BACKGROUND:Patients with medulloblastoma require craniospinal irradiation (CSI) to optimize disease control; however, cranial irradiation is associated with significant morbidity. We sought to develop a novel target volume (CTV_2340 cGy) and explore dosimetric benefits to minimize cognitive toxicity. METHODS:We conducted a literature review to confirm patterns of failure for average risk medulloblastoma to develop the CTV_2340 definition approach. Five patients (ages 4-16 years) were identified and proton and photon plans were generated for the new CTV_2340. Planning target goals included V100% ≥ 95% (the entire volume receiving at least 95% prescription dose) and V98% ≥ 97%. Proton planning included 3D robust optimization +/- 2 mm and +/- 2% range uncertainties. Photon plans included a 1 mm planning target volume. RESULTS:Medulloblastoma principally recurs in the ventricular system, periventricular region, cortical surface, or posterior fossa, supporting potential omission of remaining non-target-brain (NTB, e.g. white matter tracts, thalami). The novel CTV_2340 included these regions with a 1 mm brain expansion. All proton-based plans achieved appropriate target coverage. Median whole brain volumes were 1317.1 cc (range: 1116.0-1442.1), reflecting brain size over the age spectrum. Median NTB was 15% of the brain volume (9-31%), whereas the hippocampi were < 1%. Median NTB_V12Gy and V18Gy were: 91.7% (79.3-92.3) and 70.2% (59.8-78.2). Median NTB_minimum and NTB_mean were: 2.1 Gy (0.8-2.9) and 19.4 Gy (18.0-20.2). CTV_2340 overlapped with the hippocampi, limiting hippocampal sparing (median V18 Gy 99.1%). Photon-based planning showed inferior target coverage with minimal sparing. CONCLUSIONS:This study introduces a strategic approach to reduce radiotherapy-related neurotoxicity in medulloblastoma through proton-based sparing of critical brain regions. Multi-institutional studies are warranted to further advance this approach.

OBJECTIVE:The goal of this study was to systematically analyze tumor subgroup, location, and volume in relationship to extent of resection (EOR) through a retrospective approach and examine the role for second-look surgery with a single-institution case series. METHODS:Retrospective data review of pathologically confirmed medulloblastoma patients under the age of 21 who underwent surgery at the Mayo Clinic Rochester. RESULTS:There were 45 patients who met the inclusion criteria. All subgroups were represented, and those without subgroup data were classified as unknown with histopathologic confirmed grade IV medulloblastoma. The most common location of tumors was the fourth ventricle, though this varied by subgroup. The foramen of Lushka was the most invaded structure. Tumor size and volume were classified with respect to EOR and subgroup and there was no statistically signifcant difference noted. There were 5 non-WNT non-SHH subgroup patients who underwent second look surgery. EOR and the location of residual tumor varied, but GTR was achieved in all cases. CONCLUSIONS:When indicated, second look surgery is safe and offers an opportunity to achieve GTR. The EOR and role of second look surgery remain controversial, and larger multicenter studies will be needed.

BACKGROUND:In children with Chiari type I malformation and syringomyelia, neurosurgical posterior fossa decompression (PFD) provides clinical improvement, but whether duraplasty (incising the dura and placing a dural graft) improves outcomes is unclear. METHODS:We conducted a multicenter, cluster-randomized, controlled trial of PFD with duraplasty (PFD-D) as compared with PFD alone. Persons 21 years of age or younger with cerebellar tonsillar ectopia of at least 5 mm and a maximum syrinx diameter of 3.0 to 9.9 mm were enrolled at 38 centers. Centers were cluster-randomized: all the participants within each center underwent the same intervention. The primary outcome was surgical complications within 6 months. Secondary outcomes were clinical improvement, syrinx reduction, and repeat decompression at 10 to 24 months and the change in overall health-related quality of life at 6 to 24 months. RESULTS:A total of 162 participants were included in the trial, of whom 78 were assigned to undergo PFD-D and 84 to undergo PFD alone. The percentage of participants with complications within 6 months was 14% with PFD-D and 6% with PFD (adjusted odds ratio, 2.59; 95% confidence interval [CI], 0.86 to 7.84; P = 0.11). At 24 months, the percentage of participants with clinical improvement was 58% with PFD-D and 46% with PFD; the mean (±SD) syrinx reduction was 3.08±2.33 mm and 1.22±1.79 mm, respectively; and the percentage of participants with repeat decompression was 3% and 14%. Changes in health-related quality of life were similar in the two groups. CONCLUSIONS:The percentage of participants with surgical complications did not differ significantly between those who underwent PFD-D and and those who underwent PFD alone. Larger trials are needed to determine the relative benefits and risks of these two procedures. (Funded by the Patient-Centered Outcomes Research Institute and others; ClinicalTrials.gov number, NCT02669836.).

