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.

Systematic review of clinician awareness of mycotoxin impact in neural tube defects and best practices for pediatric neurosurgeons: implications for public health and policy.

PURPOSE: In lower-income populations, high rates of neural tube defects (NTDs) are a concern. Nutritional folate deficiencies and mycotoxins in contaminated food supplies increase risk of NTDs. As physicians in public health and involved in the care of children with NTDs, pediatric neurosurgeons have an interest in the treatment and prevention of NTDs. We aimed to evaluate the literature to assess the awareness and the existence of best practices/educational materials on this issue to better guide management. METHODS: A systematic review using the National Library of Medicine PubMed database was conducted to find articles related to mycotoxins in foods causing neural tube defects. Additional citation searches of key publications and personal collections were used. Two reviewers evaluated the resulting studies for subject area analysis. Best practice recommendations were drawn from articles selected for full-text review. RESULTS: Seventy-three articles were identified. Most articles were found in "nutritional sciences" (18), "teratology" (14), and "toxicology" (13). No articles were found in neurosurgery. Thirty-two additional articles were identified through other sources to screen best practice recommendations. Of the 105 articles, 34 journal articles were included in best practice recommendation guidelines. Key recommendations included education of proper food storage, hygienic agricultural practices, decontamination techniques, diet diversification, folate supplementation, risk assessment, and food safety policy and public health initiatives. CONCLUSION: There is an absence of neurosurgical literature-related mycotoxins and NTDs. We suggest a set of best practices/educational materials on this topic and advocate pediatric neurosurgery engagement in public health initiatives targeted towards populations most affected by mycotoxins.

The Role of Pharmacotherapy in Treatment of Meningioma: A Systematic Review.

The safety and efficacy of various pharmacotherapeutic regimens on refractory meningiomas have been the focus of investigations. We present a comprehensive review of the previous efforts and the current state of ongoing clinical trials. A PRISMA-compliant review of the MEDLINE and ClinicalTrial.gov databases of the National Library of Medicine were performed. The primary outcomes of interest for included articles were radiographic response, overall survival, progression-free survival, six-month progression-free survival, and adverse events. Overall, 34 completed trials and 27 ongoing clinical trials were eligible. Six-month progression-free survival was reported in 6-100% of patients in the completed studies. Hematological disorders were the most common adverse events. Of the ongoing clinical trials identified, nine studies are phase I clinical trials, eleven are phase II trials, two are phase I and II trials, one is phase II and III, and two trials do not have a designated phase. Currently, there is no effective chemotherapy for refractory or recurrent meningiomas. Several promising targeted agents have been developed and are currently being investigated in the hope of identifying novel therapeutic strategies for the treatment of this pathology.

3-Dimensional Modeling in Virtual Reality for Resection of a Pineal Region Falcotentorial Meningioma.

We present a parietal interhemispheric approach to resect a pineal region falcotentorial meningioma. Three-dimensional (3D) modeling was used to visualize and plan the surgical approach in virtual reality (Video 1). A 78-year-old woman was incidentally found to have a slow-growing falcotentorial meningioma. The tumor was first treated with stereotactic radiosurgery, but the patient had progressive confusion, memory issues, and bilateral temporal field cuts with interval expansion of the tumor and significantly increased peritumoral vasogenic edema on magnetic resonance imaging. After recommending tumor resection, the patient consented to surgery and underwent resection via a posterior interhemispheric subsplenial approach. Using a 3D model in virtual reality, we discuss the advantages and disadvantages of various classical approaches to the pineal region for resection of this tumor.1-3 Falcotentorial meningiomas often displace the deep veins inferiorly, making an interhemispheric approach more favorable.4-6 Preoperative visualization of critical deep venous structures with the 3D model was a valuable adjunct to magnetic resonance imaging for achieving safe resection. We depict key steps of the surgical planning process using virtual reality and demonstrate how simulation can be used to evaluate risks and benefits of different surgical corridors. A small rim of residual tumor adherent to the deep cerebral veins was intentionally left behind in order to minimize risk of morbidity to the patient.7 At 1-month follow-up, the patient's cognition had returned to baseline and her vision had significantly improved. Ultimately, surgical planning using virtual reality promotes both neurosurgical education and patient safety through clear visualization and understanding of different surgical approaches.

