Daniels, David J.

Abstract Background Cadaveric dissection remains a preferred and irreplaceable learning modality among neurosurgery residents. We aimed to develop and describe a tiered, quantifiable, and practical curriculum for cranial neurosurgical anatomy education. We report the structure and evaluation of our 2-year pilot study to serve as a suggested guide for other neurosurgery programs. Methods Our Complex Cranial Dissection Program is tailored to the needs of junior-level neurosurgery residents based on their postgraduation years 1 to 4. Dissections are performed in a sequential manner, each of which emphasize a particular set of manual skills and neuroanatomical knowledge. Dissections are scored on a scale of 10 points. The grading was based on specific landmarks and anatomical structures, which need to be exposed, explored, and preserved. Results Out of 16 residents, 14 individuals (87.5%) attended the dissections in the first iteration of the program and 16 individuals (100%) attended the dissections in the second iteration. A total of 17 dissections were performed across all years. In survey feedback about the program, 100% (Year 1) and 94% (Year 2) of residents considered the assigned dissections to be appropriate for their respective training levels. Further, 100% (Year 1) and 94% (Year 2) of residents endorsed that the dissections were important and helpful for their practice prior to similar operating room experiences. Conclusion The development and implementation of structured dissection programs within residency training, along with dedicated staff, and objective feedback serve a crucial role in neurosurgical education to further develop and enhance surgical skills in the operative setting.

Pediatric high-grade gliomas are a devastating subset of brain tumors, characterized by their aggressive pathophysiology and limited treatment options. Among them, H3 K27-altered diffuse midline gliomas (DMG) of the brainstem stand out due to their distinct molecular features and dismal prognosis. Recent advances in molecular profiling techniques have unveiled the critical role of H3 K27 alterations, particularly a lysine-to-methionine mutation on position 27 (K27M) of the histone H3 tail, in the pathogenesis of DMG. These mutations result in epigenetic dysregulation, which leads to altered chromatin structure and gene expression patterns in DMG tumor cells, ultimately contributing to the aggressive phenotype of DMG. The exploration of targeted therapeutic avenues for DMG has gained momentum in recent years. Therapies, including epigenetic modifiers, kinase inhibitors, and immunotherapies, are under active investigation; these approaches aim to disrupt aberrant signaling cascades and overcome the various mechanisms of therapeutic resistance in DMG. Challenges, including blood–brain barrier penetration and DMG tumor heterogeneity, require innovative approaches to improve drug delivery and personalized treatment strategies. This review aims to provide a comprehensive overview of the evolving understanding of DMG, focusing on the intricate molecular mechanisms driving tumorigenesis/tumor progression and the current landscape of emerging targeted interventions.

OBJECTIVE Chiari malformation type I (CM-I) is a congenital disorder occurring in 0.1% of the population. In symptomatic cases, surgery with posterior fossa decompression (PFD) is the treatment of choice. Surgery is, however, associated with peri- and postoperative complications that may require readmission or renewed surgical intervention. Given the associated financial costs and the impact on patients’ well-being, there is a need for predictive tools that can assess the likelihood of such adverse events. The aim of this study was therefore to leverage machine learning algorithms to develop a predictive model for 30-day readmissions and reoperations after PFD in pediatric patients with CM-I. METHODS This was a retrospective study based on data from the National Surgical Quality Improvement Program–Pediatric database. Eligible patients were those undergoing PFD (Current Procedural Terminology code 61343) for CM-I between 2012 and 2021. Patients undergoing surgery for tumors or vascular lesions were excluded. Unplanned 30-day readmission and unplanned 30-day reoperation were the main study outcomes. Additional outcome data considered included the length of hospital stay, 30-day complications, discharge disposition, and 30-day mortality. Training and testing samples were randomly generated (80:20) to study the 30-day readmission and reoperation using logistic regression, decision tree, random forest (RF), K-nearest neighbors, and Gaussian naive Bayes algorithms. RESULTS A total of 7106 pediatric patients undergoing PFD were included. The median age was 9.2 years (IQR 4.7, 14.2 years). Most of the patients were female (56%). The 30-day readmission and reoperation rates were 7.5% and 3.4%, respectively. Headaches (32%) and wound-related complications (30%) were the most common reasons for 30-day readmission, while wound revisions and evacuation of fluid or blood (62%), followed by CSF diversion-related procedures (28%), were the most common reasons for 30-day reoperation. RF classifiers had the highest predictive accuracy for both 30-day readmissions (area under the curve [AUC] 0.960) and reoperations (AUC 0.990) compared with the other models. On feature importance analysis, sex, developmental delay, ethnicity, respiratory disease, premature birth, hydrocephalus, and congenital/genetic anomaly were some of the variables contributing the most to both RF models. CONCLUSIONS Using a large-scale nationwide dataset, machine learning models for the prediction of both 30-day readmissions and reoperations were developed and achieved high accuracy. This highlights the utility of machine learning in risk stratification and surgical decision-making for pediatric CM-I.