Radiotherapy (RT) is the standard-of-care for diffuse intrinsic pontine glioma (DIPG); however, it functions as a palliative treatment. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is upregulated in most DIPG tumors, posing a promising therapeutic target. Immunotherapies harnessing IL-13Rα2 to selectively deliver cytotoxic payloads such as pseudomonas exotoxin A (PE) are safe in DIPG patients and efficacious in preclinical disease models. Here, we used DIPG cell lines and mouse models to compare RT alone with RT plus the IL-13Rα2-targeted PE immunotoxin GB13 (IL13.E13K-PE4E). DNA strand breaks were evaluated by γH2AX and apoptosis, as well as other on-target effects, by Western blot and immunofluorescence. Cell viability and colony formation assays delineated cell viability and proliferation. In vivo efficacy was based on survival of mice with orthotopic tumors. Animals received fractionated focal irradiation and neoadjuvant and concomitant GB13 by convection-enhanced delivery. GB13 improved the efficacy of RT in vitro through inhibition of DNA damage repair and convergent modulation of apoptotic signaling. Combined RT and intratumoral administration of GB13 decreased tumor burden and prolonged survival in orthotopic xenograft and genetically engineered mouse models. These findings indicate that RT plus GB13 is well tolerated and effective, informing future investigation of a novel therapeutic approach for DIPG. Targeting IL13Ra2-expressing diffuse midline glioma with specific immunotoxin therapy attenuates DNA-damage response and dramatically increases radiation mediated cell death, significantly improving survival.

OBJECTIVE:Craniopharyngiomas are challenging lesions, and aggressive resections may cause significant postoperative morbidity and mortality. To mitigate morbidity, a potential strategy of subtotal resection (STR) and adjuvant radiation therapy (RT) has been used, but its impact on survival when compared to gross-total resection (GTR) has been under-investigated. Thus, the objective of this study was to analyze short-term mortality between patients undergoing STR ± RT and GTR, and differences in overall survival (OS) between patients undergoing STR, STR + RT, and GTR in a large, nationally representative database. METHODS:The authors queried the National Cancer Database for patients diagnosed with craniopharyngioma between 2004 and 2017. Tumor characteristics, treatment strategies, and extent of resection were analyzed. Endpoints were 3-month mortality rate and OS, which were compared between treatment modalities. Firth's logistic regression was used to analyze 3-month mortality and was adjusted for age, sex, Charlson Comorbidity Index score, histopathological diagnosis, income quartile, insurance payor, and maximal tumor diameter. Differences in survival between treatment modalities were compared with log time-to-event analyses after excluding deaths occurring within 3 months to control for immortal time bias. RESULTS:A total of 1460 adult and 390 pediatric patients were included. Adults undergoing STR ± RT had a lower rate of 3-month mortality compared to those undergoing GTR in adjusted analysis (2.8% vs 4.6%, odds ratio 0.42; p = 0.03). Survival curves for the STR + RT and GTR cohorts did not significantly differ (p = 0.198). A strategy of STR alone showed worse OS compared with GTR and STR + RT (p < 0.01). The average follow-up length for adults was 65.5 months. For pediatric patients, 3-month mortality for those undergoing GTR and STR ± RT was similar (0% vs 1%, respectively; p = 0.33). Additionally, compared to GTR, there were no significant differences in OS between STR + RT (p = 0.41) and STR alone (p = 0.44). The average follow-up length for the pediatric cohort was 79 months. CONCLUSIONS:STR + RT was associated with a favorable perioperative mortality profile when compared with GTR and provided similar long-term survival outcomes. Therefore, STR + RT may be considered when GTR carries significant risks.

