Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects.

The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Hormone therapies in meningioma-where are we?

INTRODUCTION: Meningiomas are associated with several gonadal steroid hormone-related risk factors and demonstrate a predominance in females. These associations led to investigations of the role that hormones may have on meningioma growth and development. While it is now accepted that most meningiomas express progesterone and somatostatin receptors, the conclusion for other receptors has been less definitive. METHODS: We performed a review of what is known regarding the relationship between hormones and meningiomas in the published literature. Furthermore, we reviewed clinical trials related to hormonal agents in meningiomas using MEDLINE PubMed, Scopus, and the NIH clinical trials database. RESULTS: We identify that all steroid-hormone trials lacked receptor identification or positive receptor status in the majority of patients. In contrast, four out of five studies involving somatostatin analogs used positive receptor status as part of the inclusion criteria. CONCLUSIONS: Several clinical trials have recently been completed or are now underway using somatostatin analogs in combination with other therapies that appear promising, but a reevaluation of hormone-based monotherapy is warranted. Synthesizing this evidence, we clarify the remaining questions and present future directions for the study of the biological role and therapeutic potential of hormones in meningioma and discuss how the stratification of patients using features such as grade, receptor status, and somatic mutations, might be used for future trials to select patients most likely to benefit from specific therapies.

Associations of race and socioeconomic status with outcomes after intracranial meningioma resection: a systematic review and meta-analysis.

PURPOSE: Social determinants of health broadly affect healthcare access and outcomes. Studies report that minorities and low socioeconomic status (SES) patients undergoing intracranial meningioma resection demonstrate worse outcomes and higher mortality rates. This systematic review and meta-analysis summarizes the available research reporting racial and SES disparities in intracranial meningioma resection outcomes. METHODS: A systematic review was conducted using PRISMA guidelines and included peer-reviewed, English-language articles from the United States between 2000 and 2022 that reported racial and SES disparities in meningioma outcomes. Outcomes included overall survival (OS), extent of resection (EOR), hospitalization costs, length of stay (LOS), 30-day readmission, recurrence, and receipt of surgery and adjuvant radiotherapy. A quantitative meta-analysis was performed only on survival outcomes by race. All other variables were summarized as a systematic review. RESULTS: 633 articles were identified; 19 studies met inclusion criteria. Black or low SES patients were more likely to have increased hospitalization costs, rates of 30-day readmission, LOS, recurrence and less likely to undergo surgery, gross total resection, and adjuvant radiotherapy for their tumors. Six studies were used for the quantitative meta-analysis of race and OS. Compared to White patients, Black patients had significantly worse survival outcomes, and Asian patients had significantly better survival outcomes. CONCLUSION: Disparities in outcomes exist for patients who undergo surgery for meningioma, such that Black and low SES patients have worse outcomes. The literature is quite sparse and contains confounding relationships not often accounted for appropriately. Further studies are needed to help understand these disparities to improve outcomes.

Surgical strategies for intracranial meningioma in the molecular era.

INTRODUCTION: Surgical resection has long been the treatment of choice for meningiomas and is considered curative in many cases. Indeed, the extent of resection (EOR) remains a significant factor in determining disease recurrence and outcome optimization for patients undergoing surgery. Although the Simpson Grading Scale continues to be widely accepted as the measure of EOR and is used to predict symptomatic recurrence, its utility is under increasing scrutiny. The influence of surgery in the definitive management of meningioma is being re-appraised considering the rapid evolution of our understanding of the biology of meningioma. DISCUSSION: Although historically considered "benign" lesions, meningioma natural history can vary greatly, behaving with unexpectedly high recurrence rates and growth which do not always behave in accordance with their WHO grade. Histologically confirmed WHO grade 1 tumors may demonstrate unexpected recurrence, malignant transformation, and aggressive behavior, underscoring the molecular complexity and heterogeneity. CONCLUSION: As our understanding of the clinical predictive power of genomic and epigenomic factors matures, we here discuss the importance of surgical decision-making paradigms in the context of our rapidly evolving understanding of these molecular features.

