AB088. Spinal cord diffuse midline glioma in adults: a case report and literature review.

BACKGROUND: Spinal cord diffuse midline gliomas are rare, infiltrative entities with an extremely grim prognosis. Standard of care is limited and extrapolated from those for intracranial gliomas, focusing on maximal safe resection, chemotherapy and radiation therapy. These do not prolong survival significantly and while advances in molecular profiling and targeted therapy have been promising, further research still needs to be performed. Here, we present a case of a young lady with a cervical cord diffuse midline glioma, along with a literature review of the disease and treatment options. CASE DESCRIPTION: A 35-year-old female presented with progressive neck pain and left sided weakness. MRI revealed an intramedullary cervical spinal cord lesion. The lesion progressed rapidly to the medulla, resulting in lower cranial nerve palsies and left hemiplegia. Investigations for autoimmune and infective causes were negative. Cervical laminectomy and debulking was performed. Histological analysis showed high grade diffuse glioma, IDH-wildtype, loss of H3K27me3 staining and H3K27M positivity. The patient was treated with fractionated radiation and temozolamide, followed by lomustine and bevacizumab. A literature review was performed to better understand the molecular features, natural history and treatment options for spinal cord high grade gliomas. Our case highlights the importance of maintaining broad differentials for patients exhibiting features of cervical myelopathy. Malignant spinal cord tumours could be a differential. Molecular testing can aid in achieving an accurate diagnosis to better understand prognosis and determine treatment options. Early, function-preserving debulking with neuromonitoring is feasible. Adjuvant therapy with chemotherapy and radiation can prolong survival. CONCLUSIONS: Spinal cord diffuse midline gliomas H3 K27-altered demonstrate rapid progression and a poor prognosis. They should be considered as a differential in patients with cervical myelopathy. Molecular testing for H3 K27 alterations facilitates an accurate diagnosis. Surgical debulking and adjuvant therapy are viable treatment options.

MR Imaging-Guided Focused Ultrasound-Clinical Applications in Managing Malignant Gliomas.

Malignant gliomas (MGs) are the most common primary brain tumors in adults. Despite recent advances in understanding the biology and potential therapeutic vulnerabilities of MGs, treatment options remain limited as the delivery of drugs is often impeded by the blood-brain barrier (BBB), and safe, complete surgical resection may not always be possible, especially for deep-seated tumors. In this review, the authors highlight emerging applications for MR imaging-guided focused ultrasound (MRgFUS) as a noninvasive treatment modality for MGs. Specifically, the authors discuss MRgFUS's potential role in direct tumor cell killing, opening the BBB, and modulating antitumor immunity.

Variable screening and model construction for prognosis of elderly patients with lower-grade gliomas based on LASSO-Cox regression: a population-based cohort study.

Background: This study aimed to identify prognostic factors for survival and develop a prognostic nomogram to predict the survival probability of elderly patients with lower-grade gliomas (LGGs). Methods: Elderly patients with histologically confirmed LGG were recruited from the Surveillance, Epidemiology, and End Results (SEER) database. These individuals were randomly allocated to the training and validation cohorts at a 2:1 ratio. First, Kaplan-Meier survival analysis and subgroup analysis were performed. Second, variable screening of all 13 variables and a comparison of predictive models based on full Cox regression and LASSO-Cox regression analyses were performed, and the key variables in the optimal model were selected to construct prognostic nomograms for OS and CSS. Finally, a risk stratification system and a web-based dynamic nomogram were constructed. Results: A total of 2307 elderly patients included 1220 males and 1087 females, with a median age of 72 years and a mean age of 73.30 ± 6.22 years. Among them, 520 patients (22.5%) had Grade 2 gliomas, and 1787 (77.5%) had Grade 3 gliomas. Multivariate Cox regression analysis revealed four independent prognostic factors (age, WHO grade, surgery, and chemotherapy) that were used to construct the full Cox model. In addition, LASSO-Cox regression analysis revealed five prognostic factors (age, WHO grade, surgery, radiotherapy, and chemotherapy), and a LASSO model was constructed. A comparison of the two models revealed that the LASSO model with five variables had better predictive performance than the full Cox model with four variables. Ultimately, five key variables based on LASSO-Cox regression were utilized to develop prognostic nomograms for predicting the 1-, 2-, and 5-year OS and CSS rates. The nomograms exhibited relatively good predictive ability and clinical utility. Moreover, the risk stratification system based on the nomograms effectively divided patients into low-risk and high-risk subgroups. Conclusion: Variable screening based on LASSO-Cox regression was used to determine the optimal prediction model in this study. Prognostic nomograms could serve as practical tools for predicting survival probabilities, categorizing these patients into different mortality risk subgroups, and developing personalized decision-making strategies for elderly patients with LGGs. Moreover, the web-based dynamic nomogram could facilitate its use in the clinic.

The siEGFR nanoplexes for the enhanced brain glioma treatment: Endoplasmic reticulum biomimetic strategy to induce homing effect and non-degradable intracellular transport.

The epidermal growth factor receptor (EGFR) plays a pivotal role in tumor progression and is an essential therapeutic target for treating malignant gliomas. Small interfering RNA (siRNA) has the potential to selectively degrade EGFR mRNA, yet its clinical utilization is impeded by various challenges, such as inefficient targeting and limited escape from lysosomes. Our research introduces polyethylene glycol (PEG) and endoplasmic reticulum membrane-coated siEGFR nanoplexes (PEhCv/siEGFR NPs) as an innovative approach to brain glioma therapy by overcoming several obstacles: 1) Tumor-derived endoplasmic reticulum membrane modifications provide a homing effect, facilitating targeted accumulation and cellular uptake; 2) Endoplasmic reticulum membrane proteins mediate a non-degradable "endosome-Golgi-endoplasmic reticulum" transport pathway, circumventing lysosomal degradation. These nanoplexes demonstrated significantly enhanced siEGFR gene silencing in both in vitro and in vivo U87 glioma models. The findings of this study pave the way for the advanced design and effective application of nucleic acid-based therapeutic nanocarriers.

Consensus guidelines for the management of adult high-grade gliomas for low and middle-income countries.

High-grade glioma (HGG), a formidable and often incurable disease, presents an even greater challenge in low- and middle-income countries (LMICs) where resources and medical expertise are scarce. This scarcity not only exacerbates the suffering of patients but also contributes to poorer clinical outcomes. Particularly in LMICs, the underrepresentation of the population in clinical trials and the additional hurdles posed by financial constraints underscore an urgent need for contextspecific management strategies. In response, we have rigorously evaluated recent guidelines from leading medical societies, adapting them to suit the specific needs and limitations of the local context in Pakistan. This effort, undertaken in collaboration with local physicians, aims to provide a comprehensive, standardised approach to diagnose, treat, and follow-up with HGG patients. By focussing on the best available clinical evidence and judicious use of limited resources, we strive to improve patient care and outcomes in these challenging settings.

Consensus guidelines for the management of adult low-grade gliomas for low and middle-income countries.

Low-grade gliomas (LGG) are brain tumors of glial cells origin. They are grade 1 and grade 2 tumors according to the WHO classification. Diagnosis of LGG is made through imaging, histopathological analysis, and use of molecular markers. Imaging alone does not establish the grade of the tumor and thus a histopathological examination of tissue is crucial in establishing the definite histopathological diagnosis. Clinical presentation varies according to the location and size of the tumor. Surgical resection is strongly recommended in LGG over observation to improve overall survival as surgery leads to greater benefit due to progression-free survival. Radiation has shown benefits in LGG patients in randomized controlled trials and chemotherapy with temozolomide has also shown good results. This paper covers the principles of low-grade gliomas management and summarizes the recommendations for the LMICs.

Consensus guidelines for the management of brain stem and diffuse midline glioma for low- and middle-income countries.

The understanding of brainstem gliomas and diffuse midline gliomas has significantly increased in the last decade. However, the management paradigm remains a dilemma. The critical location is the foremost factor dictating the outcome. Recent advancements in the field of neuro-oncology are pushing the boundaries of optimal care in the developed world nevertheless, the strategies in low- and middle-income countries (LMICs) need to be tailored according to the resources to improve outcome. The objective of these guidelines is to provide an algorithm-based management plan to cater challenges for healthcare providers in LMICs.

Consensus guidelines for the management of posterior fossa tumour for low- and middle-income countries.

The posterior fossa is a limited compartment therefore lesions compressing its structures can result in devastating outcomes. It can cause significant neurological deficit due to mass effect on critical structures and hydrocephalus. Due to the nature of the infratentorial region, urgent surgical intervention is often the first-line option. Surgical neuro-oncologists guide patients and caregivers through the course of this disease and to inform them about the various options for management and long-term outcome optimisation. There is currently conflicting data; however, institutional experiences can guide us towards achieving improvements in surgical outcomes and quality of life. Advances in molecular classifications coupled with highdose radiation treatment improve our capacity for improving overall survival in these patients. Common childhood tumours are ependymomas, medulloblastomas, and juvenile pilocytic astrocytomas, while adults often present with metastases, and less commonly, cerebellar haemangioblastomas and gliomas. This paper outlines management strategies with consideration for multidisciplinary care and resourcelimited settings.

Update on the intriguing roles of AQP4 expression and redistribution in the progression and treatment of glioma.

Aquaporin 4 (AQP4) is abundant in the human brain and has an important role in brain homeostasis and diseases. AQP4 expression has been found to be associated with glioma malignancies. However, the complete understanding of the biological processes and curative importance of AQP4 in glioma remains unclear. The impact of AQP4 subcellular mislocalization on glioma progression and the precise mechanisms regarding AQP4 translocation in glioma need further investigation. In this review, we update recent findings about disturbed AQP4 expression in glioma and explore targeting AQP4 to modulate the glioma progression. Thereafter we discuss some possible mechanisms of action of AQP4 translocations in glioma. The present article offers an appropriate introduction to the potential involvement of AQP4 in the emergence and progression of glioma. Both comprehensive research into the mechanisms and systematically intervention studies focusing on AQP4 are essential. By embracing this strategy, we can obtain a new and insightful outlook on managing cancerous glioma. Although the observations summarized in this review should be confirmed with more studies, we believe that they could provide critical information for the design of more focused research that will allow for systematic and definitive evaluation of the role of AQP4 in glioma treatments.

Pre-Clinical Models for CAR T-Cell Therapy for Glioma.

Immunotherapy represents a transformative shift in cancer treatment. Among myriad immune-based approaches, chimeric antigen receptor (CAR) T-cell therapy has shown promising results in treating hematological malignancies. Despite aggressive treatment options, the prognosis for patients with malignant brain tumors remains poor. Research leveraging CAR T-cell therapy for brain tumors has surged in recent years. Pre-clinical models are crucial in evaluating the safety and efficacy of these therapies before they advance to clinical trials. However, current models recapitulate the human tumor environment to varying degrees. Novel in vitro and in vivo techniques offer the opportunity to validate CAR T-cell therapies but also have limitations. By evaluating the strengths and weaknesses of various pre-clinical glioma models, this review aims to provide a roadmap for the development and pre-clinical testing of CAR T-cell therapies for brain tumors.

Emerging and Biological Concepts in Pediatric High-Grade Gliomas.

Primary central nervous system tumors are the most frequent solid tumors in children, accounting for over 40% of all childhood brain tumor deaths, specifically high-grade gliomas. Compared with pediatric low-grade gliomas (pLGGs), pediatric high-grade gliomas (pHGGs) have an abysmal survival rate. The WHO CNS classification identifies four subtypes of pHGGs, including Grade 4 Diffuse midline glioma H3K27-altered, Grade 4 Diffuse hemispheric gliomas H3-G34-mutant, Grade 4 pediatric-type high-grade glioma H3-wildtype and IDH-wildtype, and infant-type hemispheric gliomas. In recent years, we have seen promising advancements in treatment strategies for pediatric high-grade gliomas, including immunotherapy, CAR-T cell therapy, and vaccine approaches, which are currently undergoing clinical trials. These therapies are underscored by the integration of molecular features that further stratify HGG subtypes. Herein, we will discuss the molecular features of pediatric high-grade gliomas and the evolving landscape for treating these challenging tumors.

Microenvironmental regulation of tumor-associated neutrophils in malignant glioma: from mechanism to therapy.

Glioma is the most common primary intracranial tumor in adults, with high incidence, recurrence, and mortality rates. Tumor-associated neutrophils (TANs) are essential components of the tumor microenvironment (TME) in glioma and play a crucial role in glioma cell proliferation, invasion and proneural-mesenchymal transition. Besides the interactions between TANs and tumor cells, the multi-dimensional crosstalk between TANs and other components within TME have been reported to participate in glioma progression. More importantly, several therapies targeting TANs have been developed and relevant preclinical and clinical studies have been conducted in cancer therapy. In this review, we introduce the origin of TANs and the functions of TANs in malignant behaviors of glioma, highlighting the microenvironmental regulation of TANs. Moreover, we focus on summarizing the TANs-targeted methods in cancer therapy, aiming to provide insights into the mechanisms and therapeutic opportunities of TANs in the malignant glioma microenvironment.

Gliomas in adults: Guidance on investigations, diagnosis, treatment and surveillance.

Primary brain tumours are rare but carry a significant morbidity and mortality burden. Malignant gliomas are the most common subtype and their incidence is increasing within our ageing population. The diagnosis and treatment of gliomas involves substantial interplay between multiple specialties, including general medical physicians, radiologists, pathologists, surgeons, oncologists and allied health professionals. At any point along this pathway, patients can present to acute medicine with complications of their cancer or anti-cancer therapy. Increasing the awareness of malignant gliomas among general physicians is paramount to delivering prompt radiological and histopathological diagnoses, facilitating access to earlier and individualised treatment options and allows for effective recognition and management of anticipated complications. This article discusses evidence-based real-world practice for malignant gliomas, encompassing patient presentation, diagnostic pathways, treatments and their complications, and prognosis to guide management outside of specialist centres.

Advances in the Treatment of Pediatric Low-Grade Gliomas.

PURPOSE OF REVIEW: Pediatric low-grade gliomas (pLGGs) often result in significant long-term morbidities despite high overall survival rates. This review aims to consolidate the current understanding of pLGG biology and molecular features and provide an overview of current and emerging treatment strategies. RECENT FINDINGS: Surgical resection remains a primary treatment modality, supplemented by chemotherapy and radiotherapy in specific cases. However, recent advances have elucidated the molecular underpinnings of pLGGs, revealing key genetic abnormalities such as BRAF fusions and mutations and the involvement of the RAS/MAPK and mTOR pathways. Novel targeted therapies, including MEK, BRAF and pan-RAF inhibitors, have shown promise in clinical trials, demonstrating significant efficacy and manageable toxicity. Understanding of pLGGs has significantly improved, leading to more personalized treatment approaches. Targeted therapies have emerged as effective alternatives, potentially reducing long-term toxicities. Future research should focus on optimizing therapy sequences, understanding long-term impacts, and ensuring global accessibility to advanced treatments.

Combination of locoregional radiotherapy with a TIM-3 aptamer improves survival in diffuse midline glioma models.

Pediatric diffuse midline gliomas (DMG) with altered H3-K27M are aggressive brain tumors that arise during childhood. Despite advances in genomic knowledge and the significant number of clinical trials testing new targeted therapies, patient outcomes are still poor. Immune checkpoint blockades with small molecules, such as aptamers, are opening new therapeutic options that represent hope for this orphan disease. Here, we demonstrated that a TIM-3 aptamer (TIM-3 Apt) as monotherapy increased the immune infiltration and elicited a strong specific immune response with a tendency to improve the overall survival of treated DMG-bearing mice. Importantly, combining TIM-3 Apt with radiotherapy increased the overall median survival and led to long-term survivor mice in 2 pediatric DMG orthotopic murine models. Interestingly, TIM-3 Apt administration increased the number of myeloid populations and the proinflammatory CD8-to-Tregs ratios in the tumor microenvironment as compared with nontreated groups after radiotherapy. Importantly, the depletion of T cells led to a major loss of the therapeutic effect achieved by the combination. This work uncovers TIM-3 targeting as an immunotherapy approach to improve the radiotherapy outcome in DMGs and offers a strong foundation for propelling a phase I clinical trial using radiotherapy and TIM-3 blockade combination as a treatment for these tumors.

