Glioblastoma Patients Research Articles

Clinical and Demographic Profile of Syrian Patients with Malignant Glioma: A Six-Month Retrospective Analysis

This study presents a retrospective analysis of glioblastoma cases admitted to Tishreen University Hospital in Lattakia, Syria, between February and August 2024. The study examines the several potential risk factors including age, sex, genetic predispositions, and lifestyle factors such as smoking and alcohol consumption. It also explores the most commonly encountered tumor grade and the presence of various neurological symptoms, as well as treatment outcomes. A total of 30 glioblastoma were enrolled in this study, 63% of which were males, and the highest age incidence was between 40 and 50 years. Only 6% had a family history of glioblastoma, and 66% of the patients were smokers. Memory disorders, visual impairments, and headaches were common symptoms, with 100% of the patients reporting nausea and vomiting. Glioblastoma diagnosis was primarily established through MRI with contrast (76%), and the predominant treatment modality was surgery combined with radiotherapy and chemotherapy (80%). Post-treatment relapse occurred in 26% of the patients, with a median remission period of four months. These findings provide important insights into the clinical characteristics and treatment outcomes of glioblastoma patients in this region.

The peritumoral edema index and related mechanisms influence the prognosis of GBM patients

BackgroundPeritumoral brain edema (PTBE) represents a characteristic phenotype of intracranial gliomas. However, there is a lack of consensus regarding the prognosis and mechanism of PTBE. In this study, clinical imaging data, along with publicly available imaging data, were utilized to assess the prognosis of PTBE in glioblastoma (GBM) patients, and the associated mechanisms were preliminarily analyzed.MethodsWe investigated relevant imaging features, including edema, in GBM patients using ITK-SNAP imaging segmentation software. Risk factors affecting progression-free survival (PFS) and overall survival (OS) were assessed using a Cox proportional hazard regression model. In addition, the impact of PTBE on PFS and OS was analyzed in clinical GBM patients using the Kaplan–Meier survival analysis method, and the results further validated by combining data from The Cancer Imaging Archive (TCIA) and The Cancer Genome Atlas (TCGA). Finally, functional enrichment analysis based on TCIA and TCGA datasets identified several pathways potentially involved in the mechanism of edema formation.ResultsThis study included a total of 32 clinical GBM patients and 132 GBM patients from public databases. Univariate and multivariate analyses indicated that age and edema index (EI) are independent risk factors for PFS, but not for OS. Kaplan–Meier curves revealed consistent survival analysis results between IE groups among both clinical patients and TCIA and TCGA patients, suggesting a significant effect of PTBE on PFS but not on OS. Furthermore, functional enrichment analysis predicted the involvement of several pathways related mainly to cellular bioenergetics and vasculogenic processes in the mechanism of PTBE formation. While these novel results warrant confirmation in a larger patient cohort, they support good prognostic value for PTBE assessment in GBM.ConclusionsOur results indicate that a low EI positively impacts disease control in GBM patients, but this does not entirely translate into an improvement in OS. Multiple genes, signaling pathways, and biological processes may contribute to the formation of peritumoral edema in GBM through cytotoxic and vascular mechanisms.

Our clock is truly ticking – a qualitative study on patients’ experiences of tumour treating fields (TTFields)

Abstract Background TTFields is recommended internationally for treatment of glioblastoma. In Sweden, TTFields requires a possibly challenging collaboration between the patient, next-of-kin, healthcare and the private company providing the device, both from an ethical and practical perspective. Little is known about glioblastoma patients’ own experiences of TTFields treatment. Methods Semi-structured individual interviews were conducted with 31 patients with glioblastoma who had been offered TTFields by the healthcare. These were analysed by qualitative content analysis. Results Participants described there being multiple actors around them as TTFields users; 1) device prescription from physicians, sometimes providing insufficient information, 2) practical assistance from next-of-kin, necessary to access treatment, 3) home visits from the private company staff for device control, where close bonds between patients and TTFields staff occurred. TTFields treatment created hope and a feeling of control in an otherwise hopeless situation, sometimes evoking worries at the time of planned treatment stop. Some refrained from TTFields or discontinued early due to fear or experience of negative effect on quality of life. Others described finding practical and mental solutions for coping with the treatment in everyday life. Conclusions Our study identified a need for better support and information from healthcare providers for TTFields. A solution is necessary for assistance with TTFields for those without support from next-of-kin. The study raises the question of possible advantages of the healthcare handling the technical support of the device instead of a private company, thereby avoiding a true or perceived influence on the patient’s decision to continue or stop treatment.

Imaging PD-L1 in the brain-Journey from the lab to the clinic.