Frailty and postoperative outcomes in brain tumor patients: a systematic review subdivided by tumor etiology.

PURPOSE: Frailty has gained prominence in neurosurgical oncology, with more studies exploring its relationship to postoperative outcomes in brain tumor patients. As this body of literature continues to grow, concisely reviewing recent developments in the field is necessary. Here we provide a systematic review of frailty in brain tumor patients subdivided by tumor type, incorporating both modern frailty indices and traditional Karnofsky Performance Status (KPS) metrics. METHODS: Systematic literature review was performed using PRISMA guidelines. PubMed and Google Scholar were queried for articles related to frailty, KPS, and brain tumor outcomes. Only articles describing novel associations between frailty or KPS and primary intracranial tumors were included. RESULTS: After exclusion criteria, systematic review yielded 52 publications. Amongst malignant lesions, 16 studies focused on glioblastoma. Amongst benign tumors, 13 focused on meningiomas, and 6 focused on vestibular schwannomas. Seventeen studies grouped all brain tumor patients together. Seven studies incorporated both frailty indices and KPS into their analyses. Studies correlated frailty with various postoperative outcomes, including complications and mortality. CONCLUSION: Our review identified several patterns of overall postsurgical outcomes reporting for patients with brain tumors and frailty. To date, reviews of frailty in patients with brain tumors have been largely limited to certain frailty indices, analyzing all patients together regardless of lesion etiology. Although this technique is beneficial in providing a general overview of frailty's use for brain tumor patients, given each tumor pathology has its own unique etiology, this combined approach potentially neglects key nuances governing frailty's use and prognostic value.

The integrated multiomic diagnosis of sporadic meningiomas: a review of its clinical implications.

INTRODUCTION: Meningiomas are generally considered "benign," however, these tumors can demonstrate variability in behavior and a surprising aggressiveness with elevated rates of recurrence. The advancement of next-generation molecular technologies have led to the understanding of the genomic and epigenomic landscape of meningiomas and more recent correlations with clinical characteristics and behavior. METHODS: Based on a thorough review of recent peer-reviewed publications (PubMed) and edited texts, we provide a molecular overview of meningiomas with a focus on relevant clinical implications. RESULTS: The identification of specific somatic driver mutations has led to the classification of several major genomic subgroups, which account for more than 80% of sporadic meningiomas, and can be distinguished using noninvasive clinical variables to help guide management decisions. Other somatic genomic modifications, including non-coding alterations and copy number variations, have also been correlated with tumor characteristics. Furthermore, epigenomic modifications in meningiomas have recently been described, with DNA methylation being the most widely studied and potentially most clinically relevant. Based on these molecular insights, several clinical trials are currently underway in an effort to establish effective medical therapeutic options for meningioma. CONCLUSION: As we enhance our multiomic understanding of meningiomas, our ability to care for patients with these tumors will continue to improve. Further biological insights will lead to additional progress in precision medicine for meningiomas.

Vessel-Targeting Nanoclovers Enable Noninvasive Delivery of Magnetic Hyperthermia-Chemotherapy Combination for Brain Cancer Treatment.

Despite being promising, the clinical application of magnetic hyperthermia for brain cancer treatment is limited by the requirement of highly invasive intracranial injections. To overcome this limitation, here we report the development of gallic acid-coated magnetic nanoclovers (GA-MNCs), which allow not only for noninvasive delivery of magnetic hyperthermia but also for targeted delivery of systemic chemotherapy to brain tumors. GA-MNCs are composed of clover-shaped MNCs in the core, which can induce magnetic heat in high efficiency, and polymerized GA on the shell, which enables tumor vessel-targeting. We demonstrate that intravenous administration of GA-MNCs following alternating magnetic field exposure effectively inhibited brain cancer development and preferentially disrupted tumor vasculature, making it possible to efficiently deliver systemic chemotherapy for further improved efficacy. Due to the noninvasive nature and high efficiency in killing tumor cells and enhancing systemic drug delivery, GA-MNCs have the potential to be translated for improved treatment of brain cancer.

Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas.