Diffuse midline glioma (DMG) is a malignant nervous system tumor that primarily affects children and adolescents. This study aims to evaluate the research trends and hotspots on radiotherapy for DMG through bibliometric analysis. Global publications on DMG radiotherapy from 2005 to 2024 were retrieved from the Web of Science Core Collection database. A total of 521 publications from 47 countries were analyzed. The United States was the leading country in this field. St. Jude Children’s Research Hospital, Harvard University, and the University of Washington were the top 3 institutions in terms of contribution. Alberto Broniscer published 20 articles, ranking first in the number of publications. Stephanie Puget had the highest citation/article ratio (104.09). However, cooperation among active authors was limited. Journal of Neuro-Oncology, Neuro-Oncology, and Child’s Nervous System were the top three journals in terms of the number of published articles. After 2020, the most prevalent keywords in research on DMG radiotherapy included “DMG,” “blood–brain barrier,” and “H3K27M.” Citation bursts of the keywords “DMG,” “H3K27M,” “pediatric high grade,” “therapy,” “classification,” “CNS (central nervous system),” and “intrinsic pontine glioma” were observed in 2024. The current research hotspots include molecular subtype classification of DMG and molecular mechanism-driven precision treatment of DMG. The discovery of the H3K27M mutation has changed our understanding of this deadly disease. Radiotherapy combined with targeted therapy, immunotherapy, and other treatment methods has emerged as a research trend. Cooperation among different researchers should be strengthened to promote research on radiotherapy for DMG.

Pediatric high-grade gliomas (pHGGs) and diffuse midline gliomas (DMGs) represent some of the most aggressive and lethal childhood brain tumors. Recent molecular and epigenetic discoveries have redefined these entities as distinct from adult gliomas, with hallmark alterations such as H3K27M and H3G34R/V mutation driving unique biological behaviors. Advances in genomic, epigenomic, and transcriptomic profiling have enabled refined diagnostic classifications, improved our understanding of tumor heterogeneity, and revealed novel therapeutic targets. Despite these insights, standard of care approaches-primarily radiotherapy-remain palliative and conventional chemotherapy has shown limited efficacy. Emerging strategies, including targeted molecular therapies, immunotherapies, and innovative drug delivery techniques, offer promise but face significant challenges related to blood-brain barrier integrity, immune evasion, and intratumoral heterogeneity. Integration of DNA methylation profiling, enhancer landscape analysis, and liquid biopsy technologies are transforming diagnostic and monitoring capabilities. Future progress will depend on interdisciplinary collaboration, the development of predictive preclinical models, multi-omic integration, and adaptive clinical trial designs. Ultimately, tackling the biological complexity of pHGGs and DMGs through personalized, molecularly targeted approaches offers the best hope for improving outcomes in this devastating disease group.

Glioblastoma is the most common primary malignant tumor of the central nervous system, with a median survival of less than two years. While the etiology of glioblastoma is unclear, viral infection has emerged as a potential contributing factor. Cytomegalovirus (CMV) was first reported to be associated with glioblastoma in 2002. Since then, many studies have detected CMV in glioblastoma tissues suggesting it may plays a role in the glioblastoma progression. While there is no direct evidence confirmings CMV as an oncogenic virus, studies have demonstrated that CMV promotes glioblastoma development in cell and animal models, with several CMV-related genes implicated in tumorigenesis. Importantly, adjuvant CMV antiviral therapy has been proven to improve glioblastoma patient survival. This review focuses on clinical studies regarding the relationship between CMV and glioblastoma, the mechanism of CMV in tumorigenesis, advances in animal models of CMV-induced glioblastoma, and key directions for future investigations.

