Haydu, Lauren E.

Abstract Background Glioblastoma (GBM) remains a devastating cancer with limited treatment options, largely due to its heterogeneity. While supramaximal resection has recently provided survival benefits, therapeutic profiling of different tumor compartments, particularly its infiltrative edge remains largely unexplored. Methods Here, we leveraged magnetic resonance imaging (MRI)-guided multi-sampling, collecting 2 cores and 2 margins per case, to query GBM heterogeneity. Whole-exome and RNA-seq with drug testing in two patient-derived 3D models were used to reveal similarities and differences in genomic and transcriptomic makeups, cellular compositions, and drug responses across cores and margins. Bioinformatics interrogations further identified response biomarkers. Results Mutation analysis showed that oncogenes exhibited a higher degree of spatial heterogeneity than tumor suppressor genes, regardless of MRI status. While the mesenchymal transcriptional subtype with extracellular matrix remodeling, stress response, and immune programs were preferentially enriched in enhancing cores, proneural tumors with neurological processes favored non-enhancing margins. Using a 15-drug GBM-targeted panel, ERK (ulixertinib) and PI3K pathway (paxalisib, CC-115) inhibitors showed preferential efficacy in enhancing cores and non-enhancing margins, respectively. The anti-apoptosis, pan-Bcl2 agent navitoclax and the epigenetic drug trotabresib represented the most effective, tumor-wide monotherapies. Importantly, drug combinations generally outperformed single agents across all regions. Conclusions This work demonstrates the regional heterogeneity of therapeutic vulnerabilities in GBM ex vivo, showing various drugs with tumor-wide or MRI-enhancement informed activity. These findings offer preclinical bases of numerous monotherapies and drug combinations for future clinical trial design.

BACKGROUND AND OBJECTIVES: The Congress of Neurological Surgeons (CNS) Leadership Institute developed the first structured leadership program designed specifically for neurosurgeons. Led by the experts in neurosurgery, health care administration, and business, the program provides formal leadership training and mentorship aimed at advancing neurosurgeons' professional development at local, regional, national, and international levels. METHODS: The CNS Leadership Institute offers 2 curricula tailored for junior and senior faculty. Training begins with assigned readings, webinars, and online lectures that establish essential leadership principles. Core learning occurs during 2 in-person courses featuring interactive lectures, feedback sessions, and a longitudinal leadership project guided by national mentors. Program outcomes were assessed through a 40-question survey of alumni evaluating training effectiveness, skill application, and career advancement. RESULTS: Since 2016, 195 neurosurgeons have completed the CNS Leadership Institute. Among the 77 survey respondents, 70.1% reported significant professional advancement (new leadership role or job transition), and 64.8% directly attributed their advancement in skills and insights acquired through the program. Overall program effectiveness was rated 4.4 of 5, and the mean likelihood-to-recommend was 8.95 (95% CI: 8.70-9.20), yielding a Net Promoter Score of +63 (95% CI: +49 to +77). Alumni have assumed prominent roles including 16 Residency Program Directors, 3 Department Chairs, 1 Vice Dean, 4 Service Line Leaders, 13 CNS Executive Committee members, and over 100 committee or editorial board appointments critical to the specialty. CONCLUSION: The CNS Leadership Institute equips neurosurgeons with structured leadership training, mentorship, and practical tools to enhance their effectiveness as leaders. Survey results confirm that the program has a measurable impact on participants' career trajectories and professional growth. This initiative provides a reproducible model for cultivating the next generation of neurosurgical leaders and advancing the specialty's capacity for strategic, transformational leadership.

