IDH-wildtype Glioblastoma Patients Research Articles

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.

MGMT METHYLATION AND ITS PROGNOSTIC SIGNIfiCANCE IN INOPERABLE IDH WILDTYPE GLIOBLASTOMA: A SIX-YEAR REVIEW AT A TERTIARY NEURO-ONCOLOGY CENTER

Abstract AIMS IDH wild-type glioblastoma has the worst prognosis among glioma patients. The methylation of the O6- Methylguanine-DNA Methyltransferase (MGMT) gene is a valid biomarker for predicting response to therapy with alkylating agents and, independently, prognosis. Patients undergoing biopsy only without subsequent treatment have poor prognosis. We aimed to study the survival impact of MGMT methylation in this subset of patients. METHOD We collected six-year retrospective (2017-2023) data at a tertiary neuro-oncology center for patients undergoing biopsy as the only surgical procedure for an unresectable IDH wildtype glioblastoma. Data was collected from patient records including neuro-oncology MDT documentation. Patients were grouped into four categories according to different types of treatment received after biopsy (biopsy only, Biopsy + chemotherapy(CT), biopsy + radiotherapy(RT), biopsy + complete/incomplete STUPP, biopsy + STUPP + 2nd Line). Analysis was performed in python and R statistical software. Survival analysis was performed with Kaplan-Meier Analysis in python. RESULTS 166 glioblastoma IDH wildtype patients were included in the study with mean age of 62.5 years (M: F = 1.5: 1). 50% (n=83) patients had unmethylated MGMT status (0-5%), 29.5% (n=49) patients had methylated MGMT status (&amp;gt;15%) and 19.2% (n=32) patients had borderline methylated MGMT status (5-15%). 21%(n=35) patients did not receive any treatment post biopsy,, 6.6% (n=11) received CT only, 15% (n=25) RT only, 27% (n= 45) complete/incomplete STUPP therapy, whereas 13.2% (n=22) received STUPP therapy along with second line treatment. In biopsy only group, there was no notable difference in survival outcomes among the different methylation statuses. For biopsy and any-other-form-of-treatment groups showed a distinct trend of better survival compared to the borderline or unmethylated groups. Overall, methylated patients had better survival as compared to unmethylated or borderline groups. CONCLUSION Methylated MGMT status is a predictor for better overall survival in unresectable IDH wildtype glioblastoma patients undergoing biopsy and treatment.

MGMT methylation and its prognostic significance in inoperable IDH-wildtype glioblastoma: the MGMT-GBM study

IntroductionThe methylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) promoter is a valid biomarker for predicting response to therapy with alkylating agents and, independently, prognosis in IDH-wildtype(IDH-w) glioblastoma. We aim to study the impact of its methylation in overall survival of the unresectable IDH-w glioblastoma undergoing biopsy and systemic treatment.MethodsWe collected six-year retrospective (2017–2023) data at a quaternary neurosurgery center for patients undergoing biopsy as the only surgical procedure for an unresectable IDH wildtype glioblastoma. Data was collected from patient records including neuro-oncology multidisciplinary team meeting (MDT) documentation. Patients were grouped into categories according to different types of treatment received after biopsy (no treatment, chemotherapy (CT), radiotherapy (RT), chemoradiotherapy (CRT), chemoradiotherapy with adjuvant temozolomide (CRT with adjuvant TMZ), EORTC-NCIC protocol followed by second line treatment) and according to methylation status (unmethylated (< 5%), borderline methylated (5–15%) and strongly methylated (> 15%)). Survival analysis was performed.Results166 glioblastoma IDH wildtype patients were included in the study with mean age of 62.5 years (M: F = 1.5: 1). 70 (49.3%) patients had unmethylated MGMT status (< 5%), 29 (20.4%) patients had borderline methylated MGMT status (5–15%) and 43 (30.2%) patients had methylated MGMT status (> 15%). 36 (25.3%) patients did not receive any treatment post biopsy, 13 (9.1%) received CT only, 27 (19%) RT only, 12 (8.4%) CRT, 33 (23.2%) CRT with adjuvant TMZ, whereas 21 (14.7%) received EORTC-NCIC protocol along with second line treatment.In biopsy only group, there was no notable difference in survival outcomes among the different methylation statuses. For biopsy and any-other-form-of-treatment methylated groups showed a distinct trend of better survival compared to the borderline or unmethylated groups. Overall, methylated patients had better survival as compared to unmethylated or borderline groups.ConclusionMethylated MGMT status are predictors for better overall survival in unresectable IDH wildtype glioblastoma patients undergoing biopsy and treatment regardless of the treatment modality.

Revisiting gliomatosis cerebri in adult-type diffuse gliomas: a comprehensive imaging, genomic and clinical analysis

Although gliomatosis cerebri (GC) has been removed as an independent tumor type from the WHO classification, its extensive infiltrative pattern may harbor a unique biological behavior. However, the clinical implication of GC in the context of the 2021 WHO classification is yet to be unveiled. This study investigated the incidence, clinicopathologic and imaging correlations, and prognostic implications of GC in adult-type diffuse glioma patients. Retrospective chart and imaging review of 1,211 adult-type diffuse glioma patients from a single institution between 2005 and 2021 was performed. Among 1,211 adult-type diffuse glioma patients, there were 99 (8.2%) patients with GC. The proportion of molecular types significantly differed between patients with and without GC (P = 0.017); IDH-wildtype glioblastoma was more common (77.8% vs. 66.5%), while IDH-mutant astrocytoma (16.2% vs. 16.9%) and oligodendroglioma (6.1% vs. 16.5%) were less common in patients with GC than in those without GC. The presence of contrast enhancement, necrosis, cystic change, hemorrhage, and GC type 2 were independent risk factors for predicting IDH mutation status in GC patients. GC remained as an independent prognostic factor (HR = 1.25, P = 0.031) in IDH-wildtype glioblastoma patients on multivariable analysis, along with clinical, molecular, and surgical factors. Overall, our data suggests that although no longer included as a distinct pathological entity in the WHO classification, recognition of GC may be crucial considering its clinical significance. There is a relatively high incidence of GC in adult-type diffuse gliomas, with different proportion according to molecular types between patients with and without GC. Imaging may preoperatively predict the molecular type in GC patients and may assist clinical decision-making. The prognostic role of GC promotes its recognition in clinical settings.

AB023. Early diagnosis and treatment lead to improve survival of glioblastoma patients.

Glioblastoma (GBM) is one of the worst prognostic cancers and one of the reasons is that GBM patients rapidly deteriorated and half of them had a Karnofsky performance status (KPS) with 70 or less at the initial presentation. We discuss the significance of early diagnosis and treatment to the clinical outcomes of GBM patients. Data of IDH-wildtype GBM patients treated at our institution between 2010 and 2019 were retrospectively reviewed. Patients were classified into early or late diagnosis groups with a threshold of 14 days from initial symptoms. Also, patients were divided into early, intermediate, and late surgery groups with thresholds of 21 and 35 days. Patients were also divided into two groups: neurosurgeon and non-neurosurgeon groups, based on the primary doctor whom patients sought for an initial evaluation. Representative symptoms and patient prognosis were examined. Of 153 patients, 72 and 81 were classified into the early and late diagnosis groups. The proportion of patients with preoperative KPS scores ≥90 was 48.6% and 29.6% in the early and late diagnosis groups (P=0.01). Median overall survival was significantly longer in the early surgery group (n=43) than in the late surgery group (n=86) (28.4 vs. 18.7 months, P=0.006). The neurosurgeon group exhibited a significantly shorter duration from the first hospital visit to the first surgery than the non-neurosurgeon group (18 vs. 29 days, P<0.001). Furthermore, the overall survival of the neurosurgeon group was significantly more prolonged than that of the non-neurosurgeon group (22.9 vs. 14.0 months, P=0.04). Early diagnosis and surgery within 3 weeks from the initial symptoms are associated with improved patient survival. Early GBM treatment will be beneficial for patients with GBM. A short duration from the first hospital visit to the first surgery is essential in enhancing GBM patient prognosis.

Prediction of O(6)-methylguanine-DNA methyltransferase promoter methylation status in IDH-wildtype glioblastoma using MRI histogram analysis.

To evaluate the utility of magnetic resonance imaging (MRI) histogram parameters in predicting O(6)-methylguanine-DNA methyltransferase promoter (pMGMT) methylation status in IDH-wildtype glioblastoma (GBM). From November 2021 to July 2023, forty-six IDH-wildtype GBM patients with known pMGMT methylation status (25 unmethylated and 21 methylated) were enrolled in this retrospective study. Conventional MRI signs (including location, across the midline, margin, necrosis/cystic changes, hemorrhage, and enhancement pattern) were assessed and recorded. Histogram parameters were extracted and calculated by Firevoxel software based on contrast-enhanced T1-weighted images (CET1). Differences and diagnostic performance of conventional MRI signs and histogram parameters between the pMGMT-unmethylated and pMGMT-methylated groups were analyzed and compared. No differences were observed in the conventional MRI signs between pMGMT-unmethylated and pMGMT-methylated groups (all p > 0.05). Compared with the pMGMT-methylated group, pMGMT-unmethylated showed a higher minimum, mean, Perc.01, Perc.05, Perc.10, Perc.25, Perc.50, and coefficient of variation (CV) (all p < 0.05). Among all significant CET1 histogram parameters, minimum achieved the best distinguishing performance, with an area under the curve of 0.836. CET1 histogram parameters could provide additional value in predicting pMGMT methylation status in patients with IDH-wildtype GBM, with minimum being the most promising parameter.

Ki67 Index Correlates with Tumoral Volumetry and 5-ALA Residual Fluorescence in Glioblastoma

BackgroundMalignant gliomas are the most prevalent primary malignant cerebral tumors. Preoperative imaging plays an important role, and the prognosis is closely related to surgical resection and histomolecular aspects. Our goal was to correlate Ki67 indexes with tumoral volumetry in semiautomatic segmentation on preoperative magnetic resonance images and residual fluorescence in a 5-ALA-assisted resection cohort. MethodsWe included eighty-six IDH-wildtype glioblastoma patients with complete preoperative imaging submitted to 5-ALA assisted resections. Clinical, surgical, and histomolecular findings were also obtained. Preoperative magnetic resonance studies were preprocessed and segmented semiautomatically on VISVA for whole tumor (WT) on 3D FLAIR, enhancing tumor (ET), and necrotic core (NC) on 3D post-gadolinium T1. We performed a linear regression analysis for Ki67 and a multivariate analysis for surgical outcomes. ResultsHigher Ki-67 indexes correlated positively with higher WT (p = 0.048) ET (p = 0.002). Lower Ki67 correlated with 5-ALA free margins (p = 0.045). WT and ET volumes correlated with the extent of resection (EOR; p = 0.002 and 0.002, respectively). Eloquence did not impact EOR (p = 0.14). ConclusionsThere is a correlation between Ki67, the metabolically active tumoral volumes (WT and ET), and 5-ALA residual fluorescence. Methodological inconsistencies are probably responsible for contradictory literature findings, and further prospective studies are needed to validate and reproduce these findings.

Racial/ethnic disparities in healthcare utilization, post-operative outcomes, and overall survival for IDH-wildtype glioblastoma stratifying by MGMT promoter methylation status.

2081 Background: Glioblastoma is the most common malignant primary brain tumor and molecular profiles such as IDH1/2 and MGMT promoter methylation status have significant influence on survival outcomes. There is no "real-world" study has investigated the racial/ethnic disparities in healthcare utilization and outcomes for IDH-wildtype glioblastoma patients with MGMT promoter methylation status. Methods: A total of 21971 IDH-wildtype glioblastoma patients ( MGMT promoter-methylated: 41.5%, 9110/21971) were derived from the National Cancer Database (NCDB, 2018-2021). Race/Ethnicity was grouped into Non-Hispanic White (NHW), Non-Hispanic Black (NHB), Asian/Pacific Islander (API), American Indian/Alaska Native (AIAN), Hispanic, and Others. Overall survival (OS) was set as primary outcome. Healthcare utilization and post-operative outcomes are secondary endpoints. Multivariable logistic regression models, Kaplan-Meier methods, and Cox proportional hazards models were performed for post-operative outcomes, healthcare utilization, and overall survival. Results: Compared to NHW, AIAN were 78% more likely to have MGMT promoter methylation after adjusting age and gender (aOR=1.78, p=0.030). API and Hispanic were significantly less likely to undergo GTR over STR comparing to NHW. The odds of receiving chemotherapy and RT for race/ethnicity minorities patients were significantly lower than NHW (Chemotherapy: NHB: aOR=0.79, AIAN: aOR=0.57, Hispanic: aOR=0.83; RT: NHB: aOR=0.88, Hispanic: aOR=0.80). The median OSs by race/ethnicity (NHW, NHB, API, AIAN, Hispanic, and Others, respectively) were: 11.5, 12.3, 14.5, 9.2, 13.6, and 15.6, months ( MGMT promoter-unmethylated, p&lt;0.001), 15.9, 18.8, 23.7, 14.8, 19.6, and 15.5, months ( MGMT promoter-methylated, p&lt;0.001). After adjusting the covariates, NHB, API, and Hispanic experienced significantly lower risk of death comparing to NHW (aHR=0.82, 0.66, and 0.75, all p&lt;0.001). Similar results were validated in stratification analysis by MGMT promoter methylation status, except MGMT promoter-unmethylated AIAN experienced 70% higher risk of death than NHW (aHR=1.70, p=0.021). Conclusions: Our findings suggests that racial/ethnic disparities exist in healthcare utilization, postoperative outcomes, and overall survival in IDH-wildtype glioblastoma population.