INTRODUCTION: Quality Improvement (QI) initiatives have improved patient outcomes and streamlined hospital processes, so the Accreditation Council for Graduate Medical Education requires residents to participate in QI. However, neurosurgeons and residents at our institution reported barriers to commencing QI projects. METHODS: A multidisciplinary team with representatives from all stakeholder groups conducted the project at the Mayo Clinic from Oct 2019-Jan 2024 following Define-Measure-Analyze-Improve-Control QI methodology, Awareness-Desire-Knowledge-Ability-Reinforcement change management framework, and Standards for QI Reporting Excellence guidelines. This initiative did not require institutional review board approval. RESULTS: The team used a charter and a Suppliers-Inputs-Processes-Outputs-Customers+Requirements tool to diagram the baseline process. Electronic databases quantified baseline metrics. An Ishikawa diagram categorized gaps in quality and Failure Modes and Effects Analysis determined that the primary barriers were suboptimal education and mentorship. The team brainstormed solutions during a Kaizen burst and evaluated proposals via an Impact/Effort grid. To improve education, residents attended a day-long QI fundamentals course and passed an examination. The team conducted three Plan-Design-Study-Act cycles to optimize mentorship. The percentage of residents who completed a project increased from 9% to 87%. Twenty-one residents, 11 neurosurgeons, 14 nurses, 9 staff, and 7 APPs participated on projects. Eleven QI projects commenced, nine were completed, eight resulted in practice changes, and two are ongoing. Interventions included a cart to streamline procedures, a reorganization of personnel to increase efficiency, protocols, and electronic medical record tools. Rigorous stakeholder analysis and sequential completion of QI phases was associated with achievement of initial aims and sustained initiatives over time. CONCLUSIONS: Using QI and change management frameworks, a team developed a novel program comprised of education and mentorship for residents to complete QI projects. We recommend that residents receive formal training and coaching from experienced mentors.

Primary gliomas arising within midline structures of the central nervous system are associated with a worse prognosis compared with hemispheric gliomas. In adults, compared to their pediatric counterparts, adult midline gliomas are not as clearly characterized on the clinical behavior, prognostic factors, and treatment approaches for these diseases. This retrospective cohort assessed all adult (≥ 18 years) patients from our institution with diffuse gliomas arising from midline structures at time of diagnosis (2014–2020). Molecular features characterized using immunohistochemistry, targeted next-generation sequencing, and chromosomal microarray analysis were collected. Patient characteristics were compared across groups using analysis of variance, Kruskal–Wallis, and the chi-square test as appropriate. Cumulative progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan–Meier method. Comparisons across groups were made using the log rank test. 79 patients were included in analysis, with a median follow-up of 22.5 months (range, 0.6–123). The mean age at diagnosis was 44.5 years (range, 19.4–76.4), and 51

OBJECTIVE:Neurosurgeon scientists play a unique role in advancing neuroscience research. While previous publications have explored trends in federal and foundation funding among neurosurgeons, funding is often dominated by neurosurgical oncologists and functional neurosurgeons. Less is known about the research efforts of pediatric neurosurgeons. The aim of this study was to survey the members of the American Society of Pediatric Neurosurgeons (ASPN) to provide an overview of past research experience, current involvement, funding, and research priorities among pediatric neurosurgeons, and to gather insights that could shape future efforts to advance pediatric neurosurgical research. METHODS:A survey was developed using the REDCap platform and distributed to all ASPN members via email. Survey questions used branching logic and were organized into 5 sections: 1) demographics, 2) research experience during training, 3) research experience as an attending physician, 4) research priorities, and 5) multicenter consortiums. RESULTS:One hundred thirty-nine respondents completed more than half of the survey, for an overall response rate of 52.1%. Most respondents (96.4%) participated in research during their training, but only 38.1% had received a grant during training. In contrast, 83.9% of respondents were actively engaged in research as an attending physician, and 48.7% reported active funding (60.7% federal, 41.8% from foundations, and 42.9% internal). Furthermore, 74.8% of respondents reported being a member of a multicenter research consortium, and 82.4% agreed that multicenter research is important. Seventy percent of respondents agreed that the ASPN should facilitate multicenter consortium-based pediatric neurosurgical research, offering free-text responses with the following suggestions: 1) set aside time at the annual meeting to discuss multicenter research (22.9%); 2) encourage collaboration and facilitate networking (42.9%); 3) provide centralized core services such as a data coordinator and biostatistician (12.9%); and 4) provide training, education, and mentoring (7.1%). CONCLUSIONS:The survey provided a cross-sectional analysis of the pediatric neurosurgical research landscape, highlighting the current state of research experience, funding, and the perspectives of pediatric neurosurgeons regarding research priorities. Despite the challenges, there is clear recognition of the importance of multicenter research collaboration. These findings reinforce the ongoing necessity of organized initiatives to support pediatric neurosurgical research and offer actionable insights into how organized pediatric neurosurgery can contribute to this critical endeavor.

