Targeted gene expression profiling predicts meningioma outcomes and radiotherapy responses.

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.

Hypermitotic meningiomas harbor DNA methylation subgroups with distinct biological and clinical features.

BACKGROUND: Meningiomas, the most common primary intracranial tumors, can be separated into 3 DNA methylation groups with distinct biological drivers, clinical outcomes, and therapeutic vulnerabilities. Alternative meningioma grouping schemes using copy number variants, gene expression profiles, somatic short variants, or integrated molecular models have been proposed. These data suggest meningioma DNA methylation groups may harbor subgroups unifying contrasting theories of meningioma biology. METHODS: A total of 565 meningioma DNA methylation profiles from patients with comprehensive clinical follow-up at independent discovery (n = 200) or validation (n = 365) institutions were reanalyzed and classified into Merlin-intact, Immune-enriched, or Hypermitotic DNA methylation groups. RNA sequencing from the discovery (n = 200) or validation (n = 302) cohort were analyzed in the context of DNA methylation groups to identify subgroups. Biological features and clinical outcomes were analyzed across meningioma grouping schemes. RESULTS: RNA sequencing revealed differential enrichment of FOXM1 target genes across two subgroups of Hypermitotic meningiomas. Differential expression and ontology analyses showed the subgroup of Hypermitotic meningiomas without FOXM1 target gene enrichment was distinguished by gene expression programs driving macromolecular metabolism. Analysis of genetic, epigenetic, gene expression, or cellular features revealed Hypermitotic meningioma subgroups were concordant with Proliferative or Hypermetabolic meningiomas, which were previously reported alongside Merlin-intact and Immune-enriched tumors using an integrated molecular model. The addition of DNA methylation subgroups to clinical models refined the prediction of postoperative outcomes compared to the addition of DNA methylation groups. CONCLUSIONS: Meningiomas can be separated into three DNA methylation groups and Hypermitotic meningiomas can be subdivided into Proliferative and Hypermetabolic subgroups, each with distinct biological and clinical features.

Multiple approaches converge on three biological subtypes of meningioma and extract new insights from published studies.

One-fifth of meningiomas classified as benign by World Health Organization (WHO) histopathological grading will behave malignantly. To better diagnose these tumors, several groups turned to DNA methylation, whereas we combined RNA-sequencing (RNA-seq) and cytogenetics. Both approaches were more accurate than histopathology in identifying aggressive tumors, but whether they revealed similar tumor types was unclear. We therefore performed unbiased DNA methylation, RNA-seq, and cytogenetic profiling on 110 primary meningiomas WHO grade I and II). Each technique distinguished the same three groups (two benign and one malignant) as our previous molecular classification; integrating these methods into one classifier further improved accuracy. Computational modeling revealed strong correlations between transcription and cytogenetic changes, particularly loss of chromosome 1p, in malignant tumors. Applying our classifier to data from previous studies also resolved certain anomalies entailed by grouping tumors by WHO grade. Accurate classification will therefore elucidate meningioma biology as well as improve diagnosis and prognosis.

Racial and Socioeconomic Disparities in Patients With Meningioma: A Retrospective Cohort Study.

BACKGROUND: Meningiomas are the most common intracranial neoplasms. Although genomic analysis has helped elucidate differences in survival, there is evidence that racial disparities may influence outcomes. African Americans have a higher incidence of meningiomas and poorer survival outcomes. The etiology of these disparities remains unclear, but may include a combination of pathophysiology and other factors. OBJECTIVE: To determine factors that contribute to different clinical outcomes in racial populations. METHODS: We retrospectively reviewed 305 patients who underwent resection for meningiomas at a single tertiary care facility. We used descriptive statistics and univariate, multivariable, and Kaplan-Meier analyses to study clinical, radiographical, and histopathological differences. RESULTS: Minority patients were more likely to present through the emergency department than an outpatient clinic (P < .0001). They were more likely to present with more advanced clinical symptoms with lower Karnofsky Performance scores, more frequently had peritumoral edema (P = .0031), and experienced longer postoperative stays in the hospital (P = .0053), and African-American patients had higher hospitalization costs (P = .046) and were more likely to be publicly insured. Extent of resection was an independent predictor of recurrence freedom (P = .039). Presentation in clinic setting trended toward an association with recurrence-free survival (P = .055). We observed no significant difference in gross total resection rates, postoperative recurrence, or recurrence-free survival. CONCLUSION: Minority patients are more likely to present with severe symptoms, require longer perioperative hospitalization, and generate higher hospitalization costs. This may be due to socioeconomic factors that affect access to health care. Targeting barriers to access, especially to subspecialty care, may facilitate more appropriate and timely diagnosis, thereby improving patient care and outcomes.

Spinal Metastases and the Evolving Role of Molecular Targeted Therapy, Chemotherapy, and Immunotherapy.

Metastatic involvement of the spine is a common complication of systemic cancer progression. Surgery and external beam radiotherapy are palliative treatment modalities aiming to preserve neurological function, control pain and maintain functional status. More recently, with development of image guidance and stereotactic delivery of high doses of conformal radiation, local tumor control has improved; however recurrent or radiation refractory disease remains a significant clinical problem with limited treatment options. This manuscript represents a narrative overview of novel targeted molecular therapies, chemotherapies, and immunotherapy treatments for patients with breast, lung, melanoma, renal cell, prostate, and thyroid cancers, which resulted in improved responses compared to standard chemotherapy. We present clinical examples of excellent responses in spinal metastatic disease which have not been specifically documented in the literature, as most clinical trials evaluate treatment response based on visceral disease. This review is useful for the spine surgeons treating patients with metastatic disease as knowledge of these responses could help with timing and planning of surgical interventions, as well as promote multidisciplinary discussions, allowing development of an individualized treatment strategy to patients presenting with widespread multifocal progressive disease, where surgery could lead to suboptimal results.