OBJECTIVE Congenital anomalies of the atlanto-occipital articulation may be present in patients with Chiari malformation type I (CM-I). However, it is unclear how these anomalies affect the biomechanical stability of the craniovertebral junction (CVJ) and whether they are associated with an increased incidence of occipitocervical fusion (OCF) following posterior fossa decompression (PFD). The objective of this study was to determine the prevalence of condylar hypoplasia and atlas anomalies in children with CM-I and syringomyelia. The authors also investigated the predictive contribution of these anomalies to the occurrence of OCF following PFD (PFD+OCF). METHODS The authors analyzed the prevalence of condylar hypoplasia and atlas arch anomalies for patients in the Park-Reeves Syringomyelia Research Consortium database who underwent PFD+OCF. Condylar hypoplasia was defined by an atlanto-occipital joint axis angle (AOJAA) ≥ 130°. Atlas assimilation and arch anomalies were identified on presurgical radiographic imaging. This PFD+OCF cohort was compared with a control cohort of patients who underwent PFD alone. The control group was matched to the PFD+OCF cohort according to age, sex, and duration of symptoms at a 2:1 ratio. RESULTS Clinical features and radiographic atlanto-occipital joint parameters were compared between 19 patients in the PFD+OCF cohort and 38 patients in the PFD-only cohort. Demographic data were not significantly different between cohorts (p > 0.05). The mean AOJAA was significantly higher in the PFD+OCF group than in the PFD group (144° ± 12° vs 127° ± 6°, p < 0.0001). In the PFD+OCF group, atlas assimilation and atlas arch anomalies were identified in 10 (53%) and 5 (26%) patients, respectively. These anomalies were absent (n = 0) in the PFD group (p < 0.001). Multivariate regression analysis identified the following 3 CVJ radiographic variables that were predictive of OCF occurrence after PFD: AOJAA ≥ 130° (p = 0.01), clivoaxial angle < 125° (p = 0.02), and occipital condyle–C2 sagittal vertical alignment (C–C2SVA) ≥ 5 mm (p = 0.01). A predictive model based on these 3 factors accurately predicted OCF following PFD (C-statistic 0.95). CONCLUSIONS The authors’ results indicate that the occipital condyle–atlas joint complex might affect the biomechanical integrity of the CVJ in children with CM-I and syringomyelia. They describe the role of the AOJAA metric as an independent predictive factor for occurrence of OCF following PFD. Preoperative identification of these skeletal abnormalities may be used to guide surgical planning and treatment of patients with complex CM-I and coexistent osseous pathology.

Abstract Diffuse gliomas are pediatric high-grade gliomas that frequently harbor heterozygous histone H3.3 K27M, G34R, or G34V mutations. These mutations alter histone methylations, although the precise mechanism(s) of gliomagenesis remains uncertain. H3.3 contains a unique Serine at position 31 that is phosphorylated in prophase and dephosphorylated in anaphase during normal cell division. Previously we have reported that chromosome missegregation triggers H3.3 S31 phosphorylation along chromosome arms in ana/telophase leading to p53-induced cell cycle arrest. Here we show, in vitro and in vivo, that H3.3 K27M, G34R, and G34V suppress S31 phosphorylation by its mitotic kinase, Chk1. In diploid cells, overexpression of H3.3 K27M, G34R, G34V, or non-phosphorylatable S31A significantly increases the frequency of chromosome missegregation, while H3.3 K36M did not. This missegregation phenotype could be rescued by overexpression of K27M/S31E or G34R/S31E double mutants. Next, we used CRISPR/Cas9 gene editing to revert K27M or G34V patient-derived DMG cells to WT or replace the mutant allele with S31A. Reversion to WT increased metaphase S31 phosphorylation and reduced chromosome missegregations, but inserting an S31A mutation caused more mitotic defects. Following a mitotic error, newly formed aneuploid cells overexpressing K27M, G34R, or G34V suppress p53 levels and continue to divide, while WT overexpressing cells always arrest. To test the effects of diminished S31 phosphorylation on gliomagenesis, we utilized a novel mouse model of glioma. Expression of PDGFß linked to H3.3K27M, H3.3G34R, and H3.3S31A in neural stem cells in vivo promoted the development of high-grade gliomas in under 100 days, whereas PDFß-H3.3WT did not. Notably, the S31A tumors had histologically normal levels of K27me3 and K36me3. This work shows that a single glioma-associated point mutation in H3.3 can generate chromosomal instability, and which is a major contributing factor to H3.3 K27M and G34-altered glioma formation. Citation Format: Charles A. Day, Florina Grigore, Alyssa Langfald, Faruck Hakkim, David Daniels, Kevin Vaughan, James Robinson, Edward Hinchcliffe. Histone H3.3 K27M and G34R/V glioma driver mutations inhibit mitotic phosphorylation of H3.3 S31, driving tumor formation by inducing chromosomal instability [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B033.

