Elevated risk of recurrence and retreatment for silent pituitary adenomas.

PURPOSE: Pituitary adenomas are the most common tumor of the pituitary gland and comprise nearly 15% of all intracranial masses. These tumors are stratified into functional or silent categories based on their pattern of hormone expression and secretion. Preliminary evidence supports differential clinical outcomes between some functional pituitary adenoma (FPA) subtypes and silent pituitary adenoma (SPA) subtypes. METHODS: We collected and analyzed the medical records of all patients undergoing resection of SPAs or FPAs from a single high-volume neurosurgeon between 2007 and 2018 at Brigham and Women's Hospital. Descriptive statistics and the Mantel-Cox log-rank test were used to identify differences in outcomes between these cohorts, and multivariate logistic regression was used to identify predictors of radiographic recurrence for SPAs. RESULTS: Our cohort included 88 SPAs and 200 FPAs. The majority of patients in both cohorts were female (48.9% of SPAs and 63.5% of FPAs). SPAs were larger in median diameter than FPAs (2.1 cm vs. 1.2 cm, p < 0.001). The most frequent subtypes of SPA were gonadotrophs (55.7%) and corticotrophs (30.7%). Gross total resection (GTR) was achieved in 70.1% of SPA resections and 86.0% of FPA resections (p < 0.001). SPAs had a higher likelihood of recurring (hazard ratio [HR] 3.2, 95% confidence interval [95%CI] 1.6-7.2) and a higher likelihood of requiring retreatment for recurrence (HR 2.5; 95%CI 1.0-6.1). Subset analyses revealed that recurrence and retreatment were more both likely for subtotally resected SPAs than subtotally resected FPAs, but this pattern was not observed in SPAs and FPAs after GTR. Among SPAs, recurrence was associated with STR (odds ratio [OR] 9.3; 95%CI 1.4-64.0) and younger age (OR 0.92 per year; 95%CI 0.88-0.98) in multivariable analysis. Of SPAs that recurred, 12 of 19 (63.2%) were retreated with repeat surgery (n = 11) or radiosurgery (n = 1), while the remainder were observed (n = 7).There were similar rates of recurrence across different SPA subtypes. CONCLUSION: Patients undergoing resection of SPAs should be closely monitored for disease recurrence through more frequent clinical follow-up and diagnostic imaging than other adenomas, particularly among patients with STR and younger patients. Several patients can be observed after radiographic recurrence, and the decision to retreat should be individualized. Longitudinal clinical follow-up of SPAs, including an assessment of symptoms, endocrine function, and imaging remains critical.

Teaching through the screen: a toolbox for creating a virtual neurosurgical subinternship program.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic disrupted the landscape of traditional neurosurgical subinternships, ramifications of which persist to this day. The outright cancellation of in-person subinternships in 2020 presented not only a challenge to both applicants and programs, but also an opportunity to establish an effective and efficient platform for virtual neurosurgical training. To address this need, the authors designed and trialed a novel virtual neurosurgical subinternship (Virtual Sub-I). METHODS: The weeklong, case-based Virtual Sub-I program combined flipped-classroom and active learning approaches. Students worked in small groups to discuss neurosurgical cases. Faculty and residents offered personalized mentorship sessions to participants. Surveys were used to assess students' experience with the authors' subinternship program, consistent with level 1 of the Kirkpatrick model. RESULTS: A total of 132 students applied from both international and American medical schools. The final cohort comprised 27 students, of whom 8 (30%) were female and 19 (70%) were male. Students characterized the subinternship as "interactive," "educational," and "engaging." One hundred percent of survey respondents were "very likely" to recommend the Virtual Sub-I to their peers. Faculty involved in the Virtual Sub-I stated that the program allowed them to determine the fit of participating medical students for their neurosurgery residency program, and that information gathered from the Virtual Sub-I had the potential to influence their ranking decisions. CONCLUSIONS: The Virtual Sub-I recapitulates the educational and interpersonal benefits of the traditional subinternship experience and can serve as a prototype for future virtual surgical education endeavors. Furthermore, the Virtual Sub-I presents a more equitable platform for introducing medical students across the undergraduate medical education spectrum to neurosurgical education and mentorship.

Differential Time-To-Promotion Trajectories Among Female and Male Neurosurgeons Contribute to Gender Disparities in Academic Rank Achievement.

