Folic Acid Functionalized AQ4N/Gd@PDA Nanoplatform with Real-Time Monitoring of Hypoxia Relief and Enhanced Synergistic Chemo/Photothermal Therapy in Glioma.

Purpose: Hypoxia is often associated with glioma chemoresistance, and alleviating hypoxia is also crucial for improving treatment efficacy. However, although there are already some methods that can improve efficacy by alleviating hypoxia, real-time monitoring that can truly achieve hypoxia relief and efficacy feedback still needs to be explored. Methods: AQ4N/Gd@PDA-FA nanoparticles (AGPF NPs) were synthesized using a one-pot method and were characterized. The effects of AGPF NPs on cell viability, cellular uptake, and apoptosis were investigated using the U87 cell line. Moreover, the effectiveness of AGPF NPs in alleviating hypoxia was explored in tumor-bearing mice through photoacoustic imaging. In addition, the diagnosis and treatment effect of AGPF NPs were evaluated by magnetic resonance imaging (MRI) and bioluminescent imaging (BLI) on orthotopic glioma mice respectively. Results: In vitro experiments showed that AGPF NPs had good dispersion, stability, and controlled release. AGPF NPs were internalized by cells through endocytosis, and could significantly reduce the survival rate of U87 cells and increase apoptosis under irradiation. In addition, we monitored blood oxygen saturation at the tumor site in real-time through photoacoustic imaging (PAI), and the results showed that synergistic mild-photothermal therapy/chemotherapy effectively alleviated tumor hypoxia. Finally, in vivo anti-tumor experiments have shown that synergistic therapy can effectively alleviate hypoxia and inhibit the growth of orthotopic gliomas. Conclusion: This work not only provides an effective means for real-time monitoring of the dynamic feedback between tumor hypoxia relief and therapeutic efficacy, but also offers a potential approach for the clinical treatment of gliomas.

Novel prognostic biomarker TBC1D1 is associated with immunotherapy resistance in gliomas.

Background: Glioma, an aggressive brain tumor, poses a challenge in understanding the mechanisms of treatment resistance, despite promising results from immunotherapy. Methods: We identified genes associated with immunotherapy resistance through an analysis of The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) databases. Subsequently, qRT-PCR and western blot analyses were conducted to measure the mRNA and protein levels of TBC1 Domain Family Member 1 (TBC1D1), respectively. Additionally, Gene Set Enrichment Analysis (GSEA) was employed to reveal relevant signaling pathways, and the expression of TBC1D1 in immune cells was analyzed using single-cell RNA sequencing (scRNA-seq) data from GEO database. Tumor Immune Dysfunction and Exclusion (TIDE) database was utilized to assess T-cell function, while Tumor Immunotherapy Gene Expression Resource (TIGER) database was employed to evaluate immunotherapy resistance in relation to TBC1D1. Furthermore, the predictive performance of molecules on prognosis was assessed using Kaplan-Meier plots, nomograms, and ROC curves. Results: The levels of TBC1D1 were significantly elevated in tumor tissue from glioma patients. Furthermore, high TBC1D1 expression was observed in macrophages compared to other cells, which negatively impacted T cell function, impaired immunotherapy response, promoted treatment tolerance, and led to poor prognosis. Inhibition of TBC1D1 was found to potentially synergistically enhance the efficacy of immunotherapy and prolong the survival of cancer patients with gliomas. Conclusion: Heightened expression of TBC1D1 may facilitate an immunosuppressive microenvironment and predict a poor prognosis. Blocking TBC1D1 could minimize immunotherapy resistance in cancer patients with gliomas.

[Primary tumors of the brain stem. State of the problem]. / Pervichnye opukholi stvola golovnogo mozga. Sostoyanie problemy.

Primary brainstem gliomas are still poorly studied in neurooncology. This concept includes tumors with different histological and genetic features, as well as variable clinical course and outcomes. Nevertheless, treatment implies radiotherapy without a clear idea of morphological substrate of disease in 80% of cases. Small number of studies and insufficient data on histological and genetic nature of brainstem tumors complicate clear diagnostic and treatment algorithms. This review provides current information regarding primary glial brainstem tumors. Appropriate problems and objectives are highlighted. The purpose of the review is to provide a comprehensive and updated understanding of the current state of brainstem glial tumors and to identify areas requiring further study for improvement of diagnosis and treatment of these diseases. Brainstem tumors are an understudied problem with small amount of data that complicates optimal treatment strategies. Further researches and histological verification are required to develop new methods of therapy, especially for diffuse forms of neoplasms.

Targeting Wnt signaling for improved glioma immunotherapy.

Introduction: Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal. Activation of glioma-intrinsic Wnt/ß-catenin signaling is associated with a poor prognosis and the proliferation of glioma stem-like cells, leading to malignant transformation and tumor progression. Impressive results in a subset of cancers have been obtained using immunotherapies including anti-CTLA4, anti-PD-1, and anti-PD-L1 or chimeric antigen receptor (CAR) T cell therapies. However, the heterogeneity of tumors, low mutational burden, single antigen targeting, and associated antigen escape contribute to non-responsiveness and potential tumor recurrence despite these therapeutic efforts. In the current study, we determined the effects of the small molecule, highly specific Wnt/CBP (CREB Binding Protein)/ß-catenin antagonist ICG-001, on glioma tumor cells and the tumor microenvironment (TME)-including its effect on immune cell infiltration, blood vessel decompression, and metabolic changes. Methods: Using multiple glioma patient-derived xenografts cell lines and murine tumors (GL261, K-Luc), we demonstrated in vitro cytostatic effects and a switch from proliferation to differentiation after treatment with ICG-001. Results: In these glioma cell lines, we further demonstrated that ICG-001 downregulated the CBP/ß-catenin target gene Survivin/BIRC5-a hallmark of Wnt/CBP/ß-catenin inhibition. We found that in a syngeneic mouse model of glioma (K-luc), ICG-001 treatment enhanced tumor infiltration by CD3+ and CD8+ cells with increased expression of the vascular endothelial marker CD31 (PECAM-1). We also observed differential gene expression and induced immune cell infiltration in tumors pretreated with ICG-001 and then treated with CAR T cells as compared with single treatment groups or when ICG-001 treatment was administered after CAR T cell therapy. Discussion: We conclude that specific Wnt/CBP/ß-catenin antagonism results in pleotropic changes in the glioma TME, including glioma stem cell differentiation, modulation of the stroma, and immune cell activation and recruitment, thereby suggesting a possible role for enhancing immunotherapy in glioma patients.

Comparison of Volumetric and 2D Measurements and Longitudinal Trajectories in the Response Assessment of BRAF V600E-Mutant Pediatric Gliomas in the Pacific Pediatric Neuro-Oncology Consortium Clinical Trial.

BACKGROUND AND PURPOSE: Response on imaging is widely used to evaluate treatment efficacy in clinical trials of pediatric gliomas. While conventional criteria rely on 2D measurements, volumetric analysis may provide a more comprehensive response assessment. There is sparse research on the role of volumetrics in pediatric gliomas. Our purpose was to compare 2D and volumetric analysis with the assessment of neuroradiologists using the Brain Tumor Reporting and Data System (BT-RADS) in BRAF V600E-mutant pediatric gliomas. MATERIALS AND METHODS: Manual volumetric segmentations of whole and solid tumors were compared with 2D measurements in 31 participants (292 follow-up studies) in the Pacific Pediatric Neuro-Oncology Consortium 002 trial (NCT01748149). Two neuroradiologists evaluated responses using BT-RADS. Receiver operating characteristic analysis compared classification performance of 2D and volumetrics for partial response. Agreement between volumetric and 2D mathematically modeled longitudinal trajectories for 25 participants was determined using the model-estimated time to best response. RESULTS: Of 31 participants, 20 had partial responses according to BT-RADS criteria. Receiver operating characteristic curves for the classification of partial responders at the time of first detection (median = 2 months) yielded an area under the curve of 0.84 (95% CI, 0.69-0.99) for 2D area, 0.91 (95% CI, 0.80-1.00) for whole-volume, and 0.92 (95% CI, 0.82-1.00) for solid volume change. There was no significant difference in the area under the curve between 2D and solid (P = .34) or whole volume (P = .39). There was no significant correlation in model-estimated time to best response (ρ = 0.39, P >.05) between 2D and whole-volume trajectories. Eight of the 25 participants had a difference of ≥90 days in transition from partial response to stable disease between their 2D and whole-volume modeled trajectories. CONCLUSIONS: Although there was no overall difference between volumetrics and 2D in classifying partial response assessment using BT-RADS, further prospective studies will be critical to elucidate how the observed differences in tumor 2D and volumetric trajectories affect clinical decision-making and outcomes in some individuals.

Oncolytic viral therapy for gliomas: Advances in the mechanisms and approaches to delivery.

Glioma is a diverse category of tumors originating from glial cells encompasses various subtypes, based on the specific type of glial cells involved. The most aggressive is glioblastoma multiforme (GBM), which stands as the predominant primary malignant tumor within the central nervous system in adults. Despite the application of treatment strategy, the median survival rate for GBM patients still hovers around 15 months. Oncolytic viruses (OVs) are artificially engineered viruses designed to selectively target and induce apoptosis in cancer cells. While clinical trials have demonstrated encouraging results with intratumoral OV injections for some cancers, applying this approach to GBM presents unique challenges. Here we elaborate on current trends in oncolytic viral therapy and their delivery methods. We delve into the various methods of delivering OVs for therapy, exploring their respective advantages and disadvantages and discussing how selecting the optimal delivery method can enhance the efficacy of this innovative treatment approach.

Adjuvant Wilms' tumour 1-specific dendritic cell immunotherapy complementing conventional therapy for paediatric patients with high-grade glioma and diffuse intrinsic pontine glioma: protocol of a monocentric phase I/II clinical trial in Belgium.

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) and paediatric high-grade glioma (pHGG) are aggressive glial tumours, for which conventional treatment modalities fall short. Dendritic cell (DC)-based immunotherapy is being investigated as a promising and safe adjuvant therapy. The Wilms' tumour protein (WT1) is a potent target for this type of antigen-specific immunotherapy and is overexpressed in DIPG and pHGG. Based on this, we designed a non-randomised phase I/II trial, assessing the feasibility and safety of WT1 mRNA-loaded DC (WT1/DC) immunotherapy in combination with conventional treatment in pHGG and DIPG. METHODS AND ANALYSIS: 10 paediatric patients with newly diagnosed or pretreated HGG or DIPG were treated according to the trial protocol. The trial protocol consists of leukapheresis of mononuclear cells, the manufacturing of autologous WT1/DC vaccines and the combination of WT1/DC-vaccine immunotherapy with conventional antiglioma treatment. In newly diagnosed patients, this comprises chemoradiation (oral temozolomide 90 mg/m2 daily+radiotherapy 54 Gy in 1.8 Gy fractions) followed by three induction WT1/DC vaccines (8-10×106 cells/vaccine) given on a weekly basis and a chemoimmunotherapy booster phase consisting of six 28-day cycles of oral temozolomide (150-200 mg/m2 on days 1-5) and a WT1/DC vaccine on day 21. In pretreated patients, the induction and booster phase are combined with best possible antiglioma treatment at hand. Primary objectives are to assess the feasibility of the production of mRNA-electroporated WT1/DC vaccines in this patient population and to assess the safety and feasibility of combining conventional antiglioma treatment with the proposed immunotherapy. Secondary objectives are to investigate in vivo immunogenicity of WT1/DC vaccination and to assess disease-specific and general quality of life. ETHICS AND DISSEMINATION: The ethics committee of the Antwerp University Hospital and the University of Antwerp granted ethics approval. Results of the clinical trial will be shared through publication in a peer-reviewed journal and presentations at conferences. TRIAL REGISTRATION NUMBER: NCT04911621.

NOP14 as a Potential Predictor of Adult-Type Diffuse Glioma Prognosis and Immunotherapy, is Related to Cell Migration, Proliferation, and CD8+T Cell Infiltration.

BACKGROUND: World Health Organization (WHO) grade 4 adult-type diffuse glioma is the most malignant primary tumor of the brain. Nucleolar protein 14 (NOP14) is recognized to contribute significantly to the assembly of small ribosomal subunits. However, the specific involvement of NOP14 in diverse cancers remains poorly understood, particularly its role in adult-type diffuse glioma, which has yet to be elucidated. METHODS: A total of 20 adult-type diffuse glioma samples with varying WHO stages were collected. The protein level of NOP14 was detected using immunohistochemistry. Additionally, NOP14 expression in LN229 and U251 cell lines and collected clinical tissue samples was quantified using the Western blot technique. Furthermore, the correlation between NOP14 and clinicopathological features, survival rates, matrix and immune scores, and immune components was investigated using data from the Cancer Gene Atlas database. RESULTS: NOP14 exhibited high expression in adult-type diffuse glioma patients, with the highest expression observed in the LN229 cell line. Moreover, elevated NOP14 expression was significantly correlated with poorer overall survival and demonstrated an association with unfavorable pathological features in a cohort of 703 glioblastoma (GBM) patients. Evidence of a connection between NOP14 and the tumor microenvironment was presented. Elevated NOP14 was linked to the infiltration of CD8+T cell and factors related to epithelial-mesenchymal transition. In in vitro assay, NOP14 was capable of suppressing adult-type diffuse glioma cell invasion and metastasis. CONCLUSIONS: NOP14 holds great promise as a candidate biomarker for detecting prognostic, molecular, and immune signatures of adult-type diffuse glioma.

Application of RNA-based therapeutics in glioma: A review.

Despite the extensive advancements made in the field of cancer therapy, the outlook of individuals suffering from glioblastoma multiforme remains highly detrimental. The absence of specific treatments for cancerous cells significantly hinders the effectiveness of conventional anticancer techniques. Multiple research studies have demonstrated that the suppression of specific genes or the augmentation of therapeutic proteins through RNA-based therapeutics may represent a valuable approach when combined with chemotherapy or immunotherapy. In recent years, there has been a significant increase in the application of RNA therapeutics in conjunction with chemotherapy and immunotherapy. This emerging field has become a prominent area of research for advancing various types of cancer treatments. The present investigation provides an in-depth overview of the classification and application of RNA therapy, focusing on the mechanisms of RNA antitumor treatment and the current status of clinical studies on RNA drugs.

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial.

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362 .

Palliative care for in-patient malignant glioma patients in Germany.

OBJECTIVE: Malignant gliomas impose a significant symptomatic burden on patients and their families. Current guidelines recommend palliative care for patients with advanced tumors within eight weeks of diagnosis, emphasizing early integration for malignant glioma cases. However, the utilization rate of palliative care for these patients in Germany remains unquantified. This study investigates the proportion of malignant glioma patients who either died in a hospital or were transferred to hospice care from 2019 to 2022, and the prevalence of in-patient specialized palliative care interventions. METHODS: In this cross-sectional, retrospective study, we analyzed data from the Institute for the Hospital Remuneration System (InEK GmbH, Siegburg, Germany), covering 2019 to 2022. We included patients with a primary or secondary diagnosis of C71 (malignant glioma) in our analysis. To refine our dataset, we identified cases with dual-coded primary and secondary diagnoses and excluded these to avoid duplication in our final tally. The data extraction process involved detailed scrutiny of hospital records to ascertain the frequency of hospital deaths, hospice transfers, and the provision of complex or specialized palliative care for patients with C71-coded diagnoses. Descriptive statistics and inferential analyses were employed to evaluate the trends and significance of the findings. RESULTS: From 2019 to 2022, of the 101,192 hospital cases involving malignant glioma patients, 6,129 (6% of all cases) resulted in in-hospital mortality, while 2,798 (2.8%) led to hospice transfers. Among these, 10,592 cases (10.5% of total) involved the administration of complex or specialized palliative medical care. This provision rate remained unchanged throughout the COVID-19 pandemic. Notably, significantly lower frequencies of complex or specialized palliative care implementation were observed in patients below 65 years (p < 0.0001) and in male patients (padjusted = 0.016). In cases of in-hospital mortality due to malignant gliomas, 2,479 out of 6,129 cases (40.4%) received specialized palliative care. CONCLUSION: Despite the poor prognosis and complex symptomatology associated with malignant gliomas, only a small proportion of affected patients received advanced palliative care. Specifically, only about 10% of hospitalized patients with malignant gliomas, and approximately 40% of those who succumb to the disease in hospital settings, were afforded complex or specialized palliative care. This discrepancy underscores an urgent need to expand palliative care access for this patient demographic. Additionally, it highlights the importance of further research to identify and address the barriers preventing wider implementation of palliative care in this context.

Theory and application of TTFields in newly diagnosed glioblastoma.

BACKGROUND: Glioblastoma is the most common primary malignant brain tumor in adults. TTFields is a therapy that use intermediate-frequency and low-intensity alternating electric fields to treat tumors. For patients with ndGBM, the addition of TTFields after the concurrent chemoradiotherapy phase of the Stupp regimen can improve prognosis. However, TTFields still has the potential to further prolong the survival of ndGBM patients. AIM: By summarizing the mechanism and application status of TTFields in the treatment of ndGBM, the application prospect of TTFields in ndbm treatment is prospected. METHODS: We review the recent literature and included 76 articles to summarize the mechanism of TTfields in the treatment of ndGBM. The current clinical application status and potential health benefits of TTFields in the treatment of ndGBM are also discussed. RESULTS: TTFields can interfere with tumor cell mitosis, lead to tumor cell apoptosis and increased autophagy, hinder DNA damage repair, induce ICD, activate tumor immune microenvironment, reduce cancer cell metastasis and invasion, and increase BBB permeability. TTFields combines with chemoradiotherapy has made progress, its optimal application time is being explored and the problems that need to be considered when retaining the electrode patches for radiotherapy are further discussed. TTFields shows potential in combination with immunotherapy, antimitotic agents, and PARP inhibitors, as well as in patients with subtentorial gliomas. CONCLUSION: This review summarizes mechanisms of TTFields in the treatment of ndGBM, and describes the current clinical application of TTFields in ndGBM. Through the understanding of its principle and application status, we believe that TTFields still has the potential to further prolong the survival of ndGBM patients. Thus,research is still needed to explore new ways to combine TTFields with other therapies and optimize the use of TTFields to realize its full potential in ndGBM patients.

Arterial Spin-Labeling and DSC Perfusion Metrics Improve Agreement in Neuroradiologists' Clinical Interpretations of Posttreatment High-Grade Glioma Surveillance MR Imaging-An Institutional Experience.

BACKGROUND AND PURPOSE: MR perfusion has shown value in the evaluation of posttreatment high-grade gliomas, but few studies have shown its impact on the consistency and confidence of neuroradiologists' interpretation in routine clinical practice. We evaluated the impact of adding MR perfusion metrics to conventional contrast-enhanced MR imaging in posttreatment high-grade glioma surveillance imaging. MATERIALS AND METHODS: This retrospective study included 45 adults with high-grade gliomas who had posttreatment perfusion MR imaging. Four neuroradiologists assigned Brain Tumor Reporting and Data System scores for each examination on the basis of the interpretation of contrast-enhanced MR imaging and then after the addition of arterial spin-labeling-CBF, DSC-relative CBV, and DSC-fractional tumor burden. Interrater agreement and rater agreement with a multidisciplinary consensus group were assessed with κ statistics. Raters used a 5-point Likert scale to report confidence scores. The frequency of clinically meaningful score changes resulting from the addition of each perfusion metric was determined. RESULTS: Interrater agreement was moderate for contrast-enhanced MR imaging alone (κ = 0.63) and higher with perfusion metrics (arterial spin-labeling-CBF, κ = 0.67; DSC-relative CBV, κ = 0.66; DSC-fractional tumor burden, κ = 0.70). Agreement between raters and consensus was highest with DSC-fractional tumor burden (κ = 0.66-0.80). Confidence scores were highest with DSC-fractional tumor burden. Across all raters, the addition of perfusion resulted in clinically meaningful interpretation changes in 2%-20% of patients compared with contrast-enhanced MR imaging alone. CONCLUSIONS: Adding perfusion to contrast-enhanced MR imaging improved interrater agreement, rater agreement with consensus, and rater confidence in the interpretation of posttreatment high-grade glioma MR imaging, with the highest agreement and confidence scores seen with DSC-fractional tumor burden. Perfusion MR imaging also resulted in interpretation changes that could change therapeutic management in up to 20% of patients.

Brain Delivery of Biomimetic Phosphorus Dendrimer/Antibody Nanocomplexes for Enhanced Glioma Immunotherapy via Immune Modulation of T Cells and Natural Killer Cells.

Fully mobilizing the activities of multiple immune cells is crucial to achieve the desired tumor immunotherapeutic efficacy yet still remains challenging. Herein, we report a nanomedicine formulation based on phosphorus dendrimer (termed AK128)/programmed cell death protein 1 antibody (aPD1) nanocomplexes (NCs) that are camouflaged with M1-type macrophage cell membranes (M1m) for enhanced immunotherapy of orthotopic glioma. The constructed AK128-aPD1@M1m NCs with a mean particle size of 160.3 nm possess good stability and cytocompatibility. By virtue of the decorated M1m having α4 and ß1 integrins, the NCs are able to penetrate the blood-brain barrier to codeliver both AK128 with intrinsic immunomodulatory activity and aPD1 to the orthotopic glioma with prolonged blood circulation time. We show that the phosphorus dendrimer AK128 can boost natural killer (NK) cell proliferation in peripheral blood mononuclear cells, while the delivered aPD1 enables immune checkpoint blockade (ICB) to restore the cytotoxic T cells and NK cells, thus promoting tumor cell apoptosis and simultaneously decreasing the tumor distribution of regulatory T cells vastly for improved glioma immunotherapy. The developed nanomedicine formulation with a simple composition achieves multiple modulations of immune cells by utilizing the immunomodulatory activity of nanocarrier and antibody-mediated ICB therapy, providing an effective strategy for cancer immunotherapy.

Protocol to generate traceable CAR T cells for syngeneic mouse cancer models.

The efficacy of chimeric antigen receptor (CAR) T cell immunotherapy is limited by insufficient infiltration and activation of T cells due to the immunosuppressive tumor microenvironment. Preclinical studies with optimized mouse CAR T cells in immunocompetent mouse cancer models will help define the mechanisms underlying immunotherapy resistance. Here, we present a protocol for preparing mouse T cells and generating CAR T cells. We then detail procedures for testing their therapeutic efficacy and tracking them in a syngeneic mouse glioma model. For complete details on the use and execution of this protocol, please refer to Zhang et al.1.

Machine learning-based investigation of regulated cell death for predicting prognosis and immunotherapy response in glioma patients.

Glioblastoma is a highly aggressive and malignant type of brain cancer that originates from glial cells in the brain, with a median survival time of 15 months and a 5-year survival rate of less than 5%. Regulated cell death (RCD) is the autonomous and orderly cell death under genetic control, controlled by precise signaling pathways and molecularly defined effector mechanisms, modulated by pharmacological or genetic interventions, and plays a key role in maintaining homeostasis of the internal environment. The comprehensive and systemic landscape of the RCD in glioma is not fully investigated and explored. After collecting 18 RCD-related signatures from the opening literature, we comprehensively explored the RCD landscape, integrating the multi-omics data, including large-scale bulk data, single-cell level data, glioma cell lines, and proteome level data. We also provided a machine learning framework for screening the potentially therapeutic candidates. Here, based on bulk and single-cell sequencing samples, we explored RCD-related phenotypes, investigated the profile of the RCD, and developed an RCD gene pair scoring system, named RCD.GP signature, showing a reliable and robust performance in predicting the prognosis of glioblastoma. Using the machine learning framework consisting of Lasso, RSF, XgBoost, Enet, CoxBoost and Boruta, we identified seven RCD genes as potential therapeutic targets in glioma and verified that the SLC43A3 highly expressed in glioma grades and glioma cell lines through qRT-PCR. Our study provided comprehensive insights into the RCD roles in glioma, developed a robust RCD gene pair signature for predicting the prognosis of glioma patients, constructed a machine learning framework for screening the core candidates and identified the SLC43A3 as an oncogenic role and a prediction biomarker in glioblastoma.