Immune checkpoint inhibitors (ICPIs) have proven to restore adaptive anti-tumor immunity in many cancers; however, no noteworthy therapeutic schedule has been established for patients with glioblastoma (GBM). High programmed death-ligand 1 (PD-L1) expression is associated with immunosuppressive and aggressive phenotypes in GBM. Presently, there is no standardized protocol for assessing PD-L1 expression levels to select patients and monitor their response to ICPI therapy. The aim of this study was to investigate the use of 89Zr-DFO-Atezolizumab to image the spatio-temporal distribution of PD-L1 in preclinical mouse models and in patients with newly diagnosed GBM treated with/without neoadjuvant Pembrolizumab. The immunoreactivity, binding affinity, and specificity of 89Zr-DFO-Atezolizumab were confirmed in vitro. Mice-bearing orthotopic GBM tumors or patients with newly diagnosed GBM treated with/without Pembrolizumab were intravenously injected with 89Zr-DFO-Atezolizumab, and PET/CT images were acquired 24, 48, and 72 hours in mice and at 48 and 72 post-injection in patients. Radioconjugate uptake was quantified in the tumor and healthy tissues. Ex vivo immunohistochemistry (IHC) and immunophenotyping were performed on mouse tumor samples or resected human tumors. 89Zr-DFO-Atezolizumab was prepared with high radiochemical purity (RCP > 99%). In vitro cell-associated radioactivity of 89Zr-DFO-Atezolizumab corroborated cell line PD-L1 expression. PD-L1 in mouse GBM tumors was detected with high specificity using 89Zr-DFO-Atezolizumab and radioconjugate uptake correlated with IHC. Patients experienced no 89Zr-DFO-Atezolizumab-related side effects. High 89Zr-DFO-Atezolizumab uptake was observed in patient tumors at 48 hours post-injection, however, the uptake varied between patients treated with/without Pembrolizumab. 89Zr-DFO-Atezolizumab can visualize distinct PD-L1 expression levels with high specificity in preclinical mouse models and in patients with GBM, whilst complementing ex vivo analysis.

Reduced T and NK Cell Activity in Glioblastoma Patients Correlates with TIM-3 and BAT3 Dysregulation

Inhibitory receptors are critical for regulating immune cell function. In cancer, these receptors are often over-expressed on the cell surface of T and NK cells, leading to reduced anti-tumor activity. Here, through the analysis of 11 commonly studied checkpoint and inhibitory receptors, we discern that only HAVCR2 (TIM3) and ENTPD1 (CD39) display significantly greater gene expression in glioblastoma compared to normal brain and lower grade glioma. Cell surface TIM-3, but not ENTPD1, was also elevated on activated CD4+ and CD8+ T cells, as well as on NK cells from glioblastoma patients compared to healthy donor T and NK cells. A subsequent analysis of molecules known to co-ordinate TIM-3 function and regulation was performed, which revealed that BAT3 expression was significantly reduced in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients compared to counterparts from healthy donors. These pro-inhibitory changes are also correlated with reduced levels of the activation marker CD69 and the pro-inflammatory cytokine IFNγ in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients. Collectively, these data reveal that glioblastoma-mediated CD4+ and CD8+ T cell and NK cell suppression is due, at least in part, to dysregulated TIM-3 and BAT3 expression and the associated downstream immunoregulatory and dysfunctional effects.

Impact of Extent of Resection on Overall Survival in Glioblastomas: An Umbrella Review of Meta-Analyses

(1) Background: Glioblastoma (GBM) is the most common malignant brain tumor in adults. Due to a lack of level 1 evidence, there is no clear consensus on the optimal extent of resection to improve overall survival. This umbrella review aggregates existing meta-analyses (MAs) to assess overall survival in patients undergoing subtotal resection (STR) versus gross total resection (GTR). (2) Methods: A systematic search of PubMed, Scopus, and Web of Science identified 441 studies, with four MAs meeting inclusion criteria. Data were analyzed using the metaumbrella R package, focusing on overall survival. Quality was assessed using AMSTAR2, with scores ranging from 0 to 11. The Ioannidis criteria were applied to evaluate the credibility of the evidence. (3) Results: The quality assessment rated all four studies highly, with a mean AMSTAR2 score of 10.25. The pooled analysis revealed a significant survival advantage for GTR over STR. However, the Ioannidis classification graded the evidence as Class III, indicating weak credibility. (4) Conclusions: GTR offers a slight survival benefit over STR in GBM patients, but the credibility of the evidence is weak, highlighting the need for further research.

Prospective Longitudinal Analysis of Physiologic MRI-based Tumor Habitat Predicts Short-term Patient Outcomes in IDH-wildtype Glioblastoma.

