Pediatric diffuse midline glioma: Understanding the mechanisms and assessing the next generation of personalized therapeutics.

Diffuse midline glioma (DMG) is a pediatric cancer that originates in the midline structures of the brain. Prognosis of DMG patients remains poor due to the infiltrative nature of these tumors and the protection they receive from systemically delivered therapeutics via an intact blood-brain barrier (BBB), making treatment difficult. While the cell of origin remains disputed, it is believed to reside in the ventral pons. Recent research has pointed toward epigenetic dysregulation inducing an OPC-like transcriptomic signature in DMG cells. This epigenetic dysregulation is typically caused by a mutation (K27M) in one of two histone genes-H3F3A or HIST1H3B -and can lead to a differentiation block that increases these cells oncogenic potential. Standard treatment with radiation is not sufficient at overcoming the aggressivity of this cancer and only confers a survival benefit of a few months, and thus, discovery of new therapeutics is of utmost importance. In this review, we discuss the cell of origin of DMGs, as well as the underlying molecular mechanisms that contribute to their aggressivity and resistance to treatment. Additionally, we outline the current standard of care for DMG patients and the potential future therapeutics for this cancer that are currently being tested in preclinical and clinical trials.

Applications and current challenges of chimeric antigen receptor T cells in treating high-grade gliomas in adult and pediatric populations.

High-grade gliomas (HGGs) continue to be some of the most devastating diseases in the USA. Despite extensive efforts, the survival of HGG patients has remained relatively stagnant. Chimeric antigen receptor (CAR) T-cell immunotherapy has recently been studied in the context of improving these tumors' clinical outcomes. HGG murine models treated with CAR T cells targeting tumor antigens have shown reduced tumor burden and longer overall survival than models without treatment. Subsequent clinical trials investigating the efficacy of CAR T cells have further shown that this therapy could be safe and might reduce tumor burden. However, there are still many challenges that need to be addressed to optimize the safety and efficacy of CAR T-cell therapy in treating HGG patients.

This publication describes the current application of chimeric antigen T-cell (CAR T-cell) therapy in treating high-grade gliomas (HGGs). Treatment of various HGG models with CAR T cells has shown that this therapy is often able to shrink HGG tumors and prolong the survival of these models. Subsequent clinical trials have shown that CAR T-cell therapy can reduce tumor size in some HGG patients. Patients in these clinical trials have tolerated the treatment well, though more robust studies are needed to confirm this treatment's safety. Additionally, other challenges, such as getting CAR T cells into the brain and to the tumor, need to be addressed to improve the effectiveness of this therapy for HGG patients.

Robustness of Randomized Control Trials Supporting Current Neurosurgery Guidelines.

BACKGROUND: Treatment guidelines in neurosurgery are often based on evidence obtained from randomized controlled trials (RCTs). OBJECTIVE: To evaluate the robustness of RCTs supporting current central nervous tumor and cerebrovascular disease guidelines by calculating their fragility index (FI)-the minimum number of patients needed to switch from an event to nonevent outcome to change significant trial primary outcome. METHODS: We analyzed RCTs referenced in the Congress of Neurological Surgeons and American Association of Neurological Surgeons guidelines on central nervous tumor and cerebrovascular disease management. Trial characteristics, finding of a statistically significant difference in the primary endpoint favoring the experimental intervention, the FI, and FI minus number lost to follow-up were assessed. RESULTS: Of 312 RCTs identified, 158 (50.6%) were published from 2000 to 2010 and 106 (34%) after 2010. Sixty-three trials (19.2%) were categorized as surgical trials, and the rest studied medical treatment (82.0%) or percutaneous intervention (8.33%). The trials had a median power of 80.0% (IQR 80.0-90.0). Of these, 120 trials were eligible for FI calculation. The median FI was 7.0 (IQR 2.0-16.25). Forty-four (36.6%) trials had FI ≤ 3 indicating very low robustness. After adjusting for covariates, recently published trials and trials studying percutaneous interventions were associated with significantly higher FI compared with older trials and trials comparing surgical approaches, respectively. Trials limited to single centers were associated with significantly lower FI. CONCLUSION: Trials supporting current guidelines on neuro-oncological and neurovascular surgical interventions have low robustness. While the robustness of trials has improved over time, future guidelines must take into consideration this metric in their recommendations.

Sex-specific molecular differences in glioblastoma: assessing the clinical significance of genetic variants.

Introduction: Glioblastoma multiforme (GBM) is one of the most aggressive types of brain cancer, and despite rigorous research, patient prognosis remains poor. The characterization of sex-specific differences in incidence and overall survival (OS) of these patients has led to an investigation of the molecular mechanisms that may underlie this dimorphism. Methods: We reviewed the published literature describing the gender specific differences in GBM Biology reported in the last ten years and summarized the available information that may point towards a patient-tailored GBM therapy. Results: Radiomics analyses have revealed that imaging parameters predict OS and treatment response of GBM patients in a sex-specific manner. Moreover, gender-based analysis of the transcriptome GBM tumors has found differential expression of various genes, potentially impacting the OS survival of patients in a sex-dependent manner. In addition to gene expression differences, the timing (subclonal or clonal) of the acquisition of common GBM-driver mutations, metabolism requirements, and immune landscape of these tumors has also been shown to be sex-specific, leading to a differential therapeutic response by sex. In male patients, transformed astrocytes are more sensitive to glutaminase 1 (GLS1) inhibition due to increased requirements for glutamine uptake. In female patients, GBM is more sensitive to anti-IL1ß due to an increased population of circulating granulocytic myeloid-derived suppressor cells (gMDSC). Conclusion: Moving forward, continued elucidation of GBM sexual dimorphism will be critical in improving the OS of GBM patients by ensuring that treatment plans are structured to exploit these sex-specific, molecular vulnerabilities in GBM tumors.

Navigated 3D ultrasound-guided resection of high-grade gliomas: A case series and review.

Background: The crux in high-grade glioma surgery remains maximizing resection without affecting eloquent brain areas. Toward this, a myriad of adjunct tools and techniques has been employed to enhance surgical safety and efficacy. Despite intraoperative MRI and advanced neuronavigational techniques, as well as augmented reality, to date, the only true real-time visualization tool remains the ultrasound (US). Neuroultrasonography is a cost-efficient imaging modality that offers instant, real-time information about the changing anatomical landscape intraoperatively. Recent advances in technology now allow for the integration of intraoperative US with neuronavigation. Case Description: In this report, we present the resection technique for three cases of high-grade gliomas (two glioblastomas and one anaplastic astrocytoma). The patient presented with a variable clinical spectrum. All three cases have been performed using the Brainlab® neuronavigation system (BrainLAB, Munich, Germany) and the bk5000 US Machine® (BK Medical, Analogic Corporation, Peabody, Massachusetts, USA). Conclusion: Gross total resection was achieved in all three cases. The use of 3D navigated US was a reliable adjunct surgical tool in achieving favorable resection outcomes in these patients.

3D printing applications in spine surgery: an evidence-based assessment toward personalized patient care.

PURPOSE: Spine surgery entails a wide spectrum of complicated pathologies. Over the years, numerous assistive tools have been introduced to the modern neurosurgeon's armamentarium including neuronavigation and visualization technologies. In this review, we aimed to summarize the available data on 3D printing applications in spine surgery as well as an assessment of the future implications of 3D printing. METHODS: We performed a comprehensive review of the literature on 3D printing applications in spine surgery. RESULTS: Over the past decade, 3D printing and additive manufacturing applications, which allow for increased precision and customizability, have gained significant traction, particularly spine surgery. 3D printing applications in spine surgery were initially limited to preoperative visualization, as 3D printing had been primarily used to produce preoperative models of patient-specific deformities or spinal tumors. More recently, 3D printing has been used intraoperatively in the form of 3D customizable implants and personalized screw guides. CONCLUSIONS: Despite promising preliminary results, the applications of 3D printing are so recent that the available data regarding these new technologies in spine surgery remains scarce, especially data related to long-term outcomes.

The Subventricular Zone in Glioblastoma: Genesis, Maintenance, and Modeling.