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.

Virtual Interviews in Neurosurgery Resident Selection-A Work in Progress.

INTRODUCTION: Due to the COVID-19 pandemic, the ACGME recommended all interviews for the 2021 residency application cycle be held virtually. Because this is major shift from neurosurgical interviews in past years, this study aims to evaluate both applicant and interviewer satisfaction of conducting interviews virtually. METHODS: For faculty, an 11-question online survey was sent to 116 United States neurosurgery training programs. A 14-question online survey was sent to 255 neurosurgery applicants. The resulting data were analyzed qualitatively and quantitatively. RESULTS: From applicants, 118 responses were received. From faculty, 171 individual responses were received. Thirty-five percent (34.7%) of applicants agreed that they were satisfied with the virtual interview process as a whole. Although 44.5% of faculty disagreed with the statement "I would like to replace in-person interviews with virtual interviews in the future", 57.3% of faculty agreed that they were likely to implement virtual interviews in the future. CONCLUSIONS: Some things might be better assessed through in-person interviews, but there are clear benefits to virtual interviews. Future iterations of the interview process, incorporating virtual interviews, might help determine how and in which situations virtual interviews can be utilized in future residency application cycles.

Intracranial Solitary Fibrous Tumor of the Skull Base: 2 Cases and Systematic Review of the Literature.

BACKGROUND: Intracranial solitary fibrous tumors (ISFTs) are rare neoplasms of mesenchymal origin that originate from the meninges. ISFTs of the skull base can be challenging to treat, as resection can be complicated by skull base anatomy. We present 2 cases of ISFT, the first manifesting with compressive cranial neuropathy from Meckel cave involvement and the second a posterior fossa lesion causing symptomatic hydrocephalus. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed database was queried with title/abstract keywords "intracranial," "solitary fibrous tumor," "hemangiopericytoma," "SFT," and "HPC." Search results were reviewed to exclude cases not involving the skull base. References from all selected articles were reviewed for potential additional cases. Patient demographic and clinical data from 58 identified skull base cases were collected for qualitative synthesis. RESULTS: Visual disturbances were the most common presenting symptom (30 cases, 52%) followed by headache (22 cases, 38%). The most common site of involvement was the sellar/parasellar region (18 cases, 31%) followed by middle fossa/temporal bone (14 cases, 24%). Resection was performed in 55 cases; gross total resection was reported in 26 cases (45%) and subtotal resection was reported in 21 cases (36%). Tumor recurrence was documented in 15 cases (26%) with median and mean follow-up periods of 16 and 29.9 months, respectively. CONCLUSIONS: We discuss presentation, imaging, histopathology, and management considerations for ISFTs while highlighting the potentially complex nature of skull base lesions and need for multidisciplinary approach to treatment.

Predictors of postoperative seizure outcome in supratentorial meningioma.