This study validates MRI-based tumor habitats in predicting time-to-progression (TTP), overall survival (OS), and progression site in isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients. Seventy-nine patients were prospectively enrolled between January 2020 and June 2022. MRI, including diffusion-weighted and dynamic susceptibility contrast imaging, were obtained immediately post-operation and at three serial timepoints. Voxels from cerebral blood volume and apparent diffusion coefficient maps were grouped into three habitats (hypervascular cellular, hypovascular cellular, and nonviable tissue) using k-means clustering. Pre-defined cutoffs for increases in hypervascular and hypovascular cellular habitat were applied to calculate the habitat risk score. Associations between spatiotemporal habitats, habitat risk score, TTP, and OS were investigated using Cox proportional hazards modeling. Habitat risk score was compared to tumor volume using time-dependent receiver operating characteristics analysis. Progression sites were matched with spatial habitats. Increases in hypervascular and hypovascular cellular habitats and habitat risk scores were associated with shorter TTP and OS (all p < .05). Hypovascular cellular habitat and habitat risk scores 1 and 2 independently predicted TTP (hazard ratio [HR], 4.14; p=.03, HR, 4.51; p=.001 and HR, 10.02; p<.001, respectively). Hypovascular cellular habitat and habitat risk score 2 independently predicted OS (HR, 4.01, p=.003; and HR, 3.27, p<.001, respectively). Habitat risk score outperformed tumor volume in predicting TTP (12-month AUC, 0.762 vs. 0.646, p=.048). Hypovascular cellular habitat predicted progression sites (mean Dice index: 0.31). Multiparametric physiologic MRI-based spatiotemporal tumor habitats and habitat risk scores are useful biomarkers for early tumor progression and outcomes in IDH-wildtype glioblastoma patients.

Repeatability and Reproducibility of pseudo-Continuous Arterial Spin Labeling Measured Brain Perfusion in Healthy Volunteers and Glioblastoma Patients.

Arterial spin labeled (ASL) MRI has gained recognition as a quantitative perfusion imaging method for managing patients with brain tumors. Limited studies have so far investigated the reproducibility of ASL-derived perfusion in patients with brain tumors. This study aims to evaluate intrasession repeatability and intersession reproducibility of perfusion measurements using 3D pseudo-continuous ASL (pCASL) with Cartesian TSE (TSE-CASPR) in healthy volunteers (HV) and glioblastoma (GBM) patients at 3 Tesla and compare against 3D pCASL with GRASE. This prospective study (NCT03922984) was approved by the institutional review board and written informed consent was obtained from all subjects. HV underwent repeated pCASL evaluations 2-4 weeks apart between November 2021 and October 2022. GBM patients were recruited for longitudinal MRI from September 2019 to February 2023. Intrasession repeatability (HV and GBM) and intersession reproducibility (HV only) of pCASL were assessed using linear regression, Bland-Altman analyses, intraclass correlation coefficient (ICC) with 95% confidence interval (CI), and within-subject coefficients of variation (wsCV). Twenty HV (9 men, age: 25.1±1.7 years, range 23-30 years) and 21 GBM patients (15 men; age: 59.8±14.3 years, range 28-81 years) were enrolled. Within imaging session, 3D pCASL measured perfusion with TSE-CASPR and GRASE respectively achieved high R2 values (0.88-0.95; 0.93-0.96), minimal biases (-0.46 to 0.81; -0.08 to 0.35 mL/100g/min), high ICC [95% CI] (0.96-0.98 [0.94-0.98]; 0.96-0.98 [0.92-0.99]), and low wsCV (6.64%-9.07%; 5.20%-8.16%) in HV (N=20) and GBM patients (N=21). Across imaging session, 3D pCASL in HV (N=20) achieved high R2 values (0.71; 0.82), minimal biases (-1.2; -0.90 mL/100g/min), high ICC [95% CI] values (0.85 [0.81-0.89]; 0.90 [0.87-0.93]), and low wsCV values (13.82%; 9.98%). Our study demonstrated excellent intrasession repeatability of 3D pCASL measured cerebral perfusion in HV and GBM patients and good to excellent intersession reproducibility in HV. 3D pCASL with GRASE performed slightly better than 3D pCASL with TSE-CASPR in HV; however, in GBM patients, 3D pCASL with TSE-CASPR showed better performance in tumor regions with nearly twofold higher SNR. ASL measured perfusion could serve as a non-contrast quantitative imaging biomarker to facilitate the management of GBM patients. ASL = arterial spin labeling; pCASL = pseudo-continuous arterial spin labeling; GBM = glioblastoma; CBF = cerebral blood flow; CASPR = Cartesian acquisition with spiral profile reordering; GRASE = gradient and spin echo; NAGM = normal-appearing gray matter.