Glioblastoma (GBM) is a malignant tumor with a median survival rate of 15-16 months with standard care; however, cases of successful treatment offer hope that an enhanced understanding of the pathology will improve the prognosis. The cell of origin in GBM remains controversial. Recent evidence has implicated stem cells as cells of origin in many cancers. Neural stem/precursor cells (NSCs) are being evaluated as potential initiators of GBM tumorigenesis. The NSCs in the subventricular zone (SVZ) have demonstrated similar molecular profiles and share several distinctive characteristics to proliferative glioblastoma stem cells (GSCs) in GBM. Genomic and proteomic studies comparing the SVZ and GBM support the hypothesis that the tumor cells and SVZ cells are related. Animal models corroborate this connection, demonstrating migratory patterns from the SVZ to the tumor. Along with laboratory and animal research, clinical studies have demonstrated improved progression-free survival in patients with GBM after radiation to the ipsilateral SVZ. Additionally, key genetic mutations in GBM for the most part carry regulatory roles in the SVZ as well. An exciting avenue towards SVZ modeling and determining its role in gliomagenesis in the human context is human brain organoids. Here we comprehensively discuss and review the role of the SVZ in GBM genesis, maintenance, and modeling.

The Evolving Role of Induced Pluripotent Stem Cells and Cerebral Organoids in Treating and Modeling Neurosurgical Diseases.

Over the past decade, the use of induced pluripotent stem cells (IPSCs), as both direct therapeutics and building blocks for 3D in vitro models, has exhibited exciting potential in both helping to elucidate pathogenic mechanisms and treating diseases relevant to neurosurgery. Transplantation of IPSCs is being studied in neurological injuries and diseases, such as spinal cord injury and Parkinson's disease, whose clinical manifestations stem from underlying neuronal and/or axonal degeneration. Both animal models and clinical trials have shown that IPSCs have the ability to regenerate damaged neural tissue. Such evidence makes IPSCs a potentially promising therapeutic modality for patients who suffer from these neurological injuries/diseases. In addition, the cerebral organoid, a 3D assembly of IPSC aggregates that develops heterogeneous brain regions, has become the first in vitro model to closely recapitulate the complexity of the brain extracellular matrix, a 3-dimensional network of molecules that structurally and biochemically support neighboring cells. Cerebral organoids have become an exciting prospect for modeling and testing drug susceptibility of brain tumors, such as glioblastoma and metastatic brain cancer. As patient-derived organoid models are becoming more faithful to the brain, they are becoming an increasingly accurate substitute for patient clinical trials; such patient-less trials would protect the patient from potentially ineffective drugs, and speed up trial results and optimize cost. In this review, we aim to describe the role of IPSCs and cerebral organoids in treating and modeling diseases that are relevant to neurosurgery.

MRI-Based Radiomics and Radiogenomics in the Management of Low-Grade Gliomas: Evaluating the Evidence for a Paradigm Shift.

Low-grade gliomas (LGGs) are tumors that affect mostly adults. These neoplasms are comprised mainly of oligodendrogliomas and diffuse astrocytomas. LGGs remain vexing to current management and therapeutic modalities although they exhibit more favorable survival rates compared with high-grade gliomas (HGGs). The specific genetic subtypes that these tumors exhibit result in variable clinical courses and the need to involve multidisciplinary teams of neurologists, epileptologists, neurooncologists and neurosurgeons. Currently, the diagnosis of an LGG pivots mainly around the preliminary radiological findings and the subsequent definitive surgical diagnosis (via surgical sampling). The introduction of radiomics as a high throughput quantitative imaging technique that allows for improved diagnostic, prognostic and predictive indices has created more interest for such techniques in cancer research and especially in neurooncology (MRI-based classification of LGGs, predicting Isocitrate dehydrogenase (IDH) and Telomerase reverse transcriptase (TERT) promoter mutations and predicting LGG associated seizures). Radiogenomics refers to the linkage of imaging findings with the tumor/tissue genomics. Numerous applications of radiomics and radiogenomics have been described in the clinical context and management of LGGs. In this review, we describe the recently published studies discussing the potential application of radiomics and radiogenomics in LGGs. We also highlight the potential pitfalls of the above-mentioned high throughput computerized techniques and, most excitingly, explore the use of machine learning artificial intelligence technologies as standalone and adjunct imaging tools en route to enhance a personalized MRI-based tumor diagnosis and management plan design.