Can targeting TSP-1 with gabapentin enhance survival in glioblastoma? A 20-year retrospective cohort study.

2048 Background: Molecularly-defined cellular subpopulations of glioblastoma secrete high levels of the synaptogenic protein thrombospondin-1 (TSP-1) which promotes functional integration of tumor into neural circuity. A greater extent of glioma-neuronal crosstalk portends worse survival for patients. In preclinical studies, gabapentin was shown to inhibit TSP-1, in turn disrupting neuronal synaptogenesis and neuronal activity-dependent glioblastoma proliferation; however, clinical survival data is lacking. We aim to determine whether treatment with gabapentin is associated with improved survival and reduced serum TSP-1 in a retrospective cohort of patients with IDH-wildtype glioblastoma. Methods: Newly-diagnosed, IDH-wildtype glioblastoma patients who received care at the UCSF Brain Tumor Center between 1997-2017 were included in this study. Kaplan-Meier curves and multivariate Cox proportional-hazards models, controlled for age, MGMT promoter methylation status, preoperative tumor volume, and extent of resection, were used for survival analyses. Differences in serum TSP-1 measured by ELISA for gabapentin treated patients and matched non-gabapentin treated controls were assessed using unpaired two-tailed student’s t-test. Control samples were matched 2:1 by age, tumor volume, and extent of resection. After 2005, patients were treated with chemoradiation with concurrent and adjuvant temodar. Results: Among 379 adult patients with glioblastoma, 36 (9.5%) were treated with gabapentin. The median daily dose of gabapentin was 600 mg (IQR: 300-900 mg). There were no significant differences between gabapentin treated and non-gabapentin treated patients by age (0.06), sex (p=0.14), or race (p=0.52). Median overall survival for gabapentin treated and non-gabapentin treated patients was 20.8 months (IQR: 11.7 - 32.1) and 14.7 months (IQR: 8.9-23.5), respectively (p= 0.02). On Kaplan-Meier survival analysis, overall survival was longer for gabapentin treated patients compared with non-gabapentin treated patients (p=0.005). In the multivariate Cox proportional-hazards model, gabapentin use was associated with decreased hazard of death (HR 0.67, p=0.030). Mean serum TSP-1 in gabapentin-treated patients was significantly lower than in the matched control group (10181 ng/ml vs 17015 ng/ml, p=0.017). Conclusions: Gabapentin use is associated with a survival benefit for patients with glioblastoma, possibly mediated through a reduction in TSP-1. This promising result lays the foundation for future prospective studies to further evaluate TSP-1 as a circulating prognostic biomarker as well as to explore the therapeutic benefits of gabapentin as a life-prolonging treatment for patients with newly diagnosed glioblastoma.

Proteomics of tumor and serum samples from isocitrate dehydrogenase-wildtype glioblastoma patients: is the detoxification of reactive oxygen species associated with shorter survival?

Proteomics has been little used for the identification of novel prognostic and/or therapeutic markers in isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GB). In this study, we analyzed 50 tumor and 30 serum samples from short- and long-term survivors of IDH-wildtype GB (STS and LTS, respectively) by data-independent acquisition mass spectrometry (DIA-MS)-based proteomics, with the aim of identifying such markers. DIA-MS identified 5422 and 826 normalized proteins in tumor and serum samples, respectively, with only three tumor proteins and 26 serum proteins displaying significant differential expression between the STS and LTS groups. These dysregulated proteins were principally associated with the detoxification of reactive oxygen species (ROS). In particular, GB patients in the STS group had high serum levels of malate dehydrogenase 1 (MDH1) and ribonuclease inhibitor 1 (RNH1) and low tumor levels of fatty acid-binding protein 7 (FABP7), which may have enabled them to maintain low ROS levels, counteracting the effects of the first-line treatment with radiotherapy plus concomitant and adjuvant temozolomide. A blood score built on the levels of MDH1 and RNH1 expression was found to be an independent prognostic factor for survival based on the serum proteome data for a cohort of 96 IDH-wildtype GB patients. This study highlights the utility of circulating MDH1 and RNH1 biomarkers for determining the prognosis of patients with IDH-wildtype GB. Furthermore, the pathways driven by these biomarkers, and the tumor FABP7 pathway, may constitute promising therapeutic targets for blocking ROS detoxification to overcome resistance to chemoradiotherapy in potential GB STS.