DNA-PK inhibition shows differential radiosensitization in orthotopic GBM PDX models based on DDR pathway deficits.

Glioblastoma (GBM) remains one of the most therapy-resistant malignancies with frequent local failures despite aggressive surgery, chemotherapy, and ionizing radiation (IR). Small molecule inhibitors of DNA-dependent protein kinase (DNA-PKi's) are potent radiosensitizers currently in clinical trials. Determining which patients may benefit from radiosensitization with DNA-PKi's is critical to avoid unnecessary increased risk of normal tissue toxicity. In this study we used GBM patient derived xenografts (PDXs) in orthotopic murine models to study the relationship between molecular features, pharmacokinetics, and the radiosensitizing potential of the DNA-PKi peposertib. We show that peposertib radiosensitizes established and PDX GBM lines in vitro at 300nM and above, with significant increase in radiosensitization by maintaining post-IR exposure for >12 hours. Radiosensitization by peposertib is mediated by catalytic inhibition of DNA-PK, and knock-down of DNA-PK by short hairpin RNA (shRNA) largely abolished the radiosensitizing effect. Peposertib decreased auto-phosphorylation of DNA-PKcs after IR in a dose-dependent manner with delay in resolution of γH2AX foci at 24 hours. The addition of peposertib to IR significantly increased survival in GBM120 orthotopic xenografts, but not in GBM10. There was no difference in plasma or average tumor concentrations of peposertib in the two cohorts. While the mechanism underpinning this discordant effect in vitro vs. in vivo is not clear, there was an association for greater sensitization in TP53 mutant lines. Transfection of a dominant-negative TP53 mutant in baseline TP53 wildtype GBM lines significantly delayed growth and decreased NHEJ efficiency (but not Homologous Recombination), after peposertib exposure.

Comparative analysis of hypofractionated short-course versus standard radiation therapy in elderly patients with glioblastoma: analysis of nationwide database.

Hypofractionated short-course radiation therapy (SCRT) is an alternative treatment option for elderly or frail patients with newly diagnosed glioblastoma (GBM) post-surgery. This study compares survival outcomes and treatment costs between patients receiving SCRT and those undergoing standard long-course radiation therapy (LCRT). This retrospective study utilized health insurance claims and national cancer registry data from Korea to compare overall survival (OS) and treatment costs between patients receiving SCRT and LCRT across all ages and sub-group analysis within the subgroup of cases aged 65 and older from 2016 onwards, a period when intensity-modulated radiotherapy (IMRT) was widely adopted. A total of 1,598 patients were included. Median OS since the first day of radiation therapy was 10.4 months (95% CI [9.6; 12.8]) for SCRT (n = 197) versus 16.2 months (95% CI [15.5; 16.9]) for LCRT (n = 1401) respectively. Subgroup analysis using stabilized inverse probability of treatment weighting (S-IPTW) showed indicating non-inferiority in elderly patients in median OS for elderly patients (≥ 65) with 10.6 months (95% CI [8.9; 14.0]) for SCRT (n = 147) versus 13.2 months (95% CI [8.9; 14.0]) for LCRT (n = 541). The median treatment cost of SCRT is about 6,000 USD lower, 25% less than LCRT. Compliance with the standard TMZ regimen post-radiation improved OS across all age groups. Considering comparable OS and shorter treatment duration, SCRT offers a viable, cost-effective option for elderly GBM patients. Adhering to standard TMZ also contributes to OS improvement. Further research reflecting key prognostic factors is essential to refining the role of SCRT.