Abstract Important challenges in developing drugs that target central nervous system (CNS) tumors include overcoming barriers for CNS delivery and reducing systemic side effects. Alisertib, an aurora A kinase inhibitor, has been examined for treatment of several CNS tumors in preclinical and clinical studies. In this study, we investigated the distribution of alisertib into the CNS, the site of efficacy for brain tumors, and into the bone marrow, the site of dose-limiting toxicity leading to myelosuppression. Mechanisms influencing site-specific distribution, such as active transport mediated by the efflux proteins, p-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), were examined. Alisertib exposure to the brain in wild-type mice was less than 1% of that in the plasma and was evenly distributed throughout various brain regions and the spinal cord. Studies using transporter knockout mice and pharmacological inhibition show that alisertib CNS distribution is influenced by P-gp, but not Bcrp. Conversely, upon systemic administration, alisertib distribution to the bone marrow occurred rapidly, was not significantly limited by efflux transporters, and reached higher concentrations than in the CNS. This study demonstrates that, given an equivalent distributional driving force exposure in plasma, the exposure of alisertib in the brain is significantly less than that in the bone marrow, suggesting that targeted delivery may be necessary to guarantee therapeutic efficacy with minimal risk for adverse events. Therefore, these data suggest that, to improve the therapeutic index when using alisertib for brain tumors, a localized regional delivery, such as convection-enhanced delivery, may be warranted. Citation Format: Juhee Oh, Erica A. Power, Wenjuan Zhang, David J. Daniels, William F. Elmquist. Murine CNS and bone marrow distribution of the aurora A kinase inhibitor alisertib: Pharmacokinetics and exposure at the sites of efficacy and toxicity [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A033.

Abstract BACKGROUND Diffuse hemispheric glioma (DHG) is an uncommon infiltrating glioma, defined in the World Health Organization 2021 guidelines by a mutation in the H3F3A gene at codon 34 (H3.G34). DHG primarily affects children and young adults. Due to its rarity, there is paucity of knowledge regarding factors affecting overall survival (OS). We retrospectively assessed our institutional experience and present a review of the literature. METHODS We searched our institution’s pathology records to identify six cases of DHG. Demographic, clinical, diagnostic, treatment, and outcome data were recorded. We next searched for published articles regarding DHG cases via PubMed through May 2023. Four-hundred-fifty-four published individual cases of H3.G34 glioma were identified, 204 of which were hemispheric/supratentorial tumors with OS data reported, providing a combined 210 cases for analysis. 132 of these cases included MGMT promoter methylation status. 111 included extent of surgical resection. Kaplan-Meier and Cox regression survival analysis was performed. RESULTS Age range for DHG patients was 7-66 years (median 17). Median OS was 18.5 months (95% CI, 17-25). Greater extent of surgical resection and presence of MGMT promoter methylation were associated with better prognosis. Median OS for biopsy alone was 12 months (95% CI, 10-NA), subtotal resection was 16 months (95% CI, 14-23), and gross total resection was 27 months (95% CI 23-NA) – log-rank p&lt; 0.001. OS for MGMT promoter unmethylated was 14 months (95% CI 12-22), MGMT promoter methylated was 24 months (95% CI, 17-30) – log-rank p=0.028. Contrary to previous reports, patient age was not found to impact prognosis (using 18, 21, and 40 years as cutoffs or as a continuous variable with Cox regression). CONCLUSION Extent of surgical resection and MGMT promoter methylation status are important prognostic factors for DHG. Unlike many primary brain tumors, survival does not appear to be significantly impacted by age.