Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy.

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.

Acute and Long-Term Management of Blunt Cerebrovascular Injury at a Quaternary Referral Level 1 Trauma Center: The Memphis Experience and Comparison of a New Scoring System.

BACKGROUND AND OBJECTIVES: The management of blunt cerebrovascular injuries (BCVIs) remains an important topic within trauma and neurosurgery today. There remains a lack of consensus within the literature and significant variation across institutions. The purpose of this study was to evaluate management of BCVI at a large, tertiary referral trauma center. METHODS: Institutional Review Board approval was obtained to conduct a retrospective review of patients with BCVI at our Level 1 Trauma Center. Computed tomography angiography was used to identify BCVI for each patient. Patient information was collected, and statistical analysis was performed. With the included risk factors for ischemic complications, a novel scoring system based on ischemic risk, the "Memphis Score," was developed and evaluated to grade BCVI. RESULTS: Two hundred seventeen patients with BCVI from July 2020 to August 2022 were identified. The most common mechanism of injury was motor vehicle collision (141, 65.0%). Vertebral arteries were the most common vessel injured (136, 51.1%) with most injuries occurring at a high cervical location (101, 38.0%). Denver Grade 1 injuries (89, 33.5%) and a Memphis Score of 1 were most frequent (172, 64.6%), and initial anticoagulation with heparin drip was initiated 56.7% of the time (123). Endovascular treatment was required in 24 patients (11.1%) and was usually performed in the first 48 hours (15, 62.5%). While Denver Grade (P = .019) and Memphis Score (P < .00001) were significantly higher in those patients undergoing endovascular treatment, only the Memphis Score demonstrated a significant difference between those patients who had stroke or worsening on follow-up imaging and those who did not (P = .0009). CONCLUSION: Although BCVI management has improved since early investigative efforts, institutions must evaluate and share their data to help clarify outcomes. The novel "Memphis Score" presents a standardized framework to communicate ischemic risk and guide management of BCVI.

Epigenetics to clinicopathological features: a bibliometric analysis of H3 G34-mutant diffuse hemispheric glioma literature.

PURPOSE: Pediatric-type diffuse high-grade gliomas are the leading cause of cancer-related morbidity and mortality in children. More than 30% of diffuse hemispheric gliomas (DHG) in adolescents harbor histone H3 G34 mutations and are recognized by the World Health Organization as a distinct tumor entity. By reporting bibliometric characteristics of the most cited publications on H3 G34-mutant DHG (H3 G34 DHG), we provide an overview of emerging literature and speculate where future research efforts may lead. METHODS: One hundred fourteen publications discussing H3 G34 DHG were identified, categorized as basic science (BSc), clinical (CL), or review (R), and ranked by citation number. Various bibliometric parameters were summarized, and a comparison between article types was performed. RESULTS: Articles within this study represent principal investigators from 15 countries and were published across 63 journals between 2012 and 2024, with 36.84% of articles originating in the United States. Overall median values were as follows: citation count, 20 (range, 0-2591), number of authors, 9 (range, 2-78), and year of publication, 2020 (range, 2012-2024). Among the top ten most cited articles, BSc articles accounted for all ten reports. Compared to CL and R articles, BSc articles were published in journals with higher impact factors. CONCLUSION: We establish variability in bibliometric parameters for the most cited publications on H3 G34 DHG. Our findings demonstrate a paucity of high-impact and highly cited CL reports and acknowledge an unmet need to intersect basic mechanism with clinical data to inform novel therapeutic approaches.

A Scoping Review of Professionalism in Neurosurgery.

BACKGROUND AND OBJECTIVES: The Accreditation Council for Graduate Medical Education's Milestones provides a foundation for professionalism in residency training. Specific professionalism concepts from neurosurgery could augment and expand milestones for the specialty. We reviewed the current literature and identified professionalism concepts within the context of neurosurgical practice and training. METHODS: We used a scoping review methodology to search PubMed/MEDLINE and Scopus and identify English-language articles with the search terms "professionalism" and "neurosurgery." We excluded articles that were not in English, not relevant to professionalism within neurosurgery, or could not be accessed. Non-peer-reviewed and qualitative publications, such as commentaries, were included in the review. RESULTS: A total of 193 articles were included in the review. We identified 6 professionalism themes among these results: professional identity (n = 53), burnout and wellness (n = 51), professional development (n = 34), ethics and conflicts of interest (n = 27), diversity and gender (n = 19), and misconduct (n = 9). CONCLUSION: These 6 concepts illustrate concerns that neurosurgeons have concerning professionalism. Diversity and gender, professional identity, and misconduct are not specifically addressed in the Accreditation Council for Graduate Medical Education's Milestones. This review could be used to aid the development of organizational policy statements on professionalism.