P02.15.A INVESTIGATING THE ROLE OF CELLULAR SENESCENCE IN BRIDGING GLIOBLASTOMA AND ALZHEIMER’S DISEASE

Abstract BACKGROUND With changing demographics, age-related diseases like neurodegenerative disorders and cancer are becoming increasingly prevalent. We previously demonstrated that over 50% of glioblastoma (GB) patients show Alzheimer’s Disease (AD)-like changes in the tumor-adjacent cortex. However, whether these diseases are biologically linked remains unclear. Here, we investigate cellular senescence, a hallmark of aging, as a shared mechanism. MATERIAL AND METHODS We utilized single cell and single nucleus RNA sequencing datasets from 110 GB patients (GBmap core atlas) and 89 individuals with varying stages of AD (SEA-AD MTG atlas). Following data integration, we assessed senescent cells using three established gene lists, performed differential gene expression and conducted gene set enrichment analysis. Senescence scores were compared across different cell types and patients. Co-expression modules with senescence-associated genes were identified using weighted gene co-expression network analysis (WGCNA). Quantitative neuropathological analysis of published measurements (Iba1, AT8, 6E10) complemented the molecular findings. RESULTS Senescence was found in both GB and AD patient cells including cell types of the microenvironment. Notably, the variability in scores per patient was significantly higher in GB as compared to AD cell types, indicating greater inter-patient heterogeneity. Microglia were specifically enriched for senescence gene sets among glial cells. Subset analysis of microglia through data harmonization identified a proinflammatory GB microglia subtype that shared high similarity with AD microglia and had highest senescence scores. Notably, the increase in senescent microglia was associated with progression to advanced disease stages in both diseases. WGCNA identified 3 consensus modules of senescence-associated genes that were coexpressed with disease-specific genes, like PTEN implicated phosphorylation in the AD module and SPP1 for extracellular matrix remodeling in the GB module. All senescence associated modules showed increased expression in more advanced disease stages. Quantitative analysis of immunohistochemistry measurements in the AD dataset confirmed that samples with a high senescence score showed a significantly higher density of tau pathology and an altered microglia morphology. CONCLUSION Our study identifies cellular senescence as one connection between GB and AD pathology by utilizing atlas-level transcriptomic datasets. Particularly microglia upregulate senescence signatures with disease progression. The co-expression of senescence-associated genes within disease-specific modules underscores the complexity of senescence in this context.

Pathomics models for CD40LG expression and prognosis prediction in glioblastoma

Glioblastoma (GBM) is the most prevalent primary malignant tumor of the nervous system. In this study, we utilized pathomics analysis to explore the expression of CD40LG and its predictive value for the prognosis of GBM patients. We analyzed the expression differences of CD40LG in GBM tissue and normal brain tissue, along with performing survival prognosis analysis. Additionally, histopathological sections of GBM were used to screen for pathological features. Subsequently, SVM and LR pathomics models were constructed, and the models’ performance was evaluated. The pathomics model was employed to predict CD40LG expression and patient prognosis. Furthermore, we investigated the potential molecular mechanisms through enrichment analysis, WGCNA analysis, immune correlation analysis, and immune checkpoint analysis. The expression level of CD40LG was significantly increased in GBM. Multivariate analysis demonstrated that high expression of CD40LG is a risk factor for overall survival (OS) in GBM patients. Five pathological features were identified, and SVM and LR pathomics models were constructed. Model evaluation showed promising predictive effects, with an AUC value of 0.779 for the SVM model, and the Hosmer–Lemeshow test confirmed the model’s prediction probability consistency (P > 0.05). The LR model achieved an AUC value of 0.785, and the Hosmer–Lemeshow test indicated good agreement between the LR model’s predicted probabilities and the true value (P > 0.05). Immune infiltration analysis revealed a significant correlation between the pathomics score (PS) and the degree of infiltration of activated DC cells, T cells CD4 naïve, Macrophages M2, Macrophages M1, and T cells CD4 memory resting. Our results demonstrate that the pathomics model exhibits predictability for CD40LG expression and GBM patient survival. These findings can be utilized to assist neurosurgeons in selecting optimal treatment strategies in clinical practice.

P13.01.A 11C-METHIONIN PET FOR RADIOTHERAPY TREATMENT PLANNING IN PATIENTS WITH RAPID EARLY PROGRESSION AFTER GLIOBLASTOMA SURGERY: PROSPECTIVE PHASE II TRIAL

Abstract BACKGROUND Radiotherapy (RT) is a standard treatment for nearly all glioblastoma patients following initial surgery. Few retrospective studies indicate negative prognostic instances of progression during the planning magnetic resonance (MR) (up to 1 week before initiating RT), termed Rapid Early Progression (REP). The optimal RT management for REP patients remains uncertain. The objective of this prospective phase II trial (NCT05608395) is to assess impact of 11C-Methionine PET used for RT planning in REP glioblastoma patients. It is one of the first prospective clinical interventional trials focused on this specific cohort of patients. MATERIAL AND METHODS We enrolled glioblastoma, IDHwt, or Astrocytoma, IDHmt, WHO grade IV patients, who developed REP characterized by 1) increase in postoperative residuum by ≥ 25%, 2) appearance of new contras enhancing lesion, 3) unequivocal progression of the unresected satelite. Patients received treatment based on the Stupp or Perry protocol. Treatment response was evaluated using RANO criteria. RT target volumes were delineated as follows: Gross tumor volume included tumor cavity, enhancing lesion and 11C-MET PET (1.3 tumor-to-background ratio). The clinical target volume was GTV plus a modified 2cm margin reflecting surrounding organs at risk. Volumetric analyses of different radiotherapy target volume were performed using EclipseTM software including patterns of failure. RESULTS During 12/2020 - 12/2023, total of 31 patients were enrolled (16 treated via abbreviated RT course); median age 60 years, ECOG 0-1 in 28 patients, median follow up 20 months. No effect of 11C-MET PET - based radiotherapy treatment planning of GBM patients with REP was observed on PFS (median 3.4 months comparing to 4.9 in historical control cohort) and OS (12.3 months comparing to 15.7 months). Median MET volume was 7.3cm3 (43% of MRI volume), MET avidity was presented in 7 patients et least 1cm beyond MRI volume. Central recurrence was presented in 87% patients. CONCLUSION The optimal treatment of patients with REP is unknown and needs to be studied in more details including dose escalation studies with reduced target margins potentialy directed also by aminoacid PET examination. Adjustment of target radiotherapy volumes using 11C-MET PET did not lead to improved PFS or OS. Supported by NU20-03-00148.

Longikaurin A induces ferroptosis and inhibits glioblastoma progression through DNA methylation - mediated GPX4 suppression.

Glioblastoma (GBM) is the most common primary intracranial tumor highly resistant to conventional clinical chemotherapy. Recently, the induction of ferroptosis is emerging as a putative strategy to treat various tumors. However, the identification of the effective and applicable tumor ferroptosis-inducing agents remains challenging. In this study, we showed that longikaurin A (LK-A), a natural diterpenoid isolated from the medicinal plant Isodon ternifolius with strong anti-GBM capacities, induced remarkable GBM cell ferroptosis along with suppressing the key anti-ferroptosis factor glutathione peroxidase 4 (GPX4). GPX4 promoter contains conserved CpG islands. The LK-A-induced GPX4 suppression coincided with the inhibition of ten-eleven translocation 2 (TET2), a key DNA demethylation enzyme and an increase in the hypermethylation of the GPX4 promoter. Further, LK-A promoted the GBM ferroptotic alterations and inhibited GBM progression in both subcutaneous and orthotopic xenograft mouse models, whereas GPX4 overexpression largely abrogated its anti-GBM effects both in vitro and in vivo, suggesting that LK-A inductions of the DNA methylation-incurred GPX4 suppression and ferroptosis are crucial for its anti-GBM functions. Together, our study has elaborated an important epigenetic pathway of GBM ferroptosis and uncovered a critical pharmacological property of LK-A for treating GBM patients.

The effect of immunonutrition support on the prognostic nutritional index in the postoperative period in brain tumors

Objective: The prognostic nutritional index (PNI) reflects the immunological response and nutritional status. We evaluated the effect of immunonutrition on PNI in patients with brain tumors receiving chemoradiotherapy and immunonutritional support. Methods: Demographic, laboratory and clinical data were collected retrospectively from 30 consecutive brain tumor patients who received brain chemoradiotherapy between 2019 and 2022 in our clinic and who were given immunonutrition support during their treatment. The cut-off PNI value before adjuvant therapy was calculated in patients who received immunonutrition support in the postoperative period and compared with the PNI values after adjuvant therapy. Results: While glioblastoma patients constitute the majority (60%) of all patients diagnosed as pathological, different histopathological brain tumors were also included in the study (meningioma, oligodendroglioma). The mean albümin value before adjuvant treatment was 4.04 g/dL, while the mean albümin value after adjuvant treatment increased to 4.16 g/dL (p=0,057). The optimal cut-off value for PNI was found to be 45.5 by ROC analysis. PNI was calculated as 49.38 ± 6.03 SD before adjuvant treatment and 49.40 ± 6.12 SD after adjuvant treatment (p&gt;0.05). Retrospective analysis was conducted on over 30 HGG patients who did not receive immunonutritional supplementation containing Arg/gln/HMB (Arginine/glutamine/Beta-Hydroxy Beta-Methylbutyrate). Interestingly, the analysis revealed that the average PNI was 45.15 before adjuvant therapy and decreased to 42.26 after adjuvant therapy, indicating a statistically significant decline in PNI among those without immunonutritional supplementation. This finding suggests a potential beneficial impact of immunonutritional supplementation on PNI. Conclusions: Immunonutrition support has positive effects on PNI and albumin levels in brain tumor patients who will undergo postoperative radiotherapy/chemoradiotherapy. It can be thought that low PNI, which may be an indicator of hematological and nutritional toxicity predicted by brain chemoradiotherapy, can be prevented by immunonutrition support.

Assessment of anti-CD69 antibody therapy alone or in combination with anti-PD-1 in murine GBM

ABSTRACT Background Glioblastoma (GBM) is an aggressive cancer with limited treatment options. Immunotherapy targeting CD69, an early activation marker on T cells, has shown promise in preclinical models of non-CNS malignancies. This study investigates anti-CD69 therapy alone or in combination with anti-PD-1 in a preclinical GBM model. Research design and methods CD69 expression in GBM patient tissues was analyzed using the TCGA database. Therapeutic efficacy of anti-CD69 was tested in a murine GBM model with different regimens. Immune cell populations in the tumor microenvironment (TME) were assessed by flow cytometry. Results Increased CD69 expression was observed in GBM patients compared to normal brain tissue and was associated with worse prognosis. Anti-CD69 treatment reduced percentages of CD69+ immune cells but did not improve survival in GBM-bearing mice. Increased PD-1 expression on NK cells was observed following anti-CD69 treatment. Anti-CD69 treatment was not improved by the addition of anti-PD-1 in vivo. Conclusions This is the first study evaluating anti-CD69 therapy in a preclinical GBM model. Despite promising preclinical data in other cancers, anti-CD69 monotherapy or combination therapy with anti-PD-1 did not improve survival in this GBM model.

Financial toxicity in patients with glioblastoma.

There has been mounting interest in understanding the impact of financial toxicity (FT) in various cancer types; however, it remains poorly understood and understudied within neuro-oncology-especially as it relates to neurosurgical components of patient care. Retrospective, single-center study of patients who underwent craniotomy for resection of glioblastoma from 2020 to 2022. OIBEE™ (Austin, Texas) software was queried to identify the subset of these patients who had a bad debt charged to their account. These patients were deemed to qualify as experiencing FT. Chi Square analysis was conducted between FT and non-FT patient groups. Additionally, survival analyses were performed to determine predictors of progression free and overall survival. 74 patients were included in this sample. 33/74 (44%) met criteria for FT. The average bad debt amount was $7,476.76 and the median debt amount was $2,015.96, with the average time to financial toxicity after surgery being approximately 127 days. FT patients were significantly younger at diagnosis than those who were not FT (64.6 years- non-FT vs. 59.0 years- FT, p = 0.0344). FT patients were more likely to have undergone subtotal resections rather than a gross total resection compared to non-FT patients (FT GTR 27.3%, non-FT GTR 52.4%, p = 0.028). Hospital length of stay was significantly longer for FT patients compared to non-FT patients (LOS FT 9.5 days, non-FT 6.5 days, p = 0.0312). Glioblastoma patients are at high risk of experiencing FT with our series showing no significant impact on overall survival. Larger studies are needed to understand the impact of FT on patient outcomes.

PROLONGED SURVIVAL IN IDH-WILDTYPE GLIOBLASTOMA: CASE REPORTS, LITERATURE REVIEW AND CURRENT PERSPECTIVES OF MOLECULAR BEHAVIOR

Abstract AIMS Glioblastoma remains one of the most aggressive primary brain tumours, with a median survival of around 12 months despite advances in treatment. However, rare cases of long-term survival challenge this prognosis. The evaluation of age, tumour location, surgical approach and strategies, adjuvant therapy, and molecular behavior provides valuable prognostic and predictive information in patients with glioblastoma. METHOD We present a case report of two patients diagnosed with wild-type glioblastoma who have survived over 10 years post-primary surgery. A review of epidemiological data, preoperative and postoperative radiological reports, surgical approach, and histology reports were studied. Additionally, we review the current literature to explore current nuances in High-Grade Glioma Wild Type prognosis and potential future directions. Three major medical database engines, PubMed (Medline), Scopus (ELSEVIER), and Cochrane were used to conduct a thorough literature search. RESULTS Both patients underwent maximal safe resection followed by the Stupp Protocol, comprising adjuvant chemotherapy with temozolomide and radiotherapy. Our case report highlights two exceptional cases of prolonged survival in Glioblastoma patients, both under 51 years-old at the moment of diagnosis, early diagnosis with isolated lobar lesions, no compromise of deep white matter, and achieving maximal safe resection and functional independence. Molecular analysis revealed specific genetic in common, including IDH Wild Type, p53 mutation, retained ATRX expression, TERT mutation, and MGMT promoter methylation, consistent with a favourable prognosis. Moreover, patients without recurrence often exhibit distinct molecular profiles, such as MGMT promoter methylation, suggesting a potential subtype associated with prolonged survival. CONCLUSION Our case reports and literature review highlight the possibility of prolonged survival in Glioblastoma patients. The age, tumor location at the time of diagnosis, comprehensive treatment approaches, may contribute to improved outcomes. Molecular profiling, particularly assessing genetic mutations and MGMT promoter methylation, holds promise for identifying patients with a higher likelihood of prolonged survival.