PURPOSE: As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. METHODS: Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features. RESULTS: Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004). CONCLUSIONS: SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade.

Surgical strategies for older patients with glioblastoma.

OBJECTIVE: While adjuvant treatment regimens have been modified for older patients with glioblastoma (GBM), surgical strategies have not been tailored. METHODS: Clinical data of 48 consecutive patients aged 70 years or older, who underwent surgical resection for GBM with intraoperative ultrasonography (IoUS) alone or combination with intraoperative MRI (IoMRI) at Yale New Haven Hospital were retrospectively reviewed. Variables were analyzed, and comparative analyses were performed. RESULTS: The addition of IoMRI was not superior to IoUS alone in terms of overall survival (OS) (P = 0.306), Karnofsky Performance Score (KPS) at postoperative 6 weeks (P = 0.704) or extent of resection (P = 0.263). Length of surgery (LOSx), however, was significantly longer (P = 0.0002) in the IoMRI group. LOSx (P = 0.015) and hospital stay (P = 0.025) were predictors of postoperative complications. Increased EOR (GTR or NTR) (P = 0.030), postoperative adjuvant treatment (P < 0.0001) and postoperative complications (P = 0.006) were predictive for OS. Patients with relatively lower preoperative KPS scores (<70) showed significant improvement at postoperative 6 weeks (P<0.0001). Patients with complications (P = 0.038) were more likely to have lower KPS at postoperative 6 weeks. CONCLUSIONS: Aggressive management with surgical resection should be considered in older patients with GBM, even those with relatively poor KPS. The use of ioMRI in this population does not appear to confer any measurable benefit over ioUS in experienced hands, but prolongs the length of surgery significantly, which is a preventable prognostic factor for impeding care.

Correction to: A quantitative model based on clinically relevant MRI features differentiates lower grade gliomas and glioblastoma.

The original version of this article, published on 05 February 2020, unfortunately contained a mistake.

A quantitative model based on clinically relevant MRI features differentiates lower grade gliomas and glioblastoma.

OBJECTIVES: To establish a quantitative MR model that uses clinically relevant features of tumor location and tumor volume to differentiate lower grade glioma (LRGG, grades II and III) and glioblastoma (GBM, grade IV). METHODS: We extracted tumor location and tumor volume (enhancing tumor, non-enhancing tumor, peritumor edema) features from 229 The Cancer Genome Atlas (TCGA)-LGG and TCGA-GBM cases. Through two sampling strategies, i.e., institution-based sampling and repeat random sampling (10 times, 70% training set vs 30% validation set), LASSO (least absolute shrinkage and selection operator) regression and nine-machine learning method-based models were established and evaluated. RESULTS: Principal component analysis of 229 TCGA-LGG and TCGA-GBM cases suggested that the LRGG and GBM cases could be differentiated by extracted features. For nine machine learning methods, stack modeling and support vector machine achieved the highest performance (institution-based sampling validation set, AUC > 0.900, classifier accuracy > 0.790; repeat random sampling, average validation set AUC > 0.930, classifier accuracy > 0.850). For the LASSO method, regression model based on tumor frontal lobe percentage and enhancing and non-enhancing tumor volume achieved the highest performance (institution-based sampling validation set, AUC 0.909, classifier accuracy 0.830). The formula for the best performance of the LASSO model was established. CONCLUSIONS: Computer-generated, clinically meaningful MRI features of tumor location and component volumes resulted in models with high performance (validation set AUC > 0.900, classifier accuracy > 0.790) to differentiate lower grade glioma and glioblastoma. KEY POINTS: • Lower grade glioma and glioblastoma have significant different location and component volume distributions. • We built machine learning prediction models that could help accurately differentiate lower grade gliomas and GBM cases. We introduced a fast evaluation model for possible clinical differentiation and further analysis.

Variations in the genomic profiles and clinical behavior of meningioma by racial and ethnic group.