Treatment outcome of IDH1/2 wildtype CNS WHO grade 4 glioma histologically diagnosed as WHO grade II or III astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH)1/2 wildtype (wt) astrocytomas formerly classified as WHO grade II or III have significantly shorter PFS and OS than IDH mutated WHO grade 2 and 3 gliomas leading to a classification as CNS WHO grade 4. It is the aim of this study to evaluate differences in the treatment-related clinical course of these tumors as they are largely unknown. METHODS: Patients undergoing surgery (between 2016-2019 in six neurosurgical departments) for a histologically diagnosed WHO grade 2-3 IDH1/2-wt astrocytoma were retrospectively reviewed to assess progression free survival (PFS), overall survival (OS), and prognostic factors. RESULTS: This multi-center study included 157 patients (mean age 58 years (20-87 years); with 36.9% females). The predominant histology was anaplastic astrocytoma WHO grade 3 (78.3%), followed by diffuse astrocytoma WHO grade 2 (21.7%). Gross total resection (GTR) was achieved in 37.6%, subtotal resection (STR) in 28.7%, and biopsy was performed in 33.8%. The median PFS (12.5 months) and OS (27.0 months) did not differ between WHO grades. Both, GTR and STR significantly increased PFS (P < 0.01) and OS (P < 0.001) compared to biopsy. Treatment according to Stupp protocol was not associated with longer OS or PFS compared to chemotherapy or radiotherapy alone. EGFR amplification (P = 0.014) and TERT-promotor mutation (P = 0.042) were associated with shortened OS. MGMT-promoter methylation had no influence on treatment response. CONCLUSIONS: WHO grade 2 and 3 IDH1/2 wt astrocytomas, treated according to the same treatment protocols, have a similar OS. Age, extent of resection, and strong EGFR expression were the most important treatment related prognostic factors.

Impact of glioma peritumoral edema, tumor size, and tumor location on alternating electric fields (AEF) therapy in realistic 3D rat glioma models: a computational study.

Objective.Alternating electric fields (AEF) therapy is a treatment modality for patients with glioblastoma. Tumor characteristics such as size, location, and extent of peritumoral edema may affect the AEF strength and distribution. We evaluated the sensitivity of the AEFs in a realistic 3D rat glioma model with respect to these properties.Approach.The electric properties of the peritumoral edema were varied based on calculated and literature-reported values. Models with different tumor composition, size, and location were created. The resulting AEFs were evaluated in 3D rat glioma models.Main results.In all cases, a pair of 5 mm diameter electrodes induced an average field strength >1 V cm-1. The simulation results showed that a negative relationship between edema conductivity and field strength was found. As the tumor core size was increased, the average field strength increased while the fraction of the shell achieving >1.5 V cm-1decreased. Increasing peritumoral edema thickness decreased the shell's mean field strength. Compared to rostrally/caudally, shifting the tumor location laterally/medially and ventrally (with respect to the electrodes) caused higher deviation in field strength.Significance.This study identifies tumor properties that are key drivers influencing AEF strength and distribution. The findings might be potential preclinical implications.

Chimeric oncolytic adenovirus evades neutralizing antibodies from human patients and exhibits enhanced anti-glioma efficacy in immunized mice.

Oncolytic viruses are a promising treatment for patients with high-grade gliomas, but neutralizing antibodies can limit their efficacy in patients with prior virus exposure or upon repeated virus injections. Data from a previous clinical trial using the oncolytic adenovirus Delta-24-RGD showed that generation of anti-viral neutralizing antibodies may affect the long-term survival of glioma patients. Past studies have examined the effects of neutralizing antibodies during systemic virus injections, but largely overlooked their impact during local virus injections into the brain. We found that immunoglobulins colocalized with viral proteins upon local oncolytic virotherapy of brain tumors, warranting a strategy to prevent virus neutralization and maximize oncolysis. Thus, we generated a chimeric virus, Delta-24-RGD-H43m, by replacing the capsid protein HVRs from the serotype 5-based Delta-24-RGD with those from the rare serotype 43. Delta-24-RGD-H43m evaded neutralizing anti-Ad5 antibodies and conferred a higher rate of long-term survival than Delta-24-RGD in glioma-bearing mice. Importantly, Delta-24-RGD-H43m activity was significantly more resistant to neutralizing antibodies present in sera of glioma patients treated with Delta-24-RGD during a phase 1 clinical trial. These findings provide a framework for a novel treatment of glioma patients that have developed immunity against Delta-24-RGD.

Protocol for investigating data quality and reporting outcomes of pediatric gliomas in population-based cancer registry research.

Cancer registry data on pediatric gliomas come with inherent limitations as inclusion criteria and registration practices of these tumors differ between registries due to specific guidelines that are lacking. These limitations can lead to biased estimates in incidence and survival outcomes. Here, we present a protocol to investigate data quality and comparability for retrospective population-based pediatric glioma studies. We describe steps for obtaining institutional permissions, dealing with data quality issues, regrouping tumors, and reporting tumors in a clinically relevant manner. For complete details on the use and execution of this protocol, please refer to Hoogendijk et al.1.