Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype.

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.

Differences in methylation profiles between long-term survivors and short-term survivors of IDH-wild-type glioblastoma.

Background: Patients with glioblastoma (GBM) have a median overall survival (OS) of approximately 16 months. However, approximately 5% of patients survive >5 years. This study examines the differences in methylation profiles between long-term survivors (>5 years, LTS) and short-term survivors (<1 year, STS) with isocitrate dehydrogenase (IDH)-wild-type GBMs. Methods: In a multicenter retrospective analysis, we identified 25 LTS with a histologically confirmed GBM. They were age- and sex-matched to an STS. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of LTS versus STS were compared. Results: After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH-wild-type GBMs, all with +7/-10 signature. LTS had significantly increased O6-methylguanine methyltransferase (MGMT) promoter methylation and higher prevalence of FGFR3-TACC3 fusion (P = .03). STS were more likely to exhibit CDKN2A/B loss (P = .01) and higher frequency of NF1 (P = .02) mutation. There were no significant CpGs identified between LTS versus STS at an adjusted P-value of .05. Unadjusted analyses identified key pathways involved in both LTS and STS. The most common pathways were the Hippo signaling pathway and the Wnt pathway in LTS, and GPCR ligand binding and cell-cell signaling in STS. Conclusions: A small group of patients with IDH-wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.

Fractionated radiotherapy for surgically resected intracranial meningiomas: A multicentre retrospective cohort study.

BACKGROUND: Aside from surgical resection, the only standard of care treatment modality for meningiomas is radiotherapy (RT). Despite this, few studies have focused on identifying clinical covariates associated with failure of fractionated RT following surgical resection (fRT), and the timing of fRT following surgery still remains controversial (adjuvant versus salvage fRT). We assessed the outcomes of the largest, multi-institutional cohort of surgically resected meningiomas treated with subsequent adjuvant and salvage fRT to identify factors associated with local freedom from recurrence (LFFR) over 3-10 years post-fRT and to determine the optimal timing of fRT. METHODS: Patients with intracranial meningiomas who underwent surgery and fRT between 1997 and 2018 were included. Primary endpoints were radiographic recurrence/progression and time to progression from the completion of fRT. RESULTS: 404 meningiomas were included for analysis. Of these, 167 (41.3%) recurred post-fRT. Clinical covariates independently associated with worse PFS post-fRT included receipt of previous RT to the meningioma, having a WHO grade 3 meningioma or recurrent meningioma, the meningioma having a higher MIB1-index or brain invasion on pathology, and older patient age at diagnosis. Subgroup analysis identified higher MIB1-index as a histological factor associated with poorer LFFR in WHO grade 2 meningiomas. 179 patients underwent adjuvant RT shortly after surgery whereas 225 patients had delayed, salvage fRT after recurrence/progression. Following propensity score matching, patients that underwent adjuvant fRT had improved LFFR post-fRT compared to those that received salvage fRT. CONCLUSION: There is a paucity of clinical factors that can predict a meningioma's response to fRT following surgery. Adjuvant fRT may be associated with improved PFS post-fRT compared to salvage fRT. Molecular biomarkers of RT-responsiveness are needed to better inform fRT treatment decisions.

Methylation Profiling Identifies Stability of Isocitrate Dehydrogenase Mutation Over Time.

OBJECTIVE: Isocitrate dehydrogenase (IDH) mutation status is a key diagnostic and prognostic feature of gliomas. It is thought to occur early in glioma tumorigenesis and remain stable over time. However, there are reports documenting a loss of IDH mutation status in a subset of patients with glioma recurrence. Here, we identified patients with a documented loss of IDH mutation status longitudinally and performed multi-platform analysis in order to determine if IDH mutations are stable throughout glioma evolution. METHODS: We retrospectively identified patients from our institution from 2009 to 2018 with immunohistochemistry (IHC)-recorded IDH mutation status changes longitudinally. Archived formalin-fixed paraffin-embedded and frozen tissue samples from these patients were collected from our institution's tumour bank. Samples were analysed using methylation profiling, copy number variation, Sanger sequencing, droplet digital PCR (ddPCR) and IHC. RESULTS: We reviewed 1491 archived glioma samples including 78 patients with multiple IDH mutant tumour samples collected longitudinally. In all instances of documented loss of IDH mutation status, multi-platform profiling identified a mixture of low tumour cell content and non-neoplastic tissue including perilesional, reactive or inflammatory cells. CONCLUSIONS: All patients with a documented loss of IDH mutation status longitudinally were resolved through multi-platform analysis. These findings support the hypothesis that IDH mutations occur early in gliomagenesis and in the absence of copy number changes at the IDH loci and are stable throughout tumour treatment and evolution. Our study highlights the importance of accurate surgical sampling and the role of DNA methylome profiling in diagnostically uncertain cases for integrated pathological and molecular diagnosis.

