IDH-wildtype Glioblastoma Research Articles

HGG-17. DECIPHERING GENETICS AND EPIGENETICS OF HIGH-GRADE GLIOMAS WITH BRAF ACTIVATING ALTERATION IS SUPPORTING THE DISCOVERY OF A NEW INTRACRANIAL SARCOMA-LIKE BRAF POSITIVE ENