Extraocular muscle electromyographic recordings for intraoperative monitoring of cranial nerves III, IV, and VI: a single-center experience with intraorbital electrodes.

OBJECTIVE: The objective of this study was to describe the quantitative features of intraoperative electromyographic recordings obtained from cranial nerve III, IV, and VI neuromonitoring using 25-mm intraorbital electrodes, in the larger context of demonstrating the practicality of this technique during neurosurgical cases. METHODS: A 25-mm-long shaft-insulated intraorbital needle electrode is routinely used at the authors' institution for extraocular muscle (EOM) electromyographic monitoring of the inferior rectus, superior oblique, and/or lateral rectus muscles when their function is at risk. Cases monitored between January 1, 2021, and December 31, 2022, were reviewed for patient demographics, tumor location and pathology, EOMs monitored, pre- and postoperative examination, and complications from electrode placement. Compound muscle action potentials on triggered electromyography, as well as neurotonic discharges on free-run electromyography, were described quantitatively. RESULTS: There were 141 cases in 139 patients reviewed during the 24-month time span, with 278 EOMs monitored (inferior rectus/superior oblique/lateral rectus muscles 68/68/142). Triggered electromyography yielded biphasic or triphasic compound muscle action potentials from EOMs with a mean onset latency of 1.51 msec (range 0.94-3.22 msec), mean maximal peak-to-trough amplitude of 1073.93 µV (range 76.75-7796.29 µV), and high specificity for the channel in nearly all cases. Neurotonic discharges were recorded in 30 of the 278 EOMs (with all 3 muscles represented) and associated with a greater incidence of new or worsened ophthalmoparesis (OR 4.62, 95% CI 1.3-16.4). There were 2 cases of small periorbital ecchymosis attributed to needle placement; additionally, 1 case of needle-related intraorbital hematoma occurred after the review period. CONCLUSIONS: The 25-mm shaft-insulated intraorbital electrode facilitates robust and consistent electromyographic recordings of EOMs that are advantageous over existing techniques. Combined with the relative ease of needle placement and low rate of complications, the technique is practical for neuromonitoring during craniotomies.

The role of occipital condyle and atlas anomalies on occipital cervical fusion outcomes in Chiari malformation type I with syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

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.

Machine learning for enhanced prognostication: predicting 30-day outcomes following posterior fossa decompression surgery for Chiari malformation type I in a pediatric cohort.

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.

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.

Anatomical Step-by-Step Dissection of Midline Suboccipital Approaches to the Fourth Ventricle for Trainees: Surgical Anatomy of the Telovelar, Transvermian, and Superior Transvelar Routes, Surgical Principles, and Illustrative Cases.

Introduction Safe, effective access to the fourth ventricle for oncologic resection remains challenging given the depth of location, restricted posterior fossa boundaries, and surrounding eloquent neuroanatomy. Despite description in the literature, a practical step-by step dissection guide of the suboccipital approaches to the fourth ventricle targeted to all training levels is lacking. Methods Two formalin-fixed, latex-injected specimens were dissected under microscopic magnification and endoscopic visualization. Dissections of the telovelar, transvermian, and supracerebellar infratentorial-superior transvelar approaches were performed by one neurosurgery resident (D.D.D.), under guidance of senior authors. The dissections were supplemented with representative clinical cases to highlight pertinent surgical principles. Results The telovelar and transvermian corridors afford excellent access to the caudal two-thirds of the fourth ventricle with the former approach offering expanded access to the lateral recess, foramen of Luschka, adjacent skull base, and cerebellopontine angle. The supracerebellar infratentorial-superior transvelar approach reaches the rostral third of the fourth ventricle, the cerebral aqueduct, and dorsal mesencephalon. Key steps described include positioning and skin incision, myofascial dissection, burr hole and craniotomy, durotomy, the aforementioned transventricular routes, and identification of relevant skull base landmarks. Conclusion The midline suboccipital craniotomy represents a foundational cranial approach, particularly for lesions involving the fourth ventricle. Operatively oriented resources that combine stepwise neuroanatomic dissections with representative cases provide a crucial foundation for neurosurgical training. We present a comprehensive guide for trainees in the surgical anatomy laboratory to optimize familiarity with fourth ventricle approaches, mastery of relevant microsurgical anatomy, and simultaneous preparation for learning in the operating room.

Shaping Our Understanding of Malignant Peripheral Nerve Sheath Tumor: A Bibliometric Analysis of the 100 Most-Cited Articles.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive soft tissue sarcomas of mesenchymal origin, characterized by a heterogeneous pathological spectrum, limited therapeutic options, and high metastatic potential. METHODS: Here, the authors conducted a comprehensive bibliometric analysis of the 100 most-cited MPNST articles by utilizing Elsevier's Scopus to identify all relevant published and indexed articles referring to MPNST, thereby aiming to elucidate the pertinent research findings regarding the disease's pathophysiology and therapeutic advancements. Articles were classified as basic science or clinical and analyzed for various bibliometric parameters. RESULTS: The majority of articles (75%) focused on clinical aspects, reflecting the extensive clinicopathological characterization of MPNSTs. Notable studies investigated prognostic factors, histological and immunohistochemical features, and diagnostic modalities. The identification of loss of function mutations in the polycomb repressive complex 2 emerged as a pivotal role, as it opened avenues for potential targets for novel therapeutic interventions. Newer articles (published in or after 2006) demonstrated higher citation rates, suggesting evolving impact and collaboration. CONCLUSIONS: This bibliometric analysis showed how developments in the understanding of MPNST pathophysiology and the creation of novel therapeutic strategies occurred throughout time. Changes that have been noticed recently could portend future innovative therapeutic approaches.

Gabapentin as part of a multimodal pain protocol for selective dorsal rhizotomy does not impact percentage of rootlets transected.

PURPOSE: We aim to determine whether preoperatively initiated gabapentin for pain control impacts the percentage of rootlets cut during monitored, limited laminectomy selective dorsal rhizotomy (SDR) procedure. METHODS: This retrospective cohort study includes participants with cerebral palsy who had SDR for treatment of spasticity between 2010 and 2019 at a single-institution tertiary care center. One-level laminectomy SDR aimed to evaluate the cauda equina roots from levels L2-S1 with EMG monitoring. Gabapentin titration began 3 weeks prior to SDR. Data was analyzed using simple linear regression. Thirty-one individuals met inclusion criteria. Mean age was 7 years, 4 months. Eighteen participants (58%) identified as male, 12 (39%) female, and one (3%) non-binary. Thirty (97%) had bilateral CP. Sixteen (52%) were GMFCS II, four (13%) GMFCS III, five (16%) GMFCS IV, and six (19%) GMFCS V. RESULTS: Mean percentage of rootlets transected was 50.75% (SD 6.00, range 36.36-60.87). There was no relationship between the dose of gabapentin at time of SDR and percentage of rootlets cut with a linear regression slope of - 0.090 and an R2 of 0.012 (P = 0.56). CONCLUSION: Results indicate that preoperative initiation of gabapentin did not impact the percentage of rootlets transected. Thus, gabapentin can be initiated prior to SDR at moderate dosages without impacting SDR surgical outcomes.

The composition of choroid plexus tumor research: a bibliometric analysis of the 100 most impactful studies to date.

PURPOSE: Choroid plexus tumors (CPT) are relatively rare CNS tumors that primarily occur in children. They are classified as low-grade choroid plexus papilloma, including atypical ones, and high-grade choroid plexus carcinoma based on histological characteristics. There has been extensive academic research regarding these complex tumors. The goal of this work was to identify the 100 most-cited articles pertaining to CPTs in order to better understand the most impactful studies to date. METHODS: In August 2023, Elsevier's Scopus database was searched for the 100 most-cited articles about CPT. To look for trends, articles were classified as either basic science or clinical, and the earliest 50 articles were separated from the latest 50 articles and then were compared. Various bibliometric parameters were summarized and compared using Pearson's chi-square exact test and Wilcoxon rank sum test/Mann-Whitney U test. RESULTS: The 100 most-cited articles were published between 1955 and 2016 in 53 different scientific journals, originating from 16 distinct countries. Over 75% of the articles were clinical in nature, and overall mean (range) values were as follows: citation count 78.5 (42-371), citation rate per year 3.4 (0.9-12), number of authors 6.2 (1-28). Newer articles had statistically higher citation rate (P < 0.01) and number of authors (P < 0.01) compared to their older counterparts. Additionally, while there was no significant difference in article focus (P = 0.64), there was a difference in study design (P < 0.01). CONCLUSION: This study used citation number as a surrogate for article impact and identified the 100 most-cited CPT articles. New mutational analyses have allowed for further subgrouping and positive trends in collaboration shine hope for improvement in treatment outcomes and long-term survival.

Evolution of neurosurgical advances and nuances in medulloblastoma therapy.

Medulloblastoma, the most common malignant brain tumor in children, presents a complex treatment challenge due to its propensity for infiltrative growth within the posterior fossa and its potential attachment to critical anatomical structures. Central to the management of medulloblastoma is the surgical resection of the tumor, which is a key determinant of patient prognosis. However, the extent of surgical resection (EOR), ranging from gross total resection (GTR) to subtotal resection (STR) or even biopsy, has been the subject of extensive debate and investigation within the medical community. Today, the impact of neurosurgical EOR on the prognosis of medulloblastoma patients remains a complex and evolving area of investigation. The conflicting findings in the literature, the challenges posed by critical surrounding anatomical structures, the potential for surgical complications and neurologic morbidity, and the nuanced interactions with molecular subgroups all contribute to the complexity of this issue. As the field continues to advance, the imperative to strike a delicate balance between maximizing resection and preserving quality of life remains central to the management of medulloblastoma patients.

Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies.

INTRODUCTION: H3 K27-altered diffuse midline glioma (DMG) is the most common malignant brainstem tumor in the pediatric population. Despite enormous preclinical and clinical efforts, the prognosis remains dismal, with fewer than 10% of patients surviving for two years after diagnosis. Fractionated radiation remains the only standard treatment options for DMG. Developing novel treatments and therapeutic delivery methods is critical to improving outcomes in this devastating disease. AREAS COVERED: This review addresses recent advances in molecularly targeted pharmacotherapy and immunotherapy in DMG. The clinical presentation, diagnostic workup, unique pathological challenges, and current clinical trials are highlighted throughout. EXPERT OPINION: Promising pharmacotherapies targeting various components of DMG pathology and the application of immunotherapies have the potential to improve patient outcomes. However, novel approaches are needed to truly revolutionize treatment for this tumor. First, combinational therapy should be employed, as DMG can develop resistance to single-agent approaches and many therapies are susceptible to rapid clearance from the brain. Second, drug-tumor residence time, i.e. the time for which a therapeutic is present at efficacious concentrations within the tumor, must be maximized to facilitate a durable treatment response. Engineering extended drug delivery methods with minimal off-tumor toxicity should be a focus of future studies.

Improvements in the Endoscopic Transsphenoidal Resection of Craniopharyngiomas: A Global Learning Curve.

BACKGROUND: Surgical management of craniopharyngiomas is nuanced and has varied in terms of the selected approach and aggressiveness of resection over time. In the past several decades, the endoscopic transsphenoidal approach has become commonly used for craniopharyngioma resection. There is a well characterized institutional 'learning curve' regarding endoscopic transsphenoidal approaches for craniopharyngiomas at specialized centers; however, the broader global learning curve remains to be characterized. METHODS: Clinical outcome data following endoscopic transsphenoidal craniopharyngioma resection were obtained from a previously published meta-analysis, including data published during or after the year 1990. Additionally, the year of publication, the country where procedures were performed, and the human development index of the country at time of publication were abstracted. Meta-regressional analyses were used to determine the significance of year and human development index as a covariate of the logit event rate of clinical outcomes. Statistical analyses were performed using the Comprehensive Meta-Analysis with a priori significance set as P < 0.05. RESULTS: A total of 100 studies (8230 patients) were examined, representing data from 19 countries. There was a significant increase in the achieved gross total resection rate (P = 0.0002) and a decrease in the achieved partial resection rate (P < 0.0001) across the time studied. Additionally, the rate of visual worsening (P = 0.025), postoperative cerebrospinal fluid leaks (P = 0.007), and development of meningitis (P = 0.032) decreased across time. CONCLUSIONS: This work suggests the existence of a global learning curve when examining clinical outcomes following endoscopic transsphenoidal craniopharyngioma resection. Globally, these findings highlight a general improvement in clinical outcomes across time.

Anatomical step-by-step dissection of common approaches to the third ventricle for trainees: surgical anatomy of the anterior transcortical and interhemispheric transcallosal approaches, surgical principles, and illustrative pediatric cases.