Integrated molecular analysis reveals hypermethylation and overexpression of HOX genes to be poor prognosticators in isocitrate dehydrogenase mutant glioma.

BACKGROUND: Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within isocitrate dehydrogenase (IDH)-mutant gliomas, there is a high variability in survival and a need to more accurately predict outcome. METHODS: To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV), and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and 2 validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA). RESULTS: Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into 2 prognostic groups strongly predicting survival that were validated using 2 independent cohorts from TCGA and DKFZ (all P-values < .0001). The methylation signatures that predicted poor outcomes also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy, and worse survival (P-value < .0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas. CONCLUSIONS: HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas.

Outcomes and predictors of response to fractionated radiotherapy as primary treatment for intracranial meningiomas.

Background: Surgery is the primary treatment for most meningiomas. However, primary fractionated radiotherapy (fRT) remains an option for patients with larger meningiomas in challenging anatomic locations or patients at prohibitively high surgical risk. Outcome prediction for these patients is uncertain and cannot be guided by histopathology without available tumor tissue from surgery. Therefore, we aimed to assess the clinical factors that contribute to treatment failure in a large cohort of meningiomas consecutively treated with fRT as primary therapy, with the goal of identifying predictors of response. Methods: Patients treated with primary fRT for intracranial meningiomas from 1998 to 2017 were reviewed. Those who received primary surgical resection, radiosurgery, previous fRT, or had <6 months of clinical follow-up were excluded. We applied logistic regression and Cox regression modeling to ascertain key predictors of treatment failure, progression-free survival (PFS), and adverse events (AE) following fRT. Results: Our cohort included 137 meningiomas, 21 of which progressed after fRT (median PFS 3.45 years). Progressive meningiomas had a larger median gross tumor volume (GTV) compared to those that remained stable (19.1 cm3 vs 9.6 cm3, p = 2.86 × 10-2). GTV > 11.27 cm3 was independently predictive of progression and larger GTV was associated with higher risk of significant (grades 3/4) AE following fRT. Cavernous sinus and optic nerve sheath meningiomas had overall excellent outcomes post-fRT. Conclusions: We present a large cohort of meningiomas treated with primary fRT and find GTV and anatomic location to be key predictors of outcome, adding to the complex treatment considerations for this heterogeneous disease.

Surgery for Recurrent Glioblastoma Multiforme: A Retrospective Case Control Study.

OBJECTIVE: The role of surgery in recurrent glioblastoma multiforme (GBM) remains a controversial topic. The goal of this study was to perform a case control analysis including time to tumor recurrence as an additional prognostic factor in order to determine which patients benefit most from repeat surgery. METHODS: Our brain tumor database was reviewed over a 10-year period for all adult (≥18 years old) patients with primary isocitrate dehydrogenase wildtype GBM who received surgery for recurrent disease. These patients were then age, sex, and treatment matched to case controls from our institution who received medical therapy for recurrent disease. RESULTS: A total of 174 adult patients with GBM were included in the study, 87 patients who received surgery for recurrent GBM (surgery cohort) and 87 patients who did not receive surgery for recurrent GBM (nonsurgery cohort). The surgery cohort had longer overall survival (P = 0.0003) and postrecurrence survival (P = 0.001) than the nonsurgery cohort. When the surgery cohort was split into 2 groups on the basis of time to tumor recurrence, the long time to recurrence group (>6 months) demonstrated significantly increased survival compared with the short time to recurrence group (P < 0.0001). Multivariate analysis of both cohorts demonstrated surgery for recurrent GBM was independently significant after adjusting for age, Karnofsky Performance Scale, and time to tumor recurrence (P < 0.0001). CONCLUSIONS: Surgery for recurrent GBM leads to improved survival independent of age, Karnofsky Performance Scale, and time to tumor recurrence. Patients with time to tumor recurrence >6 months benefit most from additional surgery.