Abstract High-grade gliomas (HGGs) are aggressive tumors with poor outcomes and limited treatment options. Here, we combined genomic and transcriptomic tumor profiling with drug testing in a patient-derived 3-dimensional culture model to identify individualized treatments and predictive biomarkers. Activity of single agents targeting frequently dysregulated glioma pathways was relatively poor ex vivo and generally reflected historical patient data. However, compounds targeting PI3K, epigenetic, and survival/senescence signaling were effective in some cases. Drug sensitivity correlated with transcriptional rather than genomic features and suggested heterogeneity as a resistance mechanism. Bromodomain and extraterminal domain inhibition was particularly effective in tumors enriched in the mesenchymal transcriptional subtype, promoted proneural transition, and was overcome by upregulated PI3K signaling. Notably, combinations were largely effective, with 6 strategies exhibiting stronger efficacy than corresponding single agents in most cases (58-77%). This study identifies HGG vulnerabilities and associated biomarkers, resistance mechanisms, and effective combination strategies that warrant further clinical validation. Graphical Abstract

ABSTRACT Background While immune checkpoint inhibitors (ICIs) have shown significant efficacy, a common side effect is cutaneous immune‐related adverse events (irAEs). This study focuses on exploring the association between specific human leukocyte antigen (HLA) alleles and the development of cutaneous irAEs in melanoma patients undergoing ICI monotherapy and combination therapy. As certain HLA types are indicative of susceptibility to autoimmune diseases, it was hypothesized that HLA typing could serve as a potential screening tool for identifying patients at increased risk for developing irAEs. Methods A retrospective chart review was performed of 515 patients with melanoma who underwent ICI therapy, either as monotherapy or in combination, and had HLA typing available. This analysis spans from 2003 to 2023 with a focus on cutaneous irAEs. Statistical analyses were conducted to assess the association between HLA alleles and irAEs. Results Our analysis revealed that the HLA‐B*51:01 allele was associated with a higher risk of cutaneous irAEs after adjusting for ICI regimen (hazard ratio: 1.71 [95% CI, 1.12–2.61], p = .013.) Conclusion This is the largest study to link an HLA allele with ICI‐induced cutaneous irAEs. The findings may support the use of HLA typing as an initial screen for developing irAEs, providing a simple, straightforward metric that can be rapidly performed on patients prior to initiation of ICIs. However, further research is needed across different cancer and toxicity types.

Abstract Background Population aging is expected to increase the burden of Alzheimer's disease (AD) and related dementias (ADRD), yet up to 45% of ADRD risk may be modified. Disparities in ADRD burden among Hispanic/Latino and Black/African Americans suggests that socioeconomic deprivation and medical comorbidities may influence AD risk. The relationship between these factors, symptomatic age of onset, and neuropathologic findings in AD remains unclear. This study aims to investigate these associations in an ethnoracially diverse, neuropathologically diagnosed AD case series. Understanding these risk factors may help develop more effective AD risk reduction strategies. Method We queried the Florida Autopsied Multi‐Ethnic (FLAME) cohort database for neuropathologically‐diagnosed AD cases with available age onset of cognitive symptoms, who self‐identified as Hispanic/Latino ( n = 75) or Black/African American ( n = 22). Cases were matched to non‐Hispanic White decedents ( n = 101) by sex and year of birth. Medical records at the time of brain donation were retrospectively reviewed, assessing completeness for demographics, clinical characteristics, and medical comorbidities (Table 1). Result The table shows a comparative analysis stratified by young‐onset AD (YOAD, onset <65 years) and late‐onset AD (LOAD, onset ≥65 years). YOAD cases had a significantly higher level of education compared to LOAD ( p = 0.003). No differences were observed in sex , APOE ε4 carriership, or Area Deprivation Index between YOAD and LOAD. However, YOAD cases had a longer disease duration and were more likely to present with atypical clinical features compared to LOAD (both p <0.001). YOAD cases also showed a faster rate of decline on MMSE compared to LOAD ( p = 0.002), higher frequency of depression ( p = 0.018), and lower frequency of stroke/TIA ( p = 0.025). YOAD cases also had lower brain weight ( p = 0.041), less cerebrovascular disease burden ( p = 0.003) and higher neurofibrillary tangle density in association cortices ( p <0.001) compared to LOAD cases. Conclusion Socioeconomic deprivation and most medical comorbidities were not associated with AD symptomatic onset. Despite having higher education levels and lower cerebrovascular burden, YOAD decedents experienced faster cognitive decline but a longer disease course, with more frequent atypical clinical presentations and depression compared to LOAD. Further discussion will address the topographic distribution of tangle and plaque pathology.