Evaluation of the clinical use of MGMT methylation in extracellular vesicle-based liquid biopsy as a tool for glioblastoma patient management

Glioblastoma (GB) is a devastating tumor of the central nervous system characterized by a poor prognosis. One of the best-established predictive biomarker in IDH-wildtype GB is O6-methylguanine-DNA methyltransferase (MGMT) methylation (mMGMT), which is associated with improved treatment response and survival. However, current efforts to monitor GB patients through mMGMT detection have proven unsuccessful. Small extracellular vesicles (sEVs) hold potential as a key element that could revolutionize clinical practice by offering new possibilities for liquid biopsy. This study aimed to determine the utility of sEV-based liquid biopsy as a predictive biomarker and disease monitoring tool in patients with IDH-wildtype GB. Our findings show consistent results with tissue-based analysis, achieving a remarkable sensitivity of 85.7% for detecting mMGMT in liquid biopsy, the highest reported to date. Moreover, we suggested that liquid biopsy assessment of sEV-DNA could be a powerful tool for monitoring disease progression in IDH-wildtype GB patients. This study highlights the critical significance of overcoming molecular underdetection, which can lead to missed treatment opportunities and misdiagnoses, possibly resulting in ineffective therapies. The outcomes of our research significantly contribute to the field of sEV-DNA-based liquid biopsy, providing valuable insights into tumor tissue heterogeneity and establishing it as a promising tool for detecting GB biomarkers. These results have substantial implications for advancing predictive and therapeutic approaches in the context of GB and warrant further exploration and validation in clinical settings.

Revisiting prognostic factors of gliomatosis cerebri in adult-type diffuse gliomas.

There is lack of comprehensive analysis evaluating the impact of clinical, molecular, imaging, and surgical data on survival of patients with gliomatosis cerebri (GC). This study aimed to investigate prognostic factors of GC in adult-type diffuse glioma patients. Retrospective chart and imaging review was performed in 99 GC patients from adult-type diffuse glioma (among 1,211 patients; 6 oligodendroglioma, 16 IDH-mutant astrocytoma, and 77 IDH-wildtype glioblastoma) from a single institution between 2005 and 2021. Predictors of overall survival (OS) of entire patients and IDH-wildtype glioblastoma patients were determined. The median OS was 16.7months (95% confidence interval [CI] 14.2-22.2) in entire patients and 14.3months (95% CI 12.2-61.9) in IDH-wildtype glioblastoma patients. In entire patients, KPS (hazard ratio [HR] = 0.98, P = 0.004), no 1p/19q codeletion (HR = 10.75, P = 0.019), MGMTp methylation (HR = 0.54, P = 0.028), and hemorrhage (HR = 3.45, P = 0.001) were independent prognostic factors on multivariable analysis. In IDH-wildtype glioblastoma patients, KPS (HR = 2.24, P = 0.075) was the only independent prognostic factor on multivariable analysis. In subgroup of IDH-wildtype glioblastoma with CE tumors, total resection of CE tumor did not remain as a significant prognostic factor (HR = 1.13, P = 0.685). The prognosis of GC patients is determined by its underlying molecular type and patient performance status. Compared with diffuse glioma without GC, aggressive surgery of CE tumor in GC patients does not improve survival.

CDPNet: a radiomic feature learning method with epigenetic application to estimating MGMT promoter methylation status in glioblastoma.

Radiomics has been widely recognized for its effectiveness in decoding tumor phenotypes through the extraction of quantitative imaging features. However, the robustness of radiomic methods to estimate clinically relevant biomarkers non-invasively remains largely untested. In this study, we propose Cascaded Data Processing Network (CDPNet), a radiomic feature learning method to predict tumor molecular status from medical images. We apply CDPNet to an epigenetic case, specifically targeting the estimation of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation from Magnetic Resonance Imaging (MRI) scans of glioblastoma patients. CDPNet has three components: 1) Principal Component Analysis (PCA), 2) Fisher Linear Discriminant (FLD), and 3) a combination of hashing and blockwise histograms. The outlined architectural framework capitalizes on PCA to reconstruct input image patches, followed by FLD to extract discriminative filter banks, and finally using binary hashing and blockwise histogram module for indexing, pooling, and feature generation. To validate the effectiveness of CDPNet, we conducted an exhaustive evaluation on a comprehensive retrospective cohort comprising 484 IDH-wildtype glioblastoma patients with pre-operative multi-parametric MRI scans (T1, T1-Gd, T2, and T2-FLAIR). The prediction of MGMT promoter methylation status was cast as a binary classification problem. The developed model underwent rigorous training via 10-fold cross-validation on a discovery cohort of 446 patients. Subsequently, the model's performance was evaluated on a distinct and previously unseen replication cohort of 38 patients. Our method achieved an accuracy of 70.11% and an area under the curve of 0.71 (95% CI: 0.65 - 0.74).

