individuals had lower employment rates and lower scores in all domains of the SF-36 compared to the general Canadian population (P < .005). Using the EQ-5D-5L, there was a high proportion of pain (64% in NF1 and 74% in NF2) and anxiety/depression (60% in NF1 and 68% in NF2). Pain interference correlated with poor quality of life in NF1 and NF2; perceived physical appearance was the main predictor of mental well-being in NF1. Conclusions Individuals with NF1 and NF2 have low quality of life, and this correlates with pain, anxiety, and depression, which are prevalent in NF1 and NF2. Perceived physical appearance predicts quality of life in NF1. A multidisciplinary approach is necessary for patients with NF1 and NF2, including mental health and pain management.

Lesion network mapping (LNM) has been applied to true lesions (e.g., cerebrovascular lesions in stroke) to identify functionally connected brain networks. No previous studies have utilized LNM for analysis of intra-axial mass lesions. Here, we implemented LNM for identification of potentially vulnerable epileptogenic networks in mass lesions causing medically-refractory epilepsy (MRE). Intra-axial brain lesions were manually segmented in patients with MRE seen at our institution (EL_INST). These lesions were then normalized to standard space and used as seeds in a high-resolution normative resting state functional magnetic resonance imaging template. The resulting connectivity maps were first thresholded (pBonferroni_cor 2.0); canonical resting-state networks preferentially engaged by EL_INSTs were the Limbic and the Frontoparietal Networks (Mean VOR > 1.5). In this proof of concept study, we demonstrate the feasibility of LNM for intra-axial mass lesions by showing that ELs have discrete functional connections and may preferentially engage in discrete resting-state networks. Thus, the underlying normative neural circuitry may, in part, explain the propensity of particular lesions toward the development of MRE. If prospectively validated, this has ramifications for patient counseling along with both approach and timing of surgery for lesions in locations prone to development of MRE.

BackgroundWe aimed to explore gaps in the care of meningioma patients that could improve quality of care by better understanding symptoms experienced by patients at various stages of treatment, and afterwards.MethodsA novel 19-item self-administered questionnaire was provided for patients with meningiomas to complete by the American Brain Tumor Association (ABTA) over a 3-month period.ResultsA total of 1852 unique respondents were included. Nearly one-third of all respondents felt they received insufficient information about meningiomas at initial diagnosis (N = 607, 32.9%) and 28.8% (N = 530) believed they received insufficient information about treatment options. In fact, 34.5% of respondents received the majority of their information from the internet and nonhealthcare professionals. The most common concerns after initial diagnosis were risks associated with surgery and/or treatment (36.5%) followed by how the tumor would impact daily life (25%) and the risk of tumor recurrence (12.4%). Respondents indicated that a list of resources available for patients with meningiomas (N = 597, 32.3%) would have been most beneficial in regards to their disease experience after their initial diagnosis. Moreover, we found that a substantial proportion of patients continued to report symptoms long after treatment, with fatigue being the most common compared to before treatment (38.2% vs. 57.7%, χ2 = 128, P < .001).ConclusionsPatients with meningiomas exhibit symptoms that continue well after treatment with fatigue and cognitive impairments as the most bothersome. Moreover, patients report key communication gaps that can be addressed to improve their disease experience and care.

Definitive diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Noninvasive diagnostic approaches provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. In the present study, we show that DNA-methylation profiles from plasma reveal highly specific signatures to detect and accurately discriminate common primary intracranial tumors that share cell-of-origin lineages and can be challenging to distinguish using standard-of-care imaging. A cell-free DNA-methylation sequencing assay accurately identifies different brain tumor types using plasma samples.

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

The Coronavirus pandemic has created unprecedented strain on medical resources at health care institutions around the world. At many institutions, this has resulted in efforts to prioritize cases with an attempt to balance the acuity of medical needs with available resources. Here, we provide a framework for institutions and governments to help adjudicate treatment allocations to patients with neuro-oncologic disease.