The Greatest Healthcare Disparity: Addressing Inequities in the Treatment of Childhood Central Nervous System Tumors in Low- and Middle-Income Countries.

The antithesis between childhood cancer survival rates in low- and middle-income countries (LMIC) and high-income countries (HIC) represents one of healthcare's most significant disparities. In HICs, the 5-year survival rate for children with cancer, including most brain tumors, exceeds 80%. Unfortunately, children in LMICs experience far worse outcomes with 5-year survival rates as low as 20%. To address inequities in the treatment of childhood cancer and disease burden globally, the World Health Organization (WHO) launched the Global Initiative for Childhood Cancer. Within this initiative, pediatric low-grade glioma (LGG) represents a unique opportunity for the neurosurgical community to directly contribute to a paradigm shift in the survival outcomes of children in LMICs, as many of these tumors can be managed with surgical resection alone. In this chapter, we discuss the burden of pediatric LGG and outline actions the neurosurgical community might consider to improve survival for children with LGG in LMICs.

The role of neurosurgery in advancing pediatric CNS tumor care worldwide.

Introduction: There is substantial inequity in survival outcomes for pediatric brain tumor patients residing in high-income countries (HICs) compared to low- and middle-income countries (LMICs). To address disparities in pediatric cancer survival, the World Health Organization (WHO) established the Global Initiative for Childhood Cancer (GICC) to expand quality care for children with cancer. Research question: To provide an overview of pediatric neurosurgical capacity and detail the burden of neurosurgical diseases impacting children. Material and methods: A narrative review of the current context of global pediatric neurosurgical capacity as it relates to neurooncology and other diseases relevant to children. Results: In this article, we provide an overview of pediatric neurosurgical capacity and detail the burden of neurosurgical diseases impacting children. We highlight concerted advocacy and legislative efforts aimed at addressing unmet neurosurgical needs in children. Finally, we discuss the potential implications of advocacy efforts on treating pediatric CNS tumors and outline strategies to improve global outcomes for children with brain tumors worldwide in the context of the WHO GICC. Discussion and conclusion: With both global pediatric oncology and neurosurgical initiatives converging on the treatment of pediatric brain tumors, significant strides toward decreasing the burden of pediatric neurosurgical diseases will hopefully be made.

Oncohistones and disrupted development in pediatric-type diffuse high-grade glioma.

Recurrent, clonal somatic mutations in histone H3 are molecular hallmarks that distinguish the genetic mechanisms underlying pediatric and adult high-grade glioma (HGG), define biological subgroups of diffuse glioma, and highlight connections between cancer, development, and epigenetics. These oncogenic mutations in histones, now termed "oncohistones", were discovered through genome-wide sequencing of pediatric diffuse high-grade glioma. Up to 80% of diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) and diffuse glioma arising in other midline structures including thalamus or spinal cord, contain histone H3 lysine 27 to methionine (K27M) mutations or, rarely, other alterations that result in a depletion of H3K27me3 similar to that induced by H3 K27M. This subgroup of glioma is now defined as diffuse midline glioma, H3K27-altered. In contrast, histone H3 Gly34Arg/Val (G34R/V) mutations are found in approximately 30% of diffuse glioma arising in the cerebral hemispheres of older adolescents and young adults, now classified as diffuse hemispheric glioma, H3G34-mutant. Here, we review how oncohistones modulate the epigenome and discuss the mutational landscape and invasive properties of histone mutant HGGs of childhood. The distinct mechanisms through which oncohistones and other mutations rewrite the epigenetic landscape provide novel insights into development and tumorigenesis and may present unique vulnerabilities for pHGGs. Lessons learned from these rare incurable brain tumors of childhood may have broader implications for cancer, as additional high- and low-frequency oncohistone mutations have been identified in other tumor types.

Pediatric Neurosurgical Capacity for the Care of Children With CNS Tumors Worldwide: A Cross-Sectional Assessment.