Integrating imaging and genomic data for the discovery of distinct glioblastoma subtypes: a joint learning approach

Glioblastoma is a highly heterogeneous disease, with variations observed at both phenotypical and molecular levels. Personalized therapies would be facilitated by non-invasive in vivo approaches for characterizing this heterogeneity. In this study, we developed unsupervised joint machine learning between radiomic and genomic data, thereby identifying distinct glioblastoma subtypes. A retrospective cohort of 571 IDH-wildtype glioblastoma patients were included in the study, and pre-operative multi-parametric MRI scans and targeted next-generation sequencing (NGS) data were collected. L21-norm minimization was used to select a subset of 12 radiomic features from the MRI scans, and 13 key driver genes from the five main signal pathways most affected in glioblastoma were selected from the genomic data. Subtypes were identified using a joint learning approach called Anchor-based Partial Multi-modal Clustering on both radiomic and genomic modalities. Kaplan–Meier analysis identified three distinct glioblastoma subtypes: high-risk, medium-risk, and low-risk, based on overall survival outcome (p < 0.05, log-rank test; Hazard Ratio = 1.64, 95% CI 1.17–2.31, Cox proportional hazard model on high-risk and low-risk subtypes). The three subtypes displayed different phenotypical and molecular characteristics in terms of imaging histogram, co-occurrence of genes, and correlation between the two modalities. Our findings demonstrate the synergistic value of integrated radiomic signatures and molecular characteristics for glioblastoma subtyping. Joint learning on both modalities can aid in better understanding the molecular basis of phenotypical signatures of glioblastoma, and provide insights into the biological underpinnings of tumor formation and progression.

Spatially Resolved Microglia/Macrophages in Recurrent Glioblastomas Overexpress Fatty Acid Metabolism and Phagocytic Genes.

Glioblastoma (GBM) tumors are rich in tumor-associated microglia/macrophages. Changes associated with treatment in this specific cell population are poorly understood. Therefore, we studied changes in gene expression of tumor-associated microglia/macrophages (Iba1+) cells in de novo versus recurrent GBMs. NanoString GeoMx® Digital Spatial Transcriptomic Profiling of microglia/macrophages (Iba1+) and glial cells (Gfap+) cells identified on tumor sections was performed on paired de novo and recurrent samples obtained from three IDH-wildtype GBM patients. The impact of differentially expressed genes on patient survival was evaluated using publicly available data. Unsupervised analyses of the NanoString GeoMx® Digital Spatial Profiling data revealed clustering based on the transcriptomic data from Iba1+ and Gfap+ cells. As expected, conventional differential gene expression and enrichment analyses revealed upregulation of immune-function-related genes in Iba1+ cells compared to Gfap+ cells. A focused differential gene expression analysis revealed upregulation of phagocytosis and fatty acid/lipid metabolism genes in Iba1+ cells in recurrent GBM samples compared to de novo GBM samples. Importantly, of these genes, the lipid metabolism gene PLD3 consistently correlated with survival in multiple different publicly available datasets. Tumor-associated microglia/macrophages in recurrent GBM overexpress genes involved in fatty acid/lipid metabolism. Further investigation is needed to fully delineate the role of PLD phospholipases in GBM progression.

Assessment of Ki-67 expression levels in IDH-wildtype glioblastoma using logistic regression modelling of VASARI features.

To investigate the value of using VASARI signs preoperatively to assess Ki-67 proliferation index levels in patients with IDH-wildtype glioblastoma (GB).Pathological and imaging data of 154 patients with GB confirmed by surgical pathology were retrospectively analysed, and the level of Ki-67 proliferative index was assessed in tumour tissue samples from patients using immunohistochemistry (IHC) staining. Patients were divided into a high and low Ki-67 proliferation index expression group. Two radiologists analysed MRI images of patients with IDH-wildtype GB using the VASARI features system. VASARI parameters between the two groups were statistically analysed to identify characteristic parameters with significant differences and their predictive performance was determined using ROC curves.Among the obtained clinical and VASARI features of IDH-wildtype GB patients, the distribution of Maximum diameter, Proportion of necrosis and Hemorrhage was significantly different between the two groups (all p < 0.05). Multivariate logistic regression analysis showed that Maximum diameter and Hemorrhage were independent risk factors distinguishing the group with high and low expression of Ki-67 proliferative index. ROC curve analysis showed that the logistic regression model achieved an AUC value of 0.730 (95% CI: 0.639, 0.822), sensitivity of 0.628 and specificity of 0.756.Logistic regression modelling of preoperative VASARI features can be used as a reliable tool for predicting the level of Ki-67 proliferative index in IDH-wildtype GB patients, which can help in preoperative development of treatment and follow-up strategies for patients.

IDH1R132H mutation increases radiotherapy efficacy and a 4-gene radiotherapy-related signature of WHO grade 4 gliomas

The prognosis for the WHO grade 4 IDH-mutant astrocytoma is better than IDH-wildtype glioblastoma (GBM) patients. The purpose of this study is to explore the potential mechanism of how IDH1 mutation can increase the efficacy of radiotherapy and to establish a risk-score model to predict the efficacy of radiotherapy in WHO grade 4 gliomas. First, we conducted experimental study on the effect of IDH1R132H mutation on glioma cells in vitro. Radiosensitivity of glioma cells was detected by γ-H2AX after 5 Gy radiation. Cell proliferation, migration and invasion were determined respectively by CCK-8, EDU, monolayer cell migration scratch assay and Transwell assay. Then we analyzed IDH1 gene status and the survival of WHO grade 4 glioma patients received radiotherapy in our center and verified our results by analyzing CGGA and TCGA database. For the risk-score model, we use CGGA data to find genetic differences between WHO grade 4 IDH-mutant astrocytoma and IDH-wildtype GBM patients, and determined a 4-gene radiotherapy-related signature through survival analysis by R software. Evaluation and verification through different glioma validation sets and different statistical methods. For in vitro experiments, we established glioma cells stably overexpressing IDH1 wild-type and IDH1-mutant proteins. γ-H2AX assay showed that IDH1-mutant glioma cells had higher radiosensitivity than wild-type. CCK-8 and EDU assay showed that proliferation capacity of IDH1-mutant glioma cells declined. Transwell assay and monolayer cell migration scratch assay also showed that IDH1-mutant glioma cells reduced migration and invasion capabilities. Among the 83 WHO grade 4 glioma patients who received radiotherapy in our center, WHO grade 4 IDH-mutant astrocytoma patients had longer OS and PFS versus IDH-wildtype GBM (P = 0.0336, P = 0.0324, respectively). TCGA and CGGA database analysis had the similar results. Through complex analysis of CGGA and TCGA databases, we established a risk-model that can predict the efficacy of radiotherapy for WHO grade 4 glioma patients. The 4-gene radiotherapy-related signature including ADD3, GRHPR, RHBDL1 and SLC9A9. Patients in the high-risk group had worse OS compared to low-risk group (P = 0.0001). High- and low-risk groups of patients receiving radiotherapy have significant survival differences, while patients who did not receive radiotherapy have no survival difference both in CGGA and TCGA databases. WHO grade 4 IDH-mutant astrocytoma is more radiosensitive than IDH-wildtype GBM patients. Our 4-gene radiotherapy-related signature can predict the radiation efficacy of WHO grade 4 glioma patients, and it may provide some reference for clinical treatment options.

SURG-03. SURVIVAL STRATIFICATION OF IDH-WILDTYPE GLIOBLASTOMA IN THE MOLECULAR ERA: A RECURSIVE PARTITIONING ANALYSIS INCORPORATING EXTENT OF RESECTION OF CONTRAST-ENHANCING AND NON-ENHANCING TUMORS

Abstract METHODS This multicenter cohort study included a development cohort of 622 IDH-wildtype glioblastoma patients from a single institution (diagnosed between 2001 and 2021) and 445 patients as validation cohorts from two institutions. All patients completed radiotherapy plus concurrent temozolomide and had complete information on IDH mutation and MGMT promoter methylation status. EOR of CE and NE tumors were evaluated. A RPA analysis was performed on behalf of results of the Cox proportional hazards model. The RPA model was compared with a previous RTOG RPA model. RESULTS In the developmental cohort, older age (hazard ratio [HR] = 1.02, P &amp;lt; 0.001), MGMT methylation (HR = 0.51, P &amp;lt; 0.001), KPS (HR = 0.98, P &amp;lt; 0.001), and EOR of CE and NE tumors (GTR of CE tumor and non-GTR of NE tumor, HR = 1.82, P &amp;lt; 0.001; non-GTR of both CE and NE tumor, HR = 2.05, P &amp;lt; 0.001; reference group as GTR of both CE and NE tumor) were independent prognostic factors on multivariable analysis. The novel RPA consisting of age, MGMT methylation, KPS, and EOR of CE and NE tumors revealed greater separation of prognostic classes compared with the previous RTOG RPA model. The prognostic significance of the novel RPA model was subsequently confirmed in the validation cohorts. CONCLUSION The RPA model in IDH-wildtype glioblastoma patients incorporating EOR of CE and NE tumors is a valid model. This simple RPA model has the potential to contribute to improving the accurate assessment of prognostic groups in IDH-wildtype glioblastoma patients and to influence clinical decision-making.