OBJECTIVE: The influence of socioeconomic factors on racial disparities among patients with sporadic meningiomas is well established, yet other potential causative factors warrant further exploration. The authors of this study aimed to determine whether there is significant variation in the genomic profile of meningiomas among patients of different races and ethnicities and its correlation with clinical outcomes. METHODS: The demographic, genomic, and clinical data of patients aged 18 years and older who had undergone surgery for sporadic meningioma between September 2008 and November 2021 were analyzed. Statistical analyses were performed to detect differences across all racial/ethnic groups, as were direct comparisons between Black and non-Black groups plus Hispanic and non-Hispanic groups. RESULTS: This study included 460 patients with intracranial meningioma. Hispanic patients were significantly younger at surgery (53.9 vs 60.2 years, p = 0.0006) and more likely to show symptoms. Black patients had a higher incidence of anterior skull base tumors (OR 3.2, 95% CI 1.7-6.3, p = 0.0008) and somatic hedgehog mutations (OR 5.3, 95% CI 1.6-16.6, p = 0.003). Hispanics were less likely to exhibit the aggressive genomic characteristic of chromosome 1p deletion (OR 0.28, 95% CI 0.07-1.2, p = 0.06) and displayed higher rates of TRAF7 somatic driver mutations (OR 2.96 95% CI 1.1-7.8, p = 0.036). Black patients had higher rates of recurrence (OR 2.6, 95% CI 1.3-5.2, p = 0.009) and shorter progression-free survival (PFS; HR 2.9, 95% CI 1.6-5.4, p = 0.002) despite extents of resection (EORs) similar to those of non-Black patients (p = 0.745). No significant differences in overall survival were observed among groups. CONCLUSIONS: Despite similar EORs, Black patients had worse clinical outcomes following meningioma resection, characterized by a higher prevalence of somatic hedgehog mutations, increased recurrence rates, and shorter PFS. Meanwhile, Hispanic patients had less aggressive meningiomas, a predisposition for TRAF7 mutations, and no difference in PFS. These findings could inform the care and treatment strategies for meningiomas, and they establish the foundation for future studies focusing on the genomic origins of these observed differences.

Meningioma: International Consortium on Meningiomas (ICOM) consensus review on scientific advances & treatment paradigms for clinicians, researchers, and patients.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and the rising availability of neuroimaging. While most exhibit non-malignant behaviour, a subset of meningiomas are biologically aggressive and lead to significant neurological morbidity and mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) working group. There also remains clinical equipoise on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas (ICOM) including field-leading experts, have prepared a comprehensive consensus narrative review directed towards clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality of life studies, and management strategies for unique meningioma patient populations. In each section we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Impact of radiotherapy delay following biopsy for patients with unresected glioblastoma.

OBJECTIVE: Because of the aggressive nature of glioblastoma, patients with unresected disease are encouraged to begin radiotherapy within approximately 1 month after craniotomy. The aim of this study was to investigate the potential association between time interval from biopsy to radiotherapy with overall survival in patients with unresected glioblastoma. METHODS: Patients with unresected glioblastoma diagnosed between 2010 and 2014 who received adjuvant radiotherapy and concurrent chemotherapy were identified in the National Cancer Database. Demographic and clinical data were compared using chi-square and Wilcoxon rank-sum tests. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression modeling. RESULTS: Among 3456 patients with unresected glioblastoma, initiation of radiotherapy within 3 weeks of biopsy was associated with a higher hazard of death compared with later initiation of radiotherapy. After excluding patients who received radiotherapy within 3 weeks of biopsy to minimize the effects of confounders associated with short time intervals from biopsy to radiotherapy, the median interval from biopsy to radiotherapy was 32 days (IQR 27-39 days). Overall, 1782 (66.82%) patients started radiotherapy within 5 weeks of biopsy, and 885 (33.18%) patients started radiotherapy beyond 5 weeks of biopsy. On multivariable analysis, there was no significant difference in overall survival between these two groups (HR 0.96, 95% CI 0.88-1.50; p = 0.374). CONCLUSIONS: In patients with unresected glioblastoma, a longer time interval from biopsy to radiotherapy does not appear to be associated with worse overall survival. However, external validation of these findings is necessary given that selection bias is a significant limitation of this study.