Background Both genetic and methylation analysis have been shown to provide insight into the diagnosis and prognosis of many brain tumors. However, the implication of methylation profiling and its interaction with genetic alterations in pediatric low-grade gliomas (PLGGs) are unclear. Methods We performed a comprehensive analysis of PLGG with long-term clinical follow-up. In total 152 PLGGs were analyzed from a range of pathological subtypes, including 40 gangliogliomas. Complete molecular analysis was compared with genome-wide methylation data and outcome in all patients. For further analysis of specific PLGG groups, including BRAF p.V600E mutant gliomas, we compiled an additional cohort of clinically and genetically defined tumors from 3 large centers. Results Unsupervised hierarchical clustering revealed 5 novel subgroups of PLGG. These were dominated by nonneoplastic factors such as tumor location and lymphocytic infiltration. Midline PLGG clustered together while deep hemispheric lesions differed from lesions in the periphery. Mutations were distributed throughout these location-driven clusters of PLGG. A novel methylation cluster suggesting high lymphocyte infiltration was confirmed pathologically and exhibited worse progression-free survival compared with PLGG harboring similar molecular alterations (P = 0.008; multivariate analysis: P = 0.035). Although the current methylation classifier revealed low confidence in 44% of cases and failed to add information in most PLGG, it was helpful in reclassifying rare cases. The addition of histopathological and molecular information to specific methylation subgroups such as pleomorphic xanthoastrocytoma–like tumors could stratify these tumors into low and high risk (P = 0.0014). Conclusion The PLGG methylome is affected by multiple nonneoplastic factors. Combined molecular and pathological analysis is key to provide additional information when methylation classification is used for PLGG in the clinical setting.

OBJECTIVETranssphenoidal surgery is advocated as the first-line management of growth hormone (GH)–secreting adenomas. Although disease control is defined by strict criteria for biochemical remission, the length of follow-up needed is not well defined in literature. In this report, the authors present their long-term remission rate and identify various predictive factors that might influence the clinical outcome.METHODSThe authors conducted a single-institute retrospective analysis of all transsphenoidal procedures for GH-secreting adenomas performed from January 2000 to June 2016. The primary outcome was defined as biochemical remission according to the 2010 consensus criteria and measured at the 1-year postoperative mark as well as on the last recorded follow-up appointment.Secondary variables included recurrence rate, patterns of clinical presentation, and outcome of adjuvant therapy (including repeat surgery). Subgroup analysis was performed for patients who had biochemical or radiological “discordance”—patients who achieved biochemical remission but with incongruent insulin-like growth factor 1 (IGF-1)/GH or residual tumor on MRI. Recurrence-free survival analysis was conducted for patients who achieved remission at 1 year after surgery.RESULTSEighty-one patients (45 female and 36 male) with confirmed acromegaly treated with transsphenoidal surgery were included. In 62 cases the patients were treated with a pure endoscopic approach and in 19 cases an endoscopically assisted microscopic approach was used.Primary biochemical remission after surgery was achieved in 59 cases (73%) at 1 year after surgery. However, only 41 patients (51%) remained in primary surgical remission (without any adjuvant treatment) at their last follow-up appointment, indicating a recurrence rate of 31% (18 of 59 patients) over the duration of follow-up (mean 100 ± 61 months). Long-term remission rates for pure endoscopic and endoscopically assisted cases were not significantly different (48% vs 52%, p = 0.6). Similarly, no significant difference in long-term remission was detected between primary surgery and repeat surgery (54% vs 33%, p = 0.22).Long-term remission was significantly influenced by extent of resection, cavernous sinus invasion (radiologically as well as surgically reported), and preoperative and early postoperative GH and IGF-1 levels (within 24–48 hours after surgery) as well as by clinical grade, with lower remission rates in patients with dysmorphic features and/or medical comorbidities (grade 2–3) compared to minimally symptomatic or silent cases (grade 1).CONCLUSIONSThe long-term surgical remission rate appears to be significantly less than “early” remission rates and is highly dependent on the extent of tumor resection. The authors advocate a long-term follow-up regimen and propose a clinical grading system that may aid in predicting long-term outcome in addition to the previously reported anatomical factors. The role of repeat surgery is highlighted.

Brain metastases comprise the majority of central nervous tumors in adults and confer poorer survival for patients with primary cancer. Systemic disease control is improving with advances in treatment for primary tumors and the complexity of brain metastases management is increasing with multimodality approaches incorporating combinations of surgery, radiotherapy, chemotherapy, targeted therapies, and immunotherapy. Accordingly, the Society for Neuro-Oncology established an annual brain metastases conference to unite colleagues from multiple disciplines with content spanning a range of timely topics relevant to improving our understanding of brain metastases and how they are optimally treated. The inaugural meeting on August 16–17, 2019 was very successful with 163 impactful presentations being delivered to a large multidisciplinary audience on current research advances in the field of neuro-oncology. This review summarizes the major themes of the meeting and highlights the main findings presented.