OBJECTIVE: Despite the increasing representation of females in neurosurgical training, the fraction of female to male neurosurgeons decreases dramatically as faculty rank (Assistant, Associate, or Full Professor) increases. To assess this discrepancy, we quantified self-reported time-to-promotion trajectories for female and male neurosurgeons holding academic appointments. METHODS: In this cross-sectional institutional review board (IRB)-approved study, 147 female and 84 male neurosurgeons currently holding faculty positions in the US were contacted via email and invited to complete an anonymous, standardized survey. Respondents provided the calendar year of postgraduate training completion, promotion to different faculty ranks, geographic region of current practice (Western, Midwest, Southern, Northeast), and practice subspecialty. RESULTS: The response rate was 44.2% for females and 59.5% for males, with 114 participants included (65 female, 49 male). On average, female neurosurgeons required 25% longer to become an Associate Professor (P = 0.017), 34% longer to become a Full Professor (P = 0.004), 37% longer for promotion from Assistant to Associate Professor (P < 0.001), and 32% longer from Assistant to Full Professor (P = 0.012). Promotion timelines did not vary by region or specialty among male and female cohorts. Linear regressions revealed that female neurosurgeons with more recent training completion experienced shorter time-to-promotion to Associate and Full Professor compared to females of earlier generations (P = 0.005 and 0.001, respectively), while male timelines remained stable. CONCLUSIONS: This study identifies a significant delay in time-to-promotion for female neurosurgeons compared to their male counterparts. Investigation and standardization of promotion timelines are necessary to ensure meaningful representation gains from the increased number of women entering neurosurgical training.

On the Difficulty Predicting Word Recognition Performance After Cochlear Implantation.

HYPOTHESIS: Preimplantation word scores cannot reliably predict postimplantation outcomes. BACKGROUND: To date, there is no model based on preoperative data that can reliably predict the postoperative outcomes of cochlear implantation in the postlingually deafened adult patient. METHODS: In a group of 228 patients who received a cochlear implant between 2002 and 2021, we tested the predictive power of nine variables (age, etiology, sex, laterality of implantation, preimplantation thresholds and word scores, as well as the design, insertion approach, and angular insertion depth of the electrode array) on postimplantation outcomes. Results of multivariable linear regression analyses were then interpreted in light of data obtained from histopathological analyses of human temporal bones. RESULTS: Age and etiology were the only significant predictors of postimplantation outcomes. In agreement with many investigations, preimplantation word scores failed to significantly predict postimplantation outcomes. Analysis of temporal bone histopathology suggests that neuronal survival must fall below 40% before word scores in quiet begin to drop. Scores fall steeply with further neurodegeneration, such that only 20% survival can support acoustically driven word scores of 50%. Because almost all cochlear implant implantees have at least 20% of their spiral ganglion neurons (SGNs) surviving, it is expected that most cochlear implant users on average should improve to at least 50% word recognition score, as we observed, even if their preimplantation score was near zero as a result of widespread hair cell damage and the fact that ~50% of their SGNs have likely lost their peripheral axons. These "disconnected" SGNs would not contribute to acoustic hearing but likely remain electrically excitable. CONCLUSION: The relationship between preimplantation word scores and data describing the survival of SGNs in humans can explain why preimplantation word scores obtained in unaided conditions fail to predict postimplantation outcomes.

Contemporary Prognostic Signatures and Refined Risk Stratification of Gliomas: An Analysis of 4,400 Tumors.

BACKGROUND: With the significant shift in the classification, risk stratification, and standards of care for gliomas, we sought to understand how the overall survival of patients with these tumors is impacted by molecular features, clinical metrics, and treatment received. METHODS: We assembled a cohort of patients with a histopathologically diagnosed glioma from The Cancer Genome Atlas, Project Genomics Evidence Neoplasia Information Exchange, and Dana-Farber Cancer Institute/Brigham and Women's Hospital. This incorporated retrospective clinical, histological, and molecular data alongside prospective assessment of patient survival. RESULTS: 4,400 gliomas were identified: 2,195 glioblastoma, 1,198 IDH1/2-mutant astrocytoma, 531 oligodendroglioma, 271 other IDH1/2-wildtype glioma, and 205 pediatric-type glioma. Molecular classification updated 27.2% of gliomas from their original histopathologic diagnosis. Examining the distribution of molecular alterations across glioma subtypes revealed mutually exclusive alterations within tumorigenic pathways. Non-TCGA patients had significantly improved overall survival compared to TCGA patients, with 26.7%, 55.6%, and 127.8% longer survival for glioblastoma, IDH1/2-mutant astrocytoma, and oligodendroglioma respectively (all p<0.01). Several prognostic features were characterized, including NF1 alteration and 21q loss in glioblastoma, and EGFR amplification and 22q loss in IDH1/2-mutant astrocytoma. Leveraging the size of this cohort, nomograms were generated to assess the probability of overall survival based on patient age, the molecular features of a tumor, and the treatment received. CONCLUSIONS: By applying modern molecular criteria, we characterize the genomic diversity across glioma subtypes, identify clinically applicable prognostic features, and provide a contemporary update on patient survival to serve as a reference for ongoing investigations.

GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant.

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

Price Transparency for Cervical Spinal Fusion Among High-Performing Spine Centers in the United States.

BACKGROUND AND OBJECTIVES: As of January 1, 2021, all US hospitals are required by the Hospital Price Transparency Final Rule (HPTFR) to publish standard charges for all items and services, yet the state of price transparency for cervical spinal fusion is unknown. Here, we assess the nationwide price transparency landscape for cervical spinal fusion among high-performing spine centers in the United States. METHODS: In this cross-sectional economic evaluation, we queried publicly available price transparency websites of 332 "high-performing" spine centers, as defined by the US News and World Report. We extracted variables including gross charges for cervical spinal fusion, payor options, price reporting methodology, and prices relevant to consumers including listed cash prices and minimum and maximum negotiated charges. RESULTS: While nearly all 332 high-performing spine surgery centers (99.4%) had an online cost estimation tool, the HPTFR compliance rate was only 8.4%. Gross charges for cervical spinal fusion were accessible for 68.1% of hospitals, discounted cash prices for 46.4% of hospitals, and minimum and maximum charges for 10.8% of hospitals. There were large IQRs for gross charges ($48 491.98-$99 293.37), discounted cash prices ($26 952.25-$66 806.63), minimum charges ($10 766.11-$21 248.36), and maximum charges ($39 280.49-$89 035.35). There was geographic variability in the gross charges of cervical spinal fusion among high-performing spine centers within and between states. There was a significant association between "excellent" discharge to home status and lower mean gross charges. CONCLUSION: Although online cost reporting has drastically increased since implementation of the HPTFR, data reported for cervical spinal fusion remain inadequate and difficult to interpret by both providers and patients.

Recent oncolytic virotherapy clinical trials outline a roadmap for the treatment of high-grade glioma.

Adult and pediatric high-grade gliomas (HGGs) are aggressive cancers of the central nervous system that confer dismal clinical prognoses. Standard radiation and chemotherapy have demonstrated only limited efficacy in HGGs, motivating the accelerated investigation of novel modalities such as oncolytic virus (OV) therapies. OV centered therapies work through a mixed mechanism centered on oncolysis and the stimulation of an antitumor immune response. Three recent clinical trials utilizing herpes simplex virus-1 and adenovirus-based oncolytic virotherapy demonstrated not only the safety and efficacy of OVs but also novel dosing strategies that augment OV response potential. Considering these recent trials, herein we present a roadmap for future clinical trials of oncolytic immunovirotherapy in both adult and pediatric HGG, as well as persistent roadblocks related to the assessment of OV efficacy within and between trials.

Updates on Pathophysiology of Discogenic Back Pain.

Discogenic back pain, a subset of chronic back pain, is caused by intervertebral disc (IVD) degeneration, and imparts a notable socioeconomic health burden on the population. However, degeneration by itself does not necessarily imply discogenic pain. In this review, we highlight the existing literature on the pathophysiology of discogenic back pain, focusing on the biomechanical and biochemical steps that lead to pain in the setting of IVD degeneration. Though the pathophysiology is incompletely characterized, the current evidence favors a framework where degeneration leads to IVD inflammation, and subsequent immune milieu recruitment. Chronic inflammation serves as a basis of penetrating neovascularization and neoinnervation into the IVD. Hence, nociceptive sensitization emerges, which manifests as discogenic back pain. Recent studies also highlight the complimentary roles of low virulence infections and central nervous system (CNS) metabolic state alteration. Targeted therapies that seek to disrupt inflammation, angiogenesis, and neurogenic pathways are being investigated. Regenerative therapy in the form of gene therapy and cell-based therapy are also being explored.

Reduced time to imaging, length of stay, and hospital charges following implementation of a novel postoperative pathway for craniotomy.