OBJECTIVE: Meningiomas are the most common primary intracranial tumor. Seizures are common sequelae of meningioma development. Meningioma patients with seizures can be effectively treated with resection, with reports of seizure freedom of 60%-90%. Still, many patients manifest persistent epilepsy. Determining factors associated with worsened seizure outcomes remains critical in improving the quality of life for these patients. The authors sought to identify clinical, radiological, and histological factors associated with worse seizure outcomes in patients with supratentorial meningioma and preoperative seizures. METHODS: The authors retrospectively reviewed the charts of 384 patients who underwent meningioma resection from 2008 to 2020. The charts of patients with a documented history of preoperative seizures were further reviewed for clinical, radiological, operative, perioperative, histological, and postoperative factors associated with seizures. Engel class at last follow-up was retrospectively assigned by the authors and further grouped into favorable (class I) and worse (class II-IV) outcomes. Factors were subsequently compared by group using comparative statistics. Univariable and multivariable regression models were utilized to identify independent predictors of worse seizure outcome. RESULTS: Fifty-nine patients (15.4%) were found to have preoperative seizures, of whom 57 had sufficient postoperative data to determine Engel class outcome. Forty-two patients (74%) had Engel class I outcomes. The median follow-up was 17 months. Distinct margins on preoperative imaging (p = 0.012), Simpson grade I resection (p = 0.004), postresection ischemia (p = 0.019), WHO grade (p = 0.019), and recurrent disease (p = 0.015) were found to be the strongest predictors of Engel class outcome in univariable logistic regression. MIB-1 index (p = 0.001) and residual volume (p = 0.014) at last follow-up were found to be the strongest predictors of Engel class outcome in univariable generalized linear regression. Postresection ischemia (p = 0.012), WHO grade (p = 0.022), recurrent disease (p = 0.038), and MIB-1 index (p = 0.002) were found to be the strongest independent predictors of Engel class outcomes in multivariable analysis. CONCLUSIONS: Postresection ischemia, higher WHO grade, elevated MIB-1 index, and disease recurrence independently predict postresection seizure persistence in patients with supratentorial meningioma. Further understanding of the etiology of these markers may aid in elucidation of this complex disease process and guide management to prevent worse outcomes.

The history of neurosurgery at Baylor College of Medicine.

The development of neurosurgery at Baylor College of Medicine began with the medical school's relocation to the new Texas Medical Center in Houston in 1943. An academic service was organized in 1949 as a section of neurosurgery within Baylor's Department of Surgery. Soon the practice, led by Dr. George Ehni, evolved to include clinical services at Methodist, Jefferson Davis (forerunner of Ben Taub), Texas Children's, the Veterans Affairs, and the University of Texas MD Anderson Cancer Center hospitals. A neurosurgery residency program was established in 1954. As the clinical practice expanded, neurosurgery was upgraded from a section to a division and then to a department. It has been led by four chiefs/chairs over the past 60 years-Dr. George Ehni (1959-1979), Dr. Robert Grossman (1980-2004), Dr. Raymond Sawaya (2005-2014), and Dr. Daniel Yoshor (2015-2020). Since the 1950s, the department has drawn strength from its robust residency program, its research base in the medical school, and its five major hospital affiliates, which have largely remained unchanged (with the exception of Baylor St. Luke's Medical Center replacing Methodist in 2004). The recent expansion of the residency program to 25 accredited positions and the growing strength of relationships with the "Baylor five" hospitals affiliated with Baylor College of Medicine portend a bright future.

Feasibility and safety of transradial access for pediatric neurointerventions.

BACKGROUND: Diagnostic cerebral angiograms are increasingly being performed by transradial access (TRA) in adults, following data from the coronary literature supporting fewer access-site complications. Despite this ongoing trend in neuroangiography, there has been no discussion of its use in the pediatric population. Pediatric TRA has scarcely been described even for coronary or other applications. This is the first dedicated large study of transradial access for neuroangiography in pediatric patients. METHODS: A multi-institutional series of consecutively performed pediatric transradial angiograms and interventions was collected. This included demographic, procedural, outcomes, and safety data. Data was prospectively recorded and retrospectively analyzed. RESULTS: Thirty-seven diagnostic angiograms and 24 interventions were performed in 47 pediatric patients. Mean age, height, and weight was 14.1 years, 158.6 cm, and 57.1 kg, respectively. The radial artery measured 2.09+/-0.54 mm distally, and 2.09+/-0.44 mm proximally. Proximal and distal angiography were performed for both diagnostic and interventional application (17 distal angiograms, two distal interventions). Clinically significant vasospasm occurred in eight patients (13.1%). Re-access was successfully performed 11 times in seven patients. Conversion to femoral access occurred in five cases (8.2%). The only access-related complication was a small asymptomatic wrist hematoma after TR band removal. CONCLUSIONS: Transradial access in pediatric patients is safe and feasible. It can be performed successfully in many cases but carries some unique challenges compared with the adult population. Despite the challenge of higher rates of vasospasm and conversion to femoral access, it is worth exploring further, given the potential benefits.

The Role of Merlin/NF2 Loss in Meningioma Biology.

Mutations in the neurofibromin 2 (NF2) gene were among the first genetic alterations implicated in meningioma tumorigenesis, based on analysis of neurofibromatosis type 2 (NF2) patients who not only develop vestibular schwannomas but later have a high incidence of meningiomas. The NF2 gene product, merlin, is a tumor suppressor that is thought to link the actin cytoskeleton with plasma membrane proteins and mediate contact-dependent inhibition of proliferation. However, the early recognition of the crucial role of NF2 mutations in the pathogenesis of the majority of meningiomas has not yet translated into useful clinical insights, due to the complexity of merlin's many interacting partners and signaling pathways. Next-generation sequencing studies and increasingly sophisticated NF2-deletion-based in vitro and in vivo models have helped elucidate the consequences of merlin loss in meningioma pathogenesis. In this review, we seek to summarize recent findings and provide future directions toward potential therapeutics for this tumor.

Infundibular Epidermoid Cyst: Case Report and Systematic Review.

BACKGROUND: Intracranial epidermoid cysts are benign, congenital, keratinizing, squamous epithelial-lined cysts filled with keratin. They are uncommon and often pose a surgical challenge owing to the adherence to surrounding structures. They are typically found at the cerebellopontine angle or in the parasellar region, where they are associated with abnormal development of the Rathke pouch; involvement of the pituitary stalk is rare. CASE DESCRIPTION: The patient's electronic health record was queried for relevant data. A systematic review of the literature using dedicated search terms for cases of infundibular epidermoid cysts was conducted. We present a unique case of a 55-year-old male who presented with vision changes and was found to have a parasellar epidermoid cyst confined to the pituitary stalk. The patient underwent endoscopic transsphenoidal resection, and gross total resection was achieved. The patient's postoperative course was significant for possible chemical meningitis and the development of panhypopituitarism. The patient's vision subjectively improved after surgery. CONCLUSIONS: Although 3 other cases of epidermoid cysts involving the pituitary stalk were identified, our patient's tumor was unique in that it was confined to the stalk. Our patient's case highlights a surgical approach to parasellar epidermoid cysts and the possible complications associated therewith.

Characterization of the dose response relationship for lung injury following acute radiation exposure in three well-established murine strains: developing an interspecies bridge to link animal models with human lung.

Approval of radiation countermeasures through the FDA Animal Rule requires pivotal efficacy screening in one or more species that are expected to react with a response similar to humans (21 C.F.R. § 314.610, drugs; § 601.91, biologics). Animal models used in screening studies should reflect the dose response relationship (DRR), clinical presentation, and pathogenesis of lung injury in humans. Over the past 5 y, the authors have characterized systematically the temporal onset, dose-response relationship (DRR), and pathologic outcomes associated with acute, high dose radiation exposure in three diverse mouse strains. In these studies, C57L/J, CBA/J, and C57BL/6J mice received wide field irradiation to the whole thorax with shielding of the head, abdomen, and forelimbs. Doses were delivered at a rate of 69 cGy min using an x-ray source operated at 320 kVp with half-value layer (HVL) of 1 mm Cu. For all strains, radiation dose was associated significantly with 180 d mortality (p < 0.0001). The lethal dose for 50% of animals within the first 180 d (LD50/180) was 11.35 Gy (95% CI 11.1-11.6 Gy) for C57L/J mice, 14.17 Gy (95% CI 13.9-14.5 Gy) for CBA/J mice, and 14.10 Gy (95% CI 12.2-16.4 Gy) for C57BL/6J mice. The LD50/180 in the C57L/J strain was most closely analogous to the DRR for clinical incidence of pneumonitis in non-human primates (10.28 Gy; 95% CI 9.9-10.7 Gy) and humans (10.60 Gy; 95% CI 9.9-12.1 Gy). Furthermore, in the C57L/J strain, there was no gender-specific difference in DRR (p = 0.5578). The reliability of the murine models is demonstrated by the reproducibility of the dose-response and consistency of disease presentation across studies.Health Phys. 106(1):000-000; 2014.