NIMG-67. REVISITING GLIOMATOSIS CEREBRI IN ADULT-TYPE DIFFUSE GLIOMAS: A COMPREHENSIVE ANALYSIS OF MANIFESTATION AND RISK FACTORS IN THE 2021 WHO CLASSIFICATION

Abstract BACKGROUND To investigate the incidence, clinicopathologic and imaging correlations and prognostic implications of gliomatosis cerebri (GC) pattern in adult-type diffuse glioma patients reflecting the 2021 WHO classification. METHODS Retrospective chart and imaging review was performed in 1,211 adult-type diffuse glioma patients at a single institution between 2005 and 2021. Clinicopathologic and imaging features were compared amongst adult-type diffuse glioma patients with and without GC based on the 2021 WHO classification. Clinical and imaging risk factors for predicting IDH mutation status within GC patients were investigated. Survival analysis was performed in entire patients and in subgroup of IDH-wildtype glioblastoma patients to evaluate whether GC is an independent prognostic factor. RESULTS Total 99 patients (8.9% of entire patients) showed GC. The distribution of tumor type was significantly different in patients with GC compared with those without GC (P = 0.017); IDH-wildtype glioblastoma being most common (77.8% vs. 68.9%), followed by IDH-mutant astrocytoma (16.2% vs 16.9%), and being less common in oligodendroglioma (6.1% vs 16.5%). Contrast enhancement, necrosis, cystic change, hemorrhage, and GC type 2 were independent risk factors for predicting IDH mutation status in GC patients. GC remained as an independent prognostic factor (HR=1.55, P=0.031) in IDH-wildtype glioblastoma patients on multivariable analyses. CONCLUSIONS The incidence of GC is 8.9% in adult-type diffuse gliomas, with IDH-wildtype glioblastoma showing significantly higher risk of GC. Preoperative imaging features may predict IDH mutation status in GC patients. GC is an independent prognostic factor in IDH-wildtype glioblastoma, and promote recognition of this pattern in clinical settings.

NIMG-69. LEPTOMENINGEAL METASTASES IN IDH-WILDTYPE GLIOBLASTOMAS REVISITED: COMPREHENSIVE ANALYSIS OF INCIDENCE, RISK FACTORS, AND PROGNOSIS BASED ON POSTCONTRAST FLAIR IMAGING

Abstract BACKGROUND To comprehensively investigate the incidence, risk factors, and prognosis of leptomeningeal metastases (LM) in isocitrate dehydrogenase (IDH)-wildtype glioblastoma patients. METHODS Total 913 IDH-wildtype glioblastoma patients with complete molecular information on IDH mutation and MGMT promoter methylation status were enrolled between 2004 and 2022. LM diagnosis was performed with MRI including postcontrast FLAIR and CSF cytology. Logistic regression analysis for LM development at initial diagnosis and recurrence was performed with clinical, surgical, imaging, and molecular data. The overall survival (OS) was compared between patients with and without LM. RESULTS The incidence of LM was 21.8% (199 patients) among patients with IDH-wildtype glioblastoma, with 11.5% (105 patients) at initial diagnosis, and 10.3% (94 patients) at recurrence. Male sex (odds ratio [OR]: 1.74, P = 0.017), MGMT promoter unmethylation (OR: 1.48, P = 0.048), nonlobar location (OR: 2.27, P &amp;lt; 0.001), and presence of necrosis (OR: 3.64, P &amp;lt; 0.001) were independent predictors of LM at initial diagnosis, whereas ventricular opening during surgery (OR: 2.96, P &amp;lt; 0.001) was the only independent predictor of LM at recurrence. The median OS was 16.2 months (interquartile range [IQR]: 9.6-30.4) in patients with LM and 19.3 months (IQR: 12.1-38.5) in patients without LM (log-rank test; P = 0.001). CONCLUSION The incidence of LM is high in patients with IDH-wildtype glioblastoma. Aggressive clinical, imaging, and molecular factors are correlated with LM at initial diagnosis, whereas ventricular entry warrant imaging surveillance for LM at recurrence. The prognosis of LM is not discouraging as expected, and promote reconsideration of focused clinical trials.