OBJECTIVE: The authors created a postoperative postanesthesia care unit (PACU) pathway to bypass routine intensive care unit (ICU) admissions of patients undergoing routine craniotomies, to improve ICU resource utilization and reduce overall hospital costs and lengths of stay while maintaining quality of care and patient satisfaction. In the present study, the authors evaluated this novel PACU-to-floor clinical pathway for a subset of patients undergoing craniotomy with a case time under 5 hours and blood loss under 500 ml. METHODS: A single-institution retrospective cohort study was performed to compare 202 patients enrolled in the PACU-to-floor pathway and 193 historical controls who would have met pathway inclusion criteria. The pathway cohort consisted of all adult supratentorial brain tumor cases from the second half of January 2021 to the end of January 2022 that met the study inclusion criteria. Control cases were selected from the beginning of January 2020 to halfway through January 2021. The authors also discuss common themes of similar previously published pathways and the logistical and clinical barriers overcome for successful PACU pathway implementation. RESULTS: Pathway enrollees had a median age of 61 years (IQR 49-69 years) and 53% were female. Age, sex, pathology, and American Society of Anesthesiologists physical status distributions were similar between pathway and control patients (p > 0.05). Most of the pathway cases (96%) were performed on weekdays, and 31% had start times before noon. Nineteen percent of pathway patients had 30-day readmissions, most frequently for headache (16%) and syncope (10%), whereas 18% of control patients had 30-day readmissions (p = 0.897). The average time to MRI was 6 hours faster for pathway patients (p < 0.001) and the time to inpatient physical therapy and/or occupational therapy evaluation was 4.1 hours faster (p = 0.046). The average total length of stay was 0.7 days shorter for pathway patients (p = 0.02). A home discharge occurred in 86% of pathway cases compared to 81% of controls (p = 0.225). The average total hospitalization charges were $13,448 lower for pathway patients, representing a 7.4% decrease (p = 0.0012, adjusted model). Seven pathway cases were escalated to the ICU postoperatively because of attending physician preference (2 cases), agitation (1 case), and new postoperative neurological deficits (4 cases), resulting in a 96.5% rate of successful discharge from the pathway. In bypassing the ICU, critical care resource utilization was improved by releasing 0.95 ICU days per patient, or 185 ICU days across the cohort. CONCLUSIONS: The featured PACU-to-floor pathway reduces the stay of postoperative craniotomy patients and does not increase the risk of early hospital readmission.

Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

Spinal level and cord involvement in the prediction of sepsis development after vertebral fracture repair for traumatic spinal injury.

OBJECTIVE: Despite understanding the associated adverse outcomes, identifying hospitalized patients at risk for sepsis is challenging. The authors aimed to characterize the epidemiology and clinical risk of sepsis in patients who underwent vertebral fracture repair for traumatic spinal injury (TSI). METHODS: The authors conducted a retrospective cohort analysis of adults undergoing vertebral fracture repair during initial hospitalization after TSI who were registered in the National Trauma Data Bank from 2011 to 2014. RESULTS: Of the 29,050 eligible patients undergoing vertebral fracture repair, 317 developed sepsis during initial hospitalization. Of these patients, most presented after a motor vehicle accident (63%) or fall (28%). Patients in whom sepsis developed had greater odds of being male (adjusted OR [aOR] 1.5, 95% CI 1.1-1.9), having diabetes mellitus (aOR 1.5, 95% CI 1.11-2.1), and being obese (aOR 1.9, 95% CI 1.4-2.5). Additionally, they had greater odds of presenting with moderate (aOR 2.7, 95% CI 1.8-4.2) or severe (aOR 3.9, 95% CI 2.9-5.2) Glasgow Coma Scale scores and of having concomitant abdominal injuries (aOR 1.9, 95% CI 1.5-2.5) but not cranial, thoracic, or lower-extremity injuries. Interestingly, cervical spine injury was significantly associated with developing sepsis (OR 1.4, 95% CI 1.1-1.8), but thoracic and lumbar spine injuries were not. Spinal cord injury (OR 1.9, 95% CI 1.5-2.5) was also associated with sepsis regardless of level. Patients with sepsis were hospitalized approximately 16 days longer. They had greater odds of being discharged to rehabilitative care or home with rehabilitative care (OR 2.4, 95% CI 1.8-3.2) and greater odds of death or discharge to hospice (OR 6.0, 95% CI 4.4-8.1). CONCLUSIONS: Among patients undergoing vertebral fracture repair, those with cervical spine fractures, spinal cord injuries, preexisting comorbidities, and severe concomitant injuries are at highest risk for developing postoperative sepsis and experiencing adverse hospital disposition.

Association of venous thromboembolism following pediatric traumatic spinal injuries with injury severity and longer hospital stays.