Advances in gene therapy for high-grade glioma: a review of the clinical evidence.

INTRODUCTION: High-grade glioma (HGG) is one of the most deadly and difficult cancers to treat. Despite intense research efforts, there has not been a significant breakthrough in treatment outcomes since the early 2000's. Anti-glioma gene therapy has demonstrated promise in preclinical studies and is under investigation in numerous clinical trials. AREAS COVERED: This manuscript reviews the current landscape of clinical trials exploring gene therapy treatment of HGG. Using information from clinicaltrials.gov, all trials initiated within the past 5 years (2018-2023) as well as other important trials were cataloged and reviewed. This review discusses trial details, innovative methodologies, and concurrent pharmacological interventions. The review also delves into the subtypes of gene therapy used, trends over time, and future directions. EXPERT OPINION: Trials are in the early stages (phase I or II), and there are reports of clinical efficacy in published results. Synergistic effects utilizing immunotherapy within or alongside gene therapy are emerging as a promising avenue for future breakthroughs. Considerable heterogeneity exists across trials concerning administration route, vector selection, drug combinations, and intervention timing. Earlier intervention in newly diagnosed HGG and avoidance of corticosteroids may improve efficacy in future trials. The results from ongoing trials demonstrate promising potential for molding the future landscape of HGG care.

Letter to the Editor: "The relationship between imaging features, therapeutic response, and overall survival in pediatric diffuse intrinsic pontine glioma".

This letter to the editor discusses the findings of Yu et al. (2024), which highlight the prognostic significance of volumetric assessments over cross-product measurements in pediatric diffuse intrinsic pontine glioma (DIPG). The study's methodology enhances precision in monitoring therapeutic responses, offering insights into treatment adjustments based on detailed imaging features. Emphasizing the value of volumetric MRI, this letter suggests its potential to improve surgical planning and therapeutic strategies, thereby optimizing patient management. This approach could revolutionize treatment paradigms, emphasizing personalized care through advanced imaging techniques.

Utilizing machine learning to tailor radiotherapy and chemoradiotherapy for low-grade glioma patients.

BACKGROUND: There is ongoing uncertainty about the effectiveness of various adjuvant treatments for low-grade gliomas (LGGs). Machine learning (ML) models that predict individual treatment effects (ITE) and provide treatment recommendations could help tailor treatments to each patient's needs. OBJECTIVE: We sought to discern the individual suitability of radiotherapy (RT) or chemoradiotherapy (CRT) in LGG patients using ML models. METHODS: Ten ML models, trained to infer ITE in 4,042 LGG patients, were assessed. We compared patients who followed treatment recommendations provided by the models with those who did not. To mitigate the risk of treatment selection bias, we employed inverse probability treatment weighting (IPTW). RESULTS: The Balanced Survival Lasso-Network (BSL) model showed the most significant protective effect among all the models we tested (hazard ratio (HR): 0.52, 95% CI, 0.41-0.64; IPTW-adjusted HR: 0.58, 95% CI, 0.45-0.74; the difference in restricted mean survival time (DRMST): 9.11, 95% CI, 6.19-12.03; IPTW-adjusted DRMST: 9.17, 95% CI, 6.30-11.83). CRT presented a protective effect in the 'recommend for CRT' group (IPTW-adjusted HR: 0.60, 95% CI, 0.39-0.93) yet presented an adverse effect in the 'recommend for RT' group (IPTW-adjusted HR: 1.64, 95% CI, 1.19-2.25). Moreover, the models predict that younger patients and patients with overlapping lesions or tumors crossing the midline are better suited for CRT (HR: 0.62, 95% CI, 0.42-0.91; IPTW-adjusted HR: 0.59, 95% CI, 0.36-0.97). CONCLUSION: Our findings underscore the potential of the BSL model in guiding the choice of adjuvant treatment for LGGs patients, potentially improving survival time. This study emphasizes the importance of ML in customizing patient care, understanding the nuances of treatment selection, and advancing personalized medicine.