Background The goal of glioblastoma (GBM) surgery is to maximize the extent of resection (EOR) while minimizing postoperative neurological complications. Awake craniotomy (AC) has been demonstrated to achieve this goal for low-grade gliomas in or near eloquent areas. However, the efficacy of AC for GBM resection has not been established. Therefore, we aimed to investigate the outcomes of AC for surgical resection of GBM using a systematic review and meta-analysis of published studies. Methods Systematic searches of Ovid MEDLINE, Embase, Cochrane Controlled Register of Controlled Trials, and PubMed were performed from database inception to September 14, 2019 for published studies reporting outcomes of AC for GBM resection. Outcome measures analyzed included EOR and the event rate of postoperative neurological deficits. Results A total of 1928 unique studies were identified. Fourteen studies reporting 278 patients were included in our meta-analysis. Mean age of patients was 46.9 years (95% confidence interval [CI]: 43.9–49.9). Early and late postoperative neurological deficits occurred in 34.5% (95% CI: 21.9–48.2) and 1.9% (95% CI: 0.0–9.2) of patients, respectively. Pooled percentage of gross total resection (GTR) was 74.7% (95% CI: 66.7–82.1), while the pooled percentage reduction in tumor volume was 95.3% (95% CI: 92.2–98.4). Conclusions Limited current evidence suggests that the use of AC for resection of supratentorial GBM is associated with a low rate of persistent neurological deficits while achieving an acceptable rate of GTR. Our findings demonstrate the potential viability of AC in GBM resection and highlight the need for further research on this topic.

Glioblastoma (GBM) is the most common primary malignant brain tumor, with a universally poor prognosis. The emergence of molecular biomarkers has had a significant impact on histological typing and diagnosis, as well as predicting patient survival and response to treatment. The methylation status of the O(6)-methylguanine-DNA methyl-transferase (MGMT) gene promoter is one such molecular biomarker. Despite the strong evidence supporting the role of MGMT methylation status in prognostication, its routine implementation in clinical practice has been challenging. The methods and optimal cutoff definitions for MGMT status determination remain controversial. Variation in detection methods between laboratories presents a major challenge for consensus. Moreover, consideration of other clinical and genetic/epigenetic factors must also be incorporated into treatment decision making. In this review, we distill the available evidence to summarize our position on the optimal use of available assays, and propose strategies for resolving cases with equivocal methylation status and a framework for incorporating this important assay into research and clinical practice.

Background Molecular signatures are being increasingly incorporated into cancer classification systems. DNA methylation-based central nervous system (CNS) tumor classification is being recognized as having the potential to aid in cases of difficult histopathological diagnoses. Here, we present our institutional clinical experience in integrating a DNA-methylation-based classifier into clinical practice and report its impact on CNS tumor patient diagnosis and treatment. Methods Prospective case review was undertaken at CNS tumor board discussions over a 3-year period and 55 tumors with a diagnosis that was not certain to two senior neuropathologists were recommended for methylation profiling based on diagnostic needs. Tumor classification, calibrated scores, and copy number variant (CNV) plots were obtained for all 55 cases. These results were integrated with histopathological findings to reach a final diagnosis. We retrospectively reviewed each patient's clinical course to determine final neuro-pathology diagnoses and the impact of methylation profiling on their clinical management, with a focus on changes that were made to treatment decisions. Results Following methylation profiling, 46 of the 55 (84%) challenging cases received a clinically relevant diagnostic alteration, with two-thirds having a change in the histopathological diagnosis and the other one-third obtaining clinically important molecular diagnostic or subtyping alterations. WHO grading changed by 27% with two-thirds receiving a higher grade. Patient care was directly changed in 15% of all cases with major changes in clinical decision-making being made for these patients to avoid unnecessary or insufficient treatment. Conclusions The integration of methylation-based CNS tumor classification into diagnostics has a substantial clinical benefit for patients with challenging CNS tumors while also avoiding unnecessary health care costs. The clinical impact shown here may prompt the expanded use of DNA methylation profiling for CNS tumor diagnostics within prominent neuro-oncology centers globally.