OBJECTIVE: Venous thromboembolism (VTE) can cause significant morbidity and mortality in hospitalized patients, and may disproportionately occur in patients with limited mobility following spinal trauma. The authors aimed to characterize the epidemiology and clinical predictors of VTE in pediatric patients following traumatic spinal injuries (TSIs). METHODS: The authors conducted a retrospective cohort analysis of children who experienced TSI, including spinal fractures and spinal cord injuries, encoded within the National Trauma Data Bank from 2011 to 2014. RESULTS: Of the 22,752 pediatric patients with TSI, 192 (0.8%) experienced VTE during initial hospitalization. Proportionally, more patients in the VTE group (77%) than in the non-VTE group (68%) presented following a motor vehicle accident. Patients developing VTE had greater odds of presenting with moderate (adjusted odds ratio [aOR] 2.6, 95% confidence interval [CI] 1.4-4.8) or severe Glasgow Coma Scale scores (aOR 4.3, 95% CI 3.0-6.1), epidural hematoma (aOR 2.8, 95% CI 1.4-5.7), and concomitant abdominal (aOR 2.4, 95% CI 1.8-3.3) and/or lower extremity (aOR 1.5, 95% CI 1.1-2.0) injuries. They also had greater odds of being obese (aOR 2.9, 95% CI 1.6-5.5). Neither cervical, thoracic, nor lumbar spine injuries were significantly associated with VTE. However, involvement of more than one spinal level was predictive of VTE (aOR 1.3, 95% CI 1.0-1.7). Spinal cord injury at any level was also significantly associated with developing VTE (aOR 2.5, 95% CI 1.8-3.5). Patients with VTE stayed in the hospital an adjusted average of 19 days longer than non-VTE patients. They also had greater odds of discharge to a rehabilitative facility or home with rehabilitative services (aOR 2.6, 95% CI 1.8-3.6). CONCLUSIONS: VTE occurs in a low percentage of hospitalized pediatric patients with TSI. Injury severity is broadly associated with increased odds of developing VTE; specific risk factors include concomitant injuries such as cranial epidural hematoma, spinal cord injury, and lower extremity injury. Patients with VTE also require hospital-based and rehabilitative care at greater rates than other patients with TSI.

Immunotherapy approaches for the treatment of diffuse midline gliomas.

Diffuse midline gliomas (DMG) are a highly aggressive and universally fatal subgroup of pediatric tumors responsible for the majority of childhood brain tumor deaths. Median overall survival is less than 12 months with a 90% mortality rate at 2 years from diagnosis. Research into the underlying tumor biology and numerous clinical trials have done little to change the invariably poor prognosis. Continued development of novel, efficacious therapeutic options for DMGs remains a critically important area of active investigation. Given that DMGs are not amenable to surgical resection, have only limited response to radiation, and are refractory to traditional chemotherapy, immunotherapy has emerged as a promising alternative treatment modality. This review summarizes the various immunotherapy-based treatments for DMG as well as their specific limitations. We explore the use of cell-based therapies, oncolytic virotherapy or immunovirotherapy, immune checkpoint inhibition, and immunomodulatory vaccination strategies, and highlight the recent clinical success of anti-GD2 CAR-T therapy in diffuse intrinsic pontine glioma (DIPG) patients. Finally, we address the challenges faced in translating preclinical and early phase clinical trial data into effective standardized treatment for DMG patients.

A molecularly integrated grade for meningioma.

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

BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma.

Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell-like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. SIGNIFICANCE: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1-BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma. See related commentary by Beytagh and Weiss, p. 2730. See related article by Mo et al., p. 2906.

Three-dimensional Navigation-guided, Prone, Single-position, Lateral Lumbar Interbody Fusion Technique.

Lateral interbody fusion provides a significant biomechanical advantage over the traditional transforaminal lumbar interbody fusion due to the large implant size and optimal implant position. However, current methods for lateral interbody cage placement require either a two-staged procedure or a single lateral decubitus position that precludes surgeons from having either full access to the posterior spine for direct decompression or comfortable pedicle screw placement. Herein is one institution's experience with 10 cases of a prone single-position approach for simultaneous access to the anterior and posterior lumbar spine. This allows both lateral lumbar interbody cage placement, direct posterior decompression, and pedicle screw placement, all in one position. Three-dimensional (3D) navigation is utilized for increased precision in both approaching the lateral spine and interbody cage placement. The traditional blind psoas muscle tubular dilation was also modified. Tubular retractors and lateral vertebral body retractor pins were used to minimize the risks to the lumbar plexus.