Brain tumor patients and COVID-19 vaccines: results of an international survey.

Background: As the COVID-19 pandemic continues to unfold, the advent of multiple approved vaccines has led to a milestone in the fight against the virus. While vaccination rates and side effects are well established in the general population, these are largely unknown in patients with brain tumors. The purpose of this study was to determine if brain tumor patients and their caregivers have received a COVID-19 vaccine, and explore their thoughts and opinions on these vaccines. Methods: An anonymous 31-question online survey available in 8 languages was conducted from June 30, 2021 to August 31, 2021. The survey was open to adult brain tumor patients over the age of 18 and included both categorical and open-ended questions. Descriptive statistics and modified thematic analyses were performed for all questions as appropriate. Results: A total of 965 unique surveys were completed from 42 countries. The vast majority of both brain tumor patients and their caregivers have been vaccinated against COVID-19 (84.5% and 89.9%, respectively). No patient reported serious adverse events from any vaccine. Less than 10% of patients decided against receiving a vaccination against COVID-19, with the most common reason being concerns over the safety of the vaccine. Patients wanted more specific information on how COVID-19 vaccines might impact their future brain tumor treatment. Conclusions: In conclusion, the majority of brain tumor patients and their caregivers have received COVID-19 vaccines with no major side effects. Patients want more information on how COVID-19 vaccines might directly impact their brain tumor and future management.

Incidence and prevalence of primary malignant brain tumours in Canada from 1992 to 2017: an epidemiologic study.

BACKGROUND: Primary malignant brain tumours account for more than one-third of all brain tumours and are associated with high morbidity and mortality. The purpose of this study was to estimate the incidence and prevalence of primary malignant central nervous system (CNS) tumours and trends in these rates in Canada from 1992 to 2017. METHODS: We conducted an epidemiologic study using publicly available data from the Canadian Cancer Registry from 1992 to 2017 (1994 to 2015 for prevalence) for all of Canada except Quebec (1992 to 2011). We calculated the incidence and prevalence per 100 000 person-years and the age-standardized incidence and prevalence per 100 000 person-years of primary malignant CNS tumours and stratified them by sex and age (pediatric [≥ 19 yr], adult [20-64 yr] and older adult [> 64 yr]). Our analyses assessed average disease duration, survival differences between males and females, and trends over time. RESULTS: During the study period, the average age-standardized incidence and prevalence rates of all primary malignant CNS tumours were 7.9 and 7.6 per 100 000 person-years, respectively. The incidence and prevalence increased by 37.5% and 40.5%, respectively, over the study period. Males accounted for more than half (26 085 [56.4%]) of all diagnoses and experienced decreased survival compared to females 1 year after diagnosis (p = 0.048). Children accounted for 4605 new diagnoses (10.0%), adults for 23 950 (51.7%), and older adults for 17 735 (38.3%). Age-standardized incidence and prevalence rates were highest among older adults. INTERPRETATION: Overall, the incidence of primary malignant CNS tumours increased from 1992 to 2017, and males and older adults were disproportionately affected. Increased health care resources and awareness are needed to improve identification of these tumours and deliver evidence-based care that balances safety, efficacy and preservation of quality of life for affected patients.

Predictors of survival in elderly patients undergoing surgery for glioblastoma.

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.

Evolution of the Neurosurgeon's Role in Clinical Trials for Glioblastoma: A Systematic Overview of the Clinicaltrials.Gov Database.

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.

Liquid Biomarkers for Improved Diagnosis and Classification of CNS Tumors.