PURPOSE: To create a high-quality, cadaver-based, operatively oriented resource documenting the anterior transcortical and interhemispheric transcallosal approaches as corridors to the third ventricle targeted towards neurosurgical trainees at all levels. METHODS: Two formalin-fixed, latex-injected specimens were dissected under microscopic magnification and endoscopic-assisted visualization. Dissections of the transcortical and transcallosal craniotomies with transforaminal, transchoroidal, and interforniceal transventricular approaches were performed. The dissections were documented in a stepwise fashion using three-dimensional photographic image acquisition techniques and supplemented with representative cases to highlight pertinent surgical principles. RESULTS: The anterior transcortical and interhemispheric corridors afford excellent access to the anterior two-thirds of the third ventricle with varying risks associated with frontal lobe versus corpus callosum disruption, respectively. The transcortical approach offers a more direct, oblique view of the ipsilateral lateral ventricle, whereas the transcallosal approach readily establishes biventricular access through a paramedian corridor. Once inside the lateral ventricle, intraventricular angled endoscopy further enhances access to the extreme poles of the third ventricle from either open transcranial approach. Subsequent selection of either the transforaminal, transchoroidal, or interforniceal routes can be performed through either craniotomy and is ultimately dependent on individual deep venous anatomy, the epicenter of ventricular pathology, and the concomitant presence of hydrocephalus or embryologic cava. Key steps described include positioning and skin incision; scalp dissection; craniotomy flap elevation; durotomy; transcortical versus interhemispheric dissection with callosotomy; the aforementioned transventricular routes; and their relevant intraventricular landmarks. CONCLUSIONS: Approaches to the ventricular system for maximal safe resection of pediatric brain tumors are challenging to master yet represent foundational cranial surgical techniques. We present a comprehensive operatively oriented guide for neurosurgery residents that combines stepwise open and endoscopic cadaveric dissections with representative case studies to optimize familiarity with third ventricle approaches, mastery of relevant microsurgical anatomy, and preparation for operating room participation.

Assessing the Impact of Shifting Enfolded Neurosurgery Fellowships to Follow the Chief Resident Experience: National Survey of Program and Fellowship Directors.

OBJECTIVE: The neurosurgery chief resident year is traditionally completed during the final residency year; however, a recent directive decried that enfolded fellowships should be undertaken following completion of the chief experience for most fellowships. METHODS: A national survey was distributed to U.S.-based neurosurgery residency/fellowship directors regarding these changes. RESULTS: We received 135 completed surveys (37% response rate). Respondents tended to feel the new post-chief enfolded fellowship mandate represented positive effects on residency training (58%) and chief experiences (54%)-overall, 47% agreed the changes are net positive, 17% neutral, and 36% negative. In addition, 66% respondents thought the enfolded fellowship was enhanced due to previous completion of the chief year. Most did not feel the directives had a negative impact on resident case minimums completion, total case volumes, or overall case mix during residency; but 64% felt it would reduce post-graduate training. Of those who said the mandate would reduce post-graduate training, 45% thought this would be positive. Throughout all questions, most respondents tended to feel strongly, although with little overall consensus across many of these questions. One area of relative agreement was a 60% preference to allow program discretion for chief/enfolded fellowship training timing-with 41% strongly supporting versus 15% strongly rejecting reversion to program-directed administration. CONCLUSIONS: Fervent bimodal opinions exist among residency program and fellowship directors regarding the directives for enfolded fellowships to follow successful completion of the chief resident experience. However, there was broad support for allowing greater program discretion for directing certain enfolded fellowship timing and structure.

Advancements in therapeutic approaches for malignant peripheral nerve sheath tumor.

Tweetable abstract Emerging targeted therapies offer hope for malignant peripheral nerve sheath tumor. Innovative drug delivery enhances potential treatments. #MPNST #TargetedTherapies #TherapeuticDelivery.

Management and Long-term Outcomes of Adults With Medulloblastoma: A Single-Center Experience.

BACKGROUND AND OBJECTIVES: Medulloblastomas are embryonal tumors predominantly affecting children. Recognition of molecularly defined subgroups has advanced management. Factors influencing the management and prognosis of adult patients with medulloblastoma remains poorly understood. METHODS: We examined the management, prognostic factors, and, when possible, molecular subgroup differences (subset) in adult patients (aged 18 years or older) with medulloblastoma from our center (specialty Neuro-Oncology clinic within a large academic practice) diagnosed between 1992 and 2020. Molecular subtyping corresponding to the 2021 WHO Classification was performed. Kaplan-Meier estimates (with log-rank test) were performed for univariate survival analysis with Cox regression used for multivariate analyses. RESULTS: We included 76 adult patients with medulloblastoma (62% male), with a median age of 32 years at diagnosis (range: 18-66) and median follow-up of 7.7 years (range: 0.6-27). A subset of 58 patients had molecular subgroup characterization-37 SHH-activated, 12 non-WNT/non-SHH, and 9 WNT-activated. Approximately 67% underwent gross total resection, 75% received chemotherapy at diagnosis, and 97% received craniospinal irradiation with boost. The median overall survival (OS) for the whole cohort was 14.8 years. The 2-, 5-, and 10-year OS rates were 93% (95% CI 88-99), 86% (78-94), and 64% (53-78), respectively. Survival was longer for younger patients (aged 30 years or older: 9.9 years; younger than 30 years: estimated >15.4 years; log-rank p < 0.001). There was no survival difference by molecular subgroup or extent of resection. Only age at diagnosis remained significant in multivariate survival analyses. DISCUSSION: We report one of the largest retrospective cohorts in adult patients with medulloblastoma with molecular subtyping. Survival and molecular subgroup frequencies were similar to prior reports. Survival was better for adult patients younger than 30 years at diagnosis and was not significantly different by molecular subgroup or management characteristics (extent of resection, RT characteristics, or chemotherapy timing or regimen).