PURPOSE: Efforts to address inequities in the treatment of pediatric CNS tumors and the burden of childhood cancer globally have prompted the designation of low-grade glioma as one of six index cancers for the World Health Organization Global Initiative for Childhood Cancer. Understanding the importance of neurosurgical interventions and evaluating pediatric neurosurgical capacity may identify critical interventions to improve outcomes for children with low-grade glioma and other CNS tumors. METHODS: An online, cross-sectional survey assessing pediatric neurosurgical practice and capacity was distributed to members of the International Society of Pediatric Neurosurgery. The survey included 36 items covering domains including patient volume, available infrastructure, scope of practice, case distribution, and multidisciplinary care. RESULTS: Responses from 196 individuals from 61 countries, spanning all WHO regions, were included. Ninety-six (49.0%) were from high-income countries, 57 (29.1%) were from upper-middle-income countries, 42 (21.4%) were from lower-middle-income countries (LMICs), and 1 was (0.5%) from a low-income country. Most respondents had a catchment population of ≥ 1 million and indicated the availability of basic neurosurgical resources such as a dedicated neurosurgical operating theater and surgical microscope. The presence of a neurosurgical intensive care unit, inpatient rehabilitation services, and infection monitoring showed similar availability across country groups. Quantitative scoring of 13 infrastructure and service items established that fewer resources were available in low-income countries/LMICs and upper-middle-income countries compared with high-income countries. The volume of pediatric CNS tumor cases and case distribution did not vary according to World Bank country groups. CONCLUSION: This study provides a comprehensive evaluation of pediatric neurosurgical capacity across the globe, establishing variability of resources on the basis of the country income level. Our findings suggest that pediatric neurosurgeons in LMICs may benefit from key neurosurgical instrumentation and increased support for multidisciplinary brain tumor programs and childhood cancer research efforts.

The role of neurosurgeons in global public health: the case of folic acid fortification of staple foods to prevent spina bifida.

OBJECTIVE: The global neurosurgery movement arose at the crossroads of unmet neurosurgical needs and public health to address the global burden of neurosurgical disease. The case of folic acid fortification (FAF) of staple foods for the prevention of spina bifida and anencephaly (SBA) represents an example of a new neurosurgical paradigm focused on public health intervention in addition to the treatment of individual cases. The Global Alliance for the Prevention of Spina Bifida-F (GAPSBiF), a multidisciplinary coalition of neurosurgeons, pediatricians, geneticists, epidemiologists, food scientists, and fortification policy experts, was formed to advocate for FAF of staple foods worldwide. This paper serves as a review of the work of GAPSBiF thus far in advocating for universal FAF of commonly consumed staple foods to equitably prevent SBA caused by folic acid insufficiency. METHODS: A narrative review was performed using the PubMed and Google Scholar databases. RESULTS: In this review, the authors describe the impact of SBA on patients, caregivers, and health systems, as well as characterize the multifaceted requirements for proper spina bifida care, including multidisciplinary clinics and the transition of care, while highlighting the role of neurosurgeons. Then they discuss prevention policy approaches, including supplementation, fortification, and hybrid efforts with folic acid. Next, they use the example of FAF of staple foods as a model for neurosurgeons' involvement in global public health through clinical practice, research, education and training, and advocacy. Last, they describe mechanisms for involvement in the above initiatives as a potential academic tenure track, including institutional partnerships, organized neurosurgery, neurosurgical expert groups, nongovernmental organizations, national or international governments, and multidisciplinary coalitions. CONCLUSIONS: The role of neurosurgeons in caring for children with spina bifida extends beyond treating patients in clinical practice and includes research, education and training, and advocacy initiatives to promote context-specific, evidence-based initiatives to public health problems. Promoting and championing FAF serves as an example of the far-reaching, impactful role that neurosurgeons worldwide may play at the intersection of neurosurgery and public health.

Hyperstoichiometric Uranium Dioxides: Rapid Synthesis and Irradiation-Induced Structural Changes.

Uranium dioxide (UO2), the primary fuel for commercial nuclear reactors, incorporates excess oxygen forming a series of hyperstoichiometric oxides. Thin layers of these oxides, such as UO2.12, form readily on the fuel surface and influence its properties, performance, and potentially geologic disposal. This work reports a rapid and straightforward combustion process in uranyl nitrate-glycine-water solutions to prepare UO2.12 nanomaterials and thin films. We also report on the investigation of the structural changes induced in the material by irradiation. Despite the simple processing aspects, the combustion synthesis of UO2.12 has a sophisticated chemical mechanism involving several exothermic steps. Raman spectroscopy and single-crystal X-ray diffraction (XRD) measurements reveal the formation of a complex compound containing the uranyl moiety, glycine, H2O, and NO3- groups in reactive solutions and dried combustion precursors. Combustion diagnostic methods, gas-phase mass spectroscopy, differential scanning calorimetry (DSC), and extracted activation energies from DSC measurements show that the rate-limiting step of the process is the reaction of ammonia with nitrogen oxides formed from the decomposition of glycine and uranyl nitrate, respectively. However, the exothermic decomposition of the complex compound determines the maximum temperature of the process. In situ transmission electron microscopy (TEM) imaging and electron diffraction measurements show that the decomposition of the complex compound directly produces UO2. The incorporation of oxygen at the cooling stage of the combustion process is responsible for the formation of UO2.12. Spin coating of the solutions and brief annealing at 670 K allow the deposition of uniform films of UO2.12 with thicknesses up to 300 nm on an aluminum substrate. Irradiation of films with Ar2+ ions (1.7 MeV energy, a fluence of up to 1 × 1017 ions/cm2) shows unusual defect-simulated grain growth and enhanced chemical mixing of UO2.12 with the substrate due to the high uranium ion diffusion in films. The method described in this work allows the preparation of actinide oxide targets for fundamental nuclear science research and studies associated with stockpile stewardship.