BACKGROUND:Atypical teratoid rhabdoid tumor (ATRT) is a deadly central nervous system embryonal tumor caused by loss of SMARCB1, a core subunit of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes. SMARCB1-deficient cancers are defined by loss of cell differentiation-associated enhancers, but how SWI/SNF interacts with other arbiters of cell differentiation (specifically lineage-specific transcription factors [TFs]) remains poorly understood. METHODS:We leveraged a multi-omics approach, patient-derived ATRT cells, and patient-derived orthotopic xenografts to investigate the interplay of SWI/SNF with lineage-specific TFs in a clinically relevant setting. RESULTS:We observe that an activating protein 1 (AP-1)-dependent transcriptional regulatory network is lost in ATRT, and AP-1 and lineage-specific TFs TEAD1 and ZIC2 require SMARCB1 for enhancer binding. SMARCB1-dependent SWI/SNF integrates transcriptional functions of lineage-specific TFs into a core regulatory circuit that depends on the AP-1 subunit c-JUN, whose expression is determined by a SMARCB1-dependent super-enhancer that is lost in ATRT-MYC. In the absence of SMARCB1, lineage-specific TFs are sequestered to promoters, where they maintain core transcriptional programs necessary for cell survival. Targeting residual, promoter-proximal TF activity by a protein degrader of the SWI/SNF ATPase SMARCA4 or small-molecule inhibitors that indirectly inhibit AP-1 and TEAD activity abrogates expression of these networks, reducing cell viability in vitro and prolonging survival in an orthotopic patient-derived xenograft model. CONCLUSIONS:These results demonstrate SWI/SNF complexes are critical for lineage-specific TF binding and activity at both promoters and enhancers. In the context of ATRT, these findings reveal a previously underappreciated therapeutic vulnerability in targeting residual promoter-proximal TF function in ATRT.

INTRODUCTION: 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. METHODS: This was a retrospective study based on data from the National Surgical Quality Improvement Program-Pediatric database. Eligible patients were those undergoing PFD for CM-I between 2012-2021. Unplanned 30-day readmission 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 supervised machine learning algorithms. RESULTS: A total of 7106 pediatric patients undergoing PFD were included. The median age was 9.2 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. Random Forest(RF) had the highest predictive accuracy for both 30-day readmissions (Accuracy=0.96) and reoperations (AUC=0.99) 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: 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.

BackgroundChiari malformation type 1 (CM1) is sometimes associated with syringomyelia, most often in the cervical spine. Many clinicians pursue additional spine imaging to identify syrinxes; however, this imaging in pediatric CM1 patients often requires general anesthesia and endotracheal intubation, with significant risk and cost considerations.ObjectivesWe aim to determine the diagnostic yield and clinical utility of additional spine imaging for syrinx detection in surgical pediatric CM1 patients.MethodsWe retrospectively reviewed the electronic medical records and imaging of all pediatric CM1 patients who underwent surgical Chiari decompression at our institution over a 20-year period. The sensitivity and negative predictive value (NPV) of brain MRIs alone for syrinx detection and the diagnostic yield of additional spine MRIs in brain MRI syrinx-negative patients were assessed.ResultsOne hundred and fifty-nine CM1 pediatric patients underwent surgical Chiari decompression at our institution from 2001 to 2020. Forty-four patients had a syrinx as determined by both brain and spine MRI, but 41 (93.2%) were identifiable on brain MRI alone. Therefore, brain MRIs had a sensitivity of 93.2% and an NPV of 93.3% for syrinx detection. Spine MRIs in patients with syrinx-negative brain MRIs had a diagnostic yield of 6.7%. Thirty-five (40.7%) of the patients with both brain and spine MRI's required general anesthesia for spine MRI.ConclusionOur retrospective cohort study demonstrates clinicians should consider the high sensitivity and NPV of brain MRIs and the low diagnostic yield, cost, and anesthesia-related risks of additional spine imaging for syrinxes in pediatric CM1 patients.

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.

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.