MDM2 Inhibition in the Treatment of Glioblastoma: From Concept to Clinical Investigation.

Inhibition of the interaction between MDM2 and p53 has emerged as a promising strategy for combating cancer, including the treatment of glioblastoma (GBM). Numerous MDM2 inhibitors have been developed and are currently undergoing rigorous testing for their potential in GBM therapy. Encouraging results from studies conducted in cell culture and animal models suggest that MDM2 inhibitors could effectively treat a specific subset of GBM patients with wild-type TP53 or functional p53. Combination therapy with clinically established treatment modalities such as radiation and chemotherapy offers the potential to achieve a more profound therapeutic response. Furthermore, an increasing array of other molecularly targeted therapies are being explored in combination with MDM2 inhibitors to increase the effects of individual treatments. While some MDM2 inhibitors have progressed to early phase clinical trials in GBM, their efficacy, alone and in combination, is yet to be confirmed. In this article, we present an overview of MDM2 inhibitors currently under preclinical and clinical investigation, with a specific focus on the drugs being assessed in ongoing clinical trials for GBM patients.

Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment.

Medulloblastoma is the most common malignant brain tumor in children. Over the last few decades, significant progress has been made in revealing the key molecular underpinnings of this disease, leading to the identification of distinct molecular subgroups with different clinical outcomes. In this review, we provide an update on the molecular landscape of medulloblastoma and treatment strategies. We discuss the four main molecular subgroups (WNT-activated, SHH-activated, and non-WNT/non-SHH groups 3 and 4), highlighting the key genetic alterations and signaling pathways associated with each entity. Furthermore, we explore the emerging role of epigenetic regulation in medulloblastoma and the mechanism of resistance to therapy. We also delve into the latest developments in targeted therapies and immunotherapies. Continuing collaborative efforts are needed to further unravel the complex molecular mechanisms and profile optimal treatment for this devastating disease.

Nanoparticle Strategies to Improve the Delivery of Anticancer Drugs across the Blood-Brain Barrier to Treat Brain Tumors.

Primary brain and central nervous system (CNS) tumors are a diverse group of neoplasms that occur within the brain and spinal cord. Although significant advances in our understanding of the intricate biological underpinnings of CNS neoplasm tumorigenesis and progression have been made, the translation of these discoveries into effective therapies has been stymied by the unique challenges presented by these tumors' exquisitely sensitive location and the body's own defense mechanisms (e.g., the brain-CSF barrier and blood-brain barrier), which normally protect the CNS from toxic insult. These barriers effectively prevent the delivery of therapeutics to the site of disease. To overcome these obstacles, new methods for therapeutic delivery are being developed, with one such approach being the utilization of nanoparticles. Here, we will cover the current state of the field with a particular focus on the challenges posed by the BBB, the different nanoparticle classes which are under development for targeted CNS tumor therapeutics delivery, and strategies which have been developed to bypass the BBB and enable effective therapeutics delivery to the site of disease.

Feasibility of probe washing after stereotactic needle biopsy as a novel technique for developing cell lines and xenografts of H3 K27-altered diffuse midline gliomas.

H3 K27-altered diffuse midline gliomas (DMGs) are frequently biopsied to obtain tissue diagnosis, inform clinical decision-making, and determine clinical trial eligibility. Tissue yield from biopsies is typically low, leaving little material available for research. To advance understanding of disease biology and promote preclinical testing of novel therapeutics, collecting viable cellular material from treatment-naive tumors is of paramount importance. Here, the authors report the feasibility of a practicable technique for creating DMG cell lines and patient-derived xenografts (PDXs) without the need for additional biopsy specimens. Tumor cells are obtained by probe washing immediately after completion of biopsy. Wash fluid is collected, and viable cells are expanded in vitro. Cultured cells are used to establish PDX rodent models. A total of 5 patient samples were collected by this technique. Viable tumor cells were obtained from 3 of the 5 samples, and cell lines suitable for experiments were obtained within 6-8 months. Orthotopic implantation and flank engraftment was successful in 1 of the 3 established cell lines. Animals harboring intracranial tumors were euthanized due to disease burden 6-7 months after stereotactic injection. Flank tumors formed within 4-5 months and were serially passaged. Molecular and tissue analyses confirmed retention of H3 K27M expression and loss of H3 K27me3 in all cell lines and PDXs.