Irradiation-Driven Restructuring of UO2 Thin Films: Amorphization and Crystallization.

Combustion synthesis in uranyl nitrate-acetylacetone-2-methoxyethanol solutions was used to deposit thin UO2 films on aluminum substrates to investigate the irradiation-induced restructuring processes. Thermal analysis revealed that the combustion reactions in these solutions are initiated at ∼160 °C. The heat released during the process and the subsequent brief annealing at 400 °C allow the deposition of polycrystalline films with 5-10 nm UO2 grains. The use of multiple deposition cycles enables tuning of the film thicknesses in the 35-260 nm range. Irradiation with Ar2+ ions (1.7 MeV energy and a fluence of up to 1 × 1017 ions/cm2) is utilized to generate a uniform distribution of atomic displacements within the films. X-ray fluorescence (XRF) and alpha-particle emission spectroscopy showed that the films were stable under irradiation and did not undergo sputtering degradation. X-ray photoelectron spectroscopy (XPS) showed that the stoichiometry and uranium ionic concentrations remain stable during irradiation. The high-resolution electron microscopy imaging and electron diffraction analysis demonstrated that at the early stages of irradiation (below 1 × 1016 ion/cm2) UO2 films show complete amorphization and beam-induced densification (sintering), resulting in a pore-free disordered film. Prolonged irradiation (5 × 1016 ion/cm2) is shown to trigger a crystallization process at the surface of the films that moves toward the UO2/Al interface, converting the entire amorphous material into a highly crystalline film. This work reports on an entirely different radiation-induced restructuring of the nanoscale UO2 compared to the coarse-grained counterpart. The preparation of thin UO2 films deposited on Al substrates fills an area of national need within the stockpile stewardship program of the National Nuclear Security Administration and fundamental research with actinides. The method reported in this work produces pure, robust, and uniform thin-film actinide targets for nuclear science measurements.

PAX3-FOXO1 drives miR-486-5p and represses miR-221 contributing to pathogenesis of alveolar rhabdomyosarcoma.

Rhabdomyosarcoma is the most common soft-tissue sarcoma in childhood and histologically resembles developing skeletal muscle. Alveolar rhabdomyosarcoma (ARMS) is an aggressive subtype with a higher rate of metastasis and poorer prognosis. The majority of ARMS tumors (80%) harbor a PAX3-FOXO1 or less commonly a PAX7-FOXO1 fusion gene. The presence of either the PAX3-FOXO1 or PAX7-FOXO1 fusion gene foretells a poorer prognosis resulting in clinical re-classification as either fusion-positive (FP-RMS) or fusion-negative RMS (FN-RMS). The PAX3/7-FOXO1 fusion genes result in the production of a rogue transcription factors that drive FP-RMS pathogenesis and block myogenic differentiation. Despite knowing the molecular driver of FP-RMS, targeted therapies have yet to make an impact for patients, highlighting the need for a greater understanding of the molecular consequences of PAX3-FOXO1 and its target genes including microRNAs. Here we show FP-RMS patient-derived xenografts and cell lines display a distinct microRNA expression pattern. We utilized both loss- and gain-of function approaches in human cell lines with knockdown of PAX3-FOXO1 in FP-RMS cell lines and expression of PAX3-FOXO1 in human myoblasts and identified microRNAs both positively and negatively regulated by the PAX3-FOXO1 fusion protein. We demonstrate PAX3-FOXO1 represses miR-221/222 that functions as a tumor suppressing microRNA through the negative regulation of CCND2, CDK6, and ERBB3. In contrast, miR-486-5p is transcriptionally activated by PAX3-FOXO1 and promotes FP-RMS proliferation, invasion, and clonogenic growth. Inhibition of miR-486-5p in FP-RMS xenografts decreased tumor growth, illustrating a proof of principle for future therapeutic intervention. Therefore, PAX3-FOXO1 regulates key microRNAs that may represent novel therapeutic vulnerabilities in FP-RMS.