Endoscopic ultrasonic aspiration of an intraparenchymal hematoma in a newborn.

Neonatal intracerebral hemorrhage is associated with substantial morbidity and mortality. Treatment is largely conservative, though interventions to evacuate intraventricular and intraparenchymal hematomas (IPHs) have been applied. Endoscopic ultrasonic aspiration for the treatment of IPH has increasingly been shown to be a useful strategy in adults; however, it has not been studied in children, and the technology has been more commonly applied to intraventricular hemorrhage (IVH). Here, the authors describe, to the best of their knowledge, the first use of endoscopic ultrasonic aspiration for IPH in a newborn.An 8-week-old female presented with IPH secondary to left M3 aneurysm rupture, which was treated with coil embolization for aneurysm securement and vessel sacrifice, followed by IPH evacuation using endoscopic ultrasonic aspiration. Through applying this approach in a newborn, the authors gained technical insight not previously reported in the application of this technique in similar cases in adults or in cases of IVH. They highlight this case to share learning points and technical challenges regarding the application of endoscopic ultrasonic aspiration in a newborn along with learning points for imaging and visualization. Endoscopic ultrasonic aspiration can be used to treat IPH in select newborns. Further study is needed to improve efficacy and ease when applying this approach in very young patients.

Identification of novel fusion transcripts in meningioma.

INTRODUCTION: Meningiomas are the most common primary intracranial tumor. Recent next generation sequencing analyses have elaborated the molecular drivers of this disease. We aimed to identify and characterize novel fusion genes in meningiomas. METHODS: We performed a secondary analysis of our RNA sequencing data of 145 primary meningioma from 140 patients to detect fusion genes. Semi-quantitative rt-PCR was performed to confirm transcription of the fusion genes in the original tumors. Whole exome sequencing was performed to identify copy number variations within each tumor sample. Comparative RNA seq analysis was performed to assess the clonality of the fusion constructs within the tumor. RESULTS: We detected six fusion events (NOTCH3-SETBP1, NF2-SPATA13, SLC6A3-AGBL3, PHF19-FOXP2 in two patients, and ITPK1-FBP2) in five out of 145 tumor samples. All but one event (NF2-SPATA13) led to extremely short reading frames, making these events de facto null alleles. Three of the five patients had a history of childhood radiation. Four out of six fusion events were detected in expression type C tumors, which represent the most aggressive meningioma. We validated the presence of the RNA transcripts in the tumor tissue by semi-quantitative RT PCR. All but the two PHF19-FOXP2 fusions demonstrated high degrees of clonality. CONCLUSIONS: Fusion genes occur infrequently in meningiomas and are more likely to be found in tumors with greater degree of genomic instability (expression type C) or in patients with history of cranial irradiation.

Routine surveillance imaging following mild traumatic brain injury with intracranial hemorrhage may not be necessary.

BACKGROUND: Mild traumatic brain injury (mTBI) comprises the majority of pediatric traumatic brain injury. Children with mTBI even with traumatic intracranial hemorrhage (tICH) rarely experience a clinically significant neurologic decline (CSND). The utility of routine surveillance imaging in the pediatric population also remains controversial, especially owing to concerns about the risks of radiation exposure at a young age. This study aims to identify demographic or injury-related characteristics that may facilitate recognition of children at risk of progression with mTBI. METHODS: We performed a retrospective review of patients <16 years old with mTBI (GCS 13-15) and tICH admitted to a Level I pediatric trauma center between 2009 and 2014. Management of these patients was directed by the Cincinnati Children's Hospital Medical Center Minor Head Injury Algorithm. We reviewed each chart with emphasis on patient demographics, injury specific data, and radiographic or clinical progression. RESULTS: 154 patients met inclusion criteria with mean age of 4 [0-16]; 116 sustained an tICH and 38 patients had isolated skull fractures. Repeat neuroimaging was obtained in 68 patients (59%). Only 9 patients (13%) with tICH had radiographic progression, none of which resulted in CSND. In addition, 9 patients experienced CSND, leading to neurosurgical intervention in 6 patients. Notably, none of these patients had repeat imaging prior to their neurologic changes. Both CSND and need for intervention were significantly higher in patients with epidural hematomas than other types of tICH (19.2% vs. 1.1%, p = 0.002). Of 154 patients, 19 did not have documented follow-up, 135 were seen as outpatients and 65 (48%) had follow up neuroimaging. All patients who had surveillance imaging in the outpatient setting had stable or resolved tICH. CONCLUSION: Few children with mTBI and tICH experience clinical decline. Importantly, all patients that required neurosurgical intervention were identified by clinical changes rather than via repeat imaging. Our study suggests that in the vast majority of cases, clinical monitoring alone is safe and sufficient in patients in order to avoid exposure to repeat radiographic imaging. LEVEL OF EVIDENCE: Level III, prognostic and epidemiological.