Women Neurosurgeons in Academic and Other Leadership Positions in the United States.

OBJECTIVE: To provide the status of women neurosurgeons (WNS) in academic faculty and/or leadership positions in neurosurgery in the United States. METHODS: Neurosurgery academic programs were defined as having an Accreditation Council for Graduate Medical Education (ACGME) neurosurgery residency program (NSRP). Using a Google search, gender, academic rank, postgraduate degrees, academic and clinical titles, and subspecialty were recorded for each neurosurgery faculty. Officer gender was recorded for the top 7 neurosurgery U.S. organizations, 7 subspecialty sections, and 50 state neurosurgical societies. RESULTS: WNS were faculty at 77% (89/115) of ACGME NSRPs and constituted 10% of the workforce (186/1773). WNS residents were in 92% of ACGME NSRPs and constituted 19% of the workforce (293/1515). Two NSRPs (8%) had neither WNS faculty nor WNS residents. Of NSRPs without WNS faculty, 52% (13/25) had a faculty size >10. WNS accounted for 3% of NSRP chair positions. Academic rank of WNS faculty was lower than academic rank of men neurosurgeons faculty (P < 0.05). WNS faculty had a higher number of postgraduate degrees (P < 0.05). Pediatrics was the most common subspecialty (30%) among WNS. Over time, WNS held 1% of the leadership positions within the top 7 U.S. neurosurgery organizations and 7% within the 7 subspecialty sections. Over the past 20 years, 28% (14/50) of U.S. state neurosurgical societies had WNS serve as president. CONCLUSIONS: In 2020, the gender gap for U.S. WNS faculty and residents still exists. By providing informed benchmarks, our study might help neurosurgery organizations, medical school leadership, hiring committees, editors, and conference speakers to plan their next steps.

The Current Landscape of Oncolytic Herpes Simplex Viruses as Novel Therapies for Brain Malignancies.

Despite advances in surgical resection and chemoradiation, high-grade brain tumors continue to be associated with significant morbidity/mortality. Novel therapeutic strategies and approaches are, therefore, desperately needed for patients and their families. Given the success experienced in treating multiple other forms of cancer, immunotherapy and, in particular, immunovirotherapy are at the forefront amongst novel therapeutic strategies that are currently under investigation for incurable brain tumors. Accordingly, herein, we provide a focused mini review of pertinent oncolytic herpes viruses (oHSV) that are being investigated in clinical trials.

Adult sports-related traumatic spinal injuries: do different activities predispose to certain injuries?

OBJECTIVE: Sports injuries are known to present a high risk of spinal trauma. The authors hypothesized that different sports predispose participants to different injuries and injury severities. METHODS: The authors conducted a retrospective cohort analysis of adult patients who experienced a sports-related traumatic spinal injury (TSI), including spinal fractures and spinal cord injuries (SCIs), encoded within the National Trauma Data Bank from 2011 through 2014. Multiple imputation was used for missing data, and multivariable linear and logistic regression models were estimated. RESULTS: The authors included 12,031 cases of TSI, which represented 15% of all sports-related trauma. The majority of patients with TSI were male (82%), and the median age was 48 years (interquartile range 32-57 years). The most frequent mechanisms of injury in this database were cycling injuries (81%), skiing and snowboarding accidents (12%), aquatic sports injuries (3%), and contact sports (3%). Spinal surgery was required during initial hospitalization for 9.1% of patients with TSI. Compared to non-TSI sports-related trauma, TSIs were associated with an average 2.3-day increase in length of stay (95% CI 2.1-2.4; p < 0.001) and discharge to or with rehabilitative services (adjusted OR 2.6, 95% CI 2.4-2.7; p < 0.001). Among sports injuries, TSIs were the cause of discharge to or with rehabilitative services in 32% of cases. SCI was present in 15% of cases with TSI. Within sports-related TSIs, the rate of SCI was 13% for cycling injuries compared to 41% and 49% for contact sports and aquatic sports injuries, respectively. Patients experiencing SCI had a longer length of stay (7.0 days longer; 95% CI 6.7-7.3) and a higher likelihood of adverse discharge disposition (adjusted OR 9.69, 95% CI 8.72-10.77) compared to patients with TSI but without SCI. CONCLUSIONS: Of patients with sports-related trauma discharged to rehabilitation, one-third had TSIs. Cycling injuries were the most common cause, suggesting that policies to make cycling safer may reduce TSI.