GLIOBLASTOMA IN THE UK POST WHO CNS 5: INITIAL fiNDINGS FROM THE HISTO-MOL GBM COLLABORATIVE

Abstract AIMS The 2021 World Health Organisation Classification (WHO CNS5) incorporated molecular diagnostic features for glioblastoma for the first time. The Histo-Mol GBM collaborative is conducting a retrospective cohort study evaluating the outcomes of patients prospectively diagnosed with WHO CNS5 IDH wild type glioblastoma. METHOD Biopsy confirmed glioblastoma patients diagnosed between 01/01-31/12/2021 were identified. Demographic, tumour, treatment, and survival data were collected. Descriptive statistics and Kaplan-Meier method were used to describe the cohort and for survival analysis respectively, assessed from surgery date. RESULTS So far, 363 glioblastoma patients were included from 13 centres (range: 11-61 patients/centre). Median age was 63.0, 65.8% were male, 77.4% had an ECOG performance status of 0-1 at diagnosis, and 28/333 had a molecular glioblastoma (8.4%). Biopsy was performed in 106/363 patients (29.2%), and gross total resection in 50/363 (13.8%). Adjuvant radiotherapy was performed in 290/363 (79.9%), and 71/290 (24.5%) had an additional pre-radiotherapy MRI with rapid early progression identified in 30/71 patients (42.3%). 128/269 (47.6%) patients received 2nd line treatment; most commonly systemic therapy (91/128, 71.1%) followed by re-resection (27/128, 21.1%). Second line systemic therapy was primarily lomustine (48/81, 52.7%). Median progression free survival was 7.7 months and median overall survival (OS) was 11.6 months. Median OS was 16.9 months with conventional fractionation chemoradiotherapy (n=169/363, 46.6%), 10.4 months with hypofractionated chemoradiotherapy (n=64/363, 17.6%), and 2.3 months with no oncological treatment (n=57/363, 15.7%). On univariate analysis age, gender, performance status, multifocality, MGMT promoter methylation, surgery extent, radiotherapy type (none, palliative, hypofractionated, conventional fractionation), larger planning target volume (PTV), receiving concurrent temozolomide, and receiving adjuvant temozolomide were statistically significant. On multivariate analysis age, and receiving concurrent temozolomide remained significant. CONCLUSION We describe the initial findings from a large real-world cohort of glioblastoma patients prospectively diagnosed according to WHO CNS5. Survival compares favourably with the practice changing phase 3 clinical trial outcomes.

MANAGEMENT OF THE OLDER PATIENT WITH GLIOBLASTOMA IN THE UK: AN INITIAL REPORT FROM THE HISTO-MOL GBM COLLABORATIVE

Abstract AIMS The management of older (&amp;gt;70 years old) patients with glioblastoma is challenging with significant variation in practice. Using the Histo-Mol GBM database we analysed the variation in practice across 11 UK centres. METHOD Biopsy confirmed glioblastoma patients diagnosed between 01/01-31/12/2021 were identified. Descriptive statistics were used to compare demographic, tumour and treatment characteristics, and the Kaplan-Meier method was used to analyse survival, assessed from surgery date. Differences in treatment between centres were assessed using one way ANOVA. RESULTS In 2021, 81/330 (24.5%) patients with glioblastoma were &amp;gt;70. Compared to younger patients, the older cohort had a greater proportion of males (79.0% vs 59.0%, p&amp;lt;0.001), a worse performance status (66.7% vs 79.5% ECOG PS 0-1, p&amp;lt;0.001), and more likely to have MGMT promoter methylation (30.9% vs 22.9%, p=0.027). Most patients received biopsy only (31/81, 38.3%), followed by subtotal resection (85-94% tumour resection) (26/81, 32.1%), whilst 8/81 (9.9%) underwent debulking, 8/81 near-total resection (95-99% tumour resection), and 8/81 gross total resection, with statistically significant variation in resection extent between centres (p=0.031). Adjuvant radiotherapy was used in 56/81 patients (69.1%) with no difference between centres (p=0.220). However, there was a statistically significant difference in radiotherapy regime between centres (p=0.041). 6/81 (7.4%) received conventional chemoradiotherapy, 28/81 (34.6%) hypofractionated chemoradiotherapy, 16/81 (19.8%) hypofractionated radiotherapy alone, 2/81 (2.5%) temozolomide alone both with MGMT promoter methylation, and 21/81 (25.9%) received no oncological treatment. Median progression free survival was 5.9 months and median overall survival (OS) was 7.1 months with no difference between centres (p=0.199 and p=0.083 respectively). Median OS was 8.4 months with conventional fractionation chemoradiotherapy, 11.2 months with hypofractionated chemoradiotherapy, 7.3 months with hypofractionated radiotherapy alone, 1.8 months with temozolomide alone, and 2.5 months with no oncological treatment. CONCLUSION We identify variations in the treatment of elderly glioblastoma patients across the UK, although these do not significantly impact survival.