Objective To determine the clinical features that identify patients with suspected rapidly progressive dementia (RPD) who will develop RPD. Methods Patients with suspected RPD were enrolled and followed at Mayo Clinic (Jacksonville, FL; January 2020 to October 2023) and Washington University (Saint Louis, MO; June 2016 to December 2019). Two dementia specialists independently reviewed clinical data and assigned diagnoses. Patients were diagnosed with RPD if they developed dementia within 1 year or incapacitation within 2 years of symptom onset. The associations between clinical features and causes and outcomes were explored via univariate and multivariate comparisons. Results Of 248 patients with suspected RPD, 185 (74.6%) met criteria for RPD. Patients with RPD were older (62.6 ± 14.5 vs 55.2 ± 18.1 years; p < 0.001), and more frequently diagnosed with Alzheimer's disease or related dementias (OR 3.13, 95% CI 1.40, 7.31) or Creutzfeldt–Jakob disease (OR 4.67, 95% CI 1.38, 15.75). Visual agnosia (15/183; 8.2%), substantial brain atrophy (27/182; 14.8%), and periodic epileptiform discharges (11/151; 7.3%) were exclusively detected in patients with RPD. After controlling for age, intensive care unit admission (OR 4.77, 95% CI 1.61, 14.12), lack of seizures (OR 2.47, 95% CI 1.15, 5.31), abnormal brain magnetic resonance imaging (OR 2.01, 95% CI 0.997, 4.05), and cerebrospinal fluid white blood cell count ≤5 cells/mm 3 (OR 3.30, 95% CI 1.60, 6.82) were also independently associated with RPD. Patients with RPD were more likely to die or develop severe dementia (mean time to outcome, 36.1 months; 95% CI 31.2–41.0). Interpretation Selected clinical features may identify patients with suspected RPD who are likely to continue to decline. Early recognition of these features may improve diagnostic accuracy and inform prognosis. ANN NEUROL 2025;98:764–776

ABSTRACT Introduction The Special Warfare Training Wing and Special Warfare Human Performance Support Group (HPSG; all-co-authors) were established in fiscal year (FY) 2019 to consolidate and oversee all Air Force Special Warfare (AFSPECWAR) training and provide embedded medical and human performance support to candidates with the goal of improving graduation rates and the longevity of the AFSPECWAR operator. The purpose of this manuscript is to assess the impact of the HPSG on AFSPECWAR graduation rates, musculoskeletal injury (MSKI) incidence, and cost. Materials and Methods Graduation rates, MSKI incidence (including incidence density and cumulative incidence probability), and MSKI-related health care costs were assessed across all AFSPECWAR training pipelines spanning 8 FYs 2015–22, including Indoctrination, Assessment, and Selection Courses (Selection); Tactical Air Control Party (TACP); Special Tactics (ST), and Guardian Angel (GA). Results A total of 5,728 distinct candidates were assessed over the time frame. There were significant decreases in attrition when comparing the HPSG era (FY 19–22) with the prior 4-year period for the ST (47% vs. 82% graduates) and TACP (34% vs. 41% graduates) training pipelines. The corresponding Selection (36% graduates) and GA (80% graduates) pipeline attrition rates remained stable. MSKI incidence rates (both incidence density and cumulative incidence probability) overall were not significantly different when comparing the pre-HPSG and HPSG time frames; however, they varied between the two time frames by course. GA candidates had a decrease in MSKI during the apprentice course in the HPSG era compared with the pre-HPSG era (2.4–1.0 cases per 100 trainee weeks; P &lt; .001), which corresponds to a nearly 20% reduction in the cumulative incidence probability (i.e., proportion of trainees injured) after 10 weeks of course. For ST and TACP courses, however, significantly increased incidence of MSKI was observed when comparing the two time frames (P &lt; .001), while for Selection courses, the rates remained stable. A significant reduction in the cost of MSKI-related management (62% total relative value units, 83% total costs) was observed. Conclusion The impact of the HPSG on attrition, MSKI incidence, and cost-of-care was not consistent across all training pipelines; however, taken together, there were no increases in attrition, and the cost of MSKI management was significantly lower.