A multivariate retrospective analysis of high-grade gliomas: Survival and prognostic factors.

OBJECTIVES: High-grade gliomas (HGGs) are highly malignant, aggressive, and have a high incidence and mortality rate. The aim of this study was to investigate survival outcomes and prognostic factors in patients with HGGs. METHODS: In this retrospective study, a total of 159 patients with histologically confirmed HGGs were included. The recruitment period was from January 2011 to December 2019. We evaluated patient demographic data, tumor characteristics, treatment methods, immunocytochemistry results, overall survival (OS) time, and progression-free survival (PFS) time using Kaplan-<>Meier survival analysis with log-rank testing. Additionally, we employed Cox regression analysis to identify independent factors associated with survival outcomes. RESULTS: Kaplan-Meier survival analysis revealed that the 1-, 2-, and 5-years OS rates were 81.8%, 50.3%, and 12.6%, respectively. Similarly, the 1-, 2-, and 5-years PFS rates were 50.9%, 22.4%, and 3.1%, respectively. The median OS duration was 35.0 months. The univariate analysis indicated that postoperative pathological classification, grade, and age were significantly associated with patient outcomes (p < 0.01). Among the patients, 147 received concurrent chemoradiotherapy, while 12 did not. The immunohistochemical markers of ki-67, MGMT, IDH1R132H, and p53 demonstrated statistically significant differences in their prognostic impact (p = 0.001, p = 0.020, p = 0.003, and p = 0.021, respectively). In conclusion, we found that grades, age, pathological classification, ki-67, MGMT, and IDH1R132H expression were statistically significantly associated with PFS (p < 0.01, p = 0.004, p = 0.003, p = 0.001, p = 0.036, and p = 0.028). Additionally, immunohistochemical expressions of TRIB3 and AURKA were significantly higher in patients with shorter survival (p = 0.015 and p = 0.023). CONCLUSIONS: Tumor grade and the use of concurrent chemoradiotherapy after surgery were independent prognostic factors that significantly influenced patient survival. Additionally, tumor grade and MGMT expression were found to be independent factors affecting progression-free survival (PFS). Notably, the expression of TRIB3 and AURKA was higher in patients with poor survival outcomes.

EphA3-targeted chimeric antigen receptor T cells are effective in glioma and generate curative memory T cell responses.

BACKGROUND: High-grade gliomas including glioblastoma (GBM) and diffuse midline gliomas (DMG) represent the most lethal and aggressive brain cancers where current treatment modalities offer limited efficacy. Chimeric antigen receptor (CAR) T cell therapies have emerged as a promising strategy, boasting tumor-specific targeting and the unique ability to penetrate the blood-brain barrier. However, the effective clinical application hinges on the optimal choice of antigen, with a limited number, currently under investigation. METHODS: We employed cell surface proteomic analysis of primary human high-grade glioma samples from both adult and pediatric patients. This led to the identification of Ephrin type-A receptor 3 (EphA3) as a prevalently expressed target. We engineered a second-generation EphA3-targeted CAR T cell and assessed function using in vitro and in vivo models of GBM and DMG. RESULTS: EphA3-targeted CAR T cells demonstrated robust antigen-specific killing of human GBM and DMG cell lines in vitro. In an orthotopic xenograft NSG mouse model, EphA3-targeted CAR T cells not only effectively eradicated tumors but also established a functional T cell population protective on rechallenge. Remarkably, mice rechallenged with a second contralateral orthotopic tumor implantation achieved complete tumor clearance and maintained a sustained complete response 6 months following initial treatment. CONCLUSION: Building on the proven safety profile of EphA3 antibodies in clinical settings, our study provides compelling preclinical evidence supporting the efficacy of EphA3-targeted CAR T cells against high-grade gliomas. These findings underscore the potential for transitioning this innovative therapy into clinical trials, aiming to revolutionize the treatment landscape for patients afflicted with these formidable brain cancers.