Liquid biopsy, as a non-invasive technique for cancer diagnosis, has emerged as a major step forward in conquering tumors. Current practice in diagnosis of central nervous system (CNS) tumors involves invasive acquisition of tumor biopsy upon detection of tumor on neuroimaging. Liquid biopsy enables non-invasive, rapid, precise and, in particular, real-time cancer detection, prognosis and treatment monitoring, especially for CNS tumors. This approach can also uncover the heterogeneity of these tumors and will likely replace tissue biopsy in the future. Key components of liquid biopsy mainly include circulating tumor cells (CTC), circulating tumor nucleic acids (ctDNA, miRNA) and exosomes and samples can be obtained from the cerebrospinal fluid, plasma and serum of patients with CNS malignancies. This review covers current progress in application of liquid biopsies for diagnosis and monitoring of CNS malignancies.

Awake craniotomy for resection of supratentorial glioblastoma: a systematic review and meta-analysis.

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.

Brain tumors and COVID-19: the patient and caregiver experience.

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.

Detection and discrimination of intracranial tumors using plasma cell-free DNA methylomes.

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.

Atypical Teratoid/Rhabdoid Sellar Tumor in an Adult with a Familial History of a Germline SMARCB1 Mutation: Case Report and Review of the Literature.

BACKGROUND: Adult sellar atypical teratoid/rhabdoid tumor (ATRT) is a rare diagnosis that has recently been shown to be a clinicopathologically and genetically distinct variant of ATRT occurring almost exclusively in middle-aged women. Although up to one third of pediatric ATRT is caused by a familial syndrome, no previous cases of a familial adult sellar ATRT have been reported. We present the first case report of a familial germline mutation causing adult sellar ATRT and a literature review of 29 previously reported cases of sporadic adult sellar ATRT. CASE DESCRIPTION: A 51-year-old woman with a family history of brain tumors spanning 3 generations presented with visual decline and was diagnosed with an adult sellar ATRT. Genetic studies showed a heterozygous splice-site loss-of-function mutation of the INI1 gene in exon 7. Treatment included endoscopic endonasal biopsy, craniospinal irradiation, and focal tumor boost, followed by adjuvant chemotherapy. CONCLUSIONS: This is the first case report of a familial germline mutation causing adult sellar ATRT. This article highlights the importance of a thorough family history and genetic testing in these individuals and reviews the current genetics, histopathology, and multidisciplinary treatment approach in this rare condition.

Risk factors for surgical site infection after intracranial electroencephalography monitoring for epilepsy in the pediatric population.

OBJECTIVE Intracranial electroencephalography (iEEG) monitoring is an important method of identifying the seizure focus in patients with medically refractory epilepsy. While previous studies have demonstrated low rates of surgical complications, reported rates of surgical site infection (SSI) are highly variable. To date, no studies have specifically evaluated the patient or operative risk factors contributing to SSI. The goals of this study were to examine the rate of SSI after iEEG monitoring for epilepsy workup in pediatric patients and to determine the variables that might contribute to the development of SSI. METHODS A retrospective analysis of hospital charts at the Hospital for Sick Children was performed for all patients who had undergone iEEG monitoring between 2000 and 2016. Univariate and multivariate analyses were performed to look for statistically significant variables in relation to SSI. RESULTS Among 199 patients eligible for analysis, 8 (4.0%) developed SSIs within a period ranging from 21 to 51 days postoperatively. Univariate analysis yielded 4 factors related to SSI: number of people present in the operating room on electrode insertion (p = 0.02), length of insertion surgery (p = 0.04), previous operation at the same surgical site (p = 0.04), and number of depth electrodes inserted (p = 0.01). Multivariate analysis revealed that both the number of people present during the implant operation (OR 0.08, 95% CI 0.01-0.70) and the number of depth electrodes inserted (OR 3.52, 95% CI 1.44-8.59) independently contributed to SSI. CONCLUSIONS This is the largest case series and the first comprehensive review of both patient and operative risk factors in the development of SSI from iEEG monitoring in a pediatric population. The authors' institution had a lower rate of infection than those in most other studies, which could be explained by their protocol of administering intravenous antibiotics perioperatively and post-implant removal antibiotics for 14 days. The authors found a correlation between SSI and the number of people present during the implant operation, as well as the number of depth electrodes; both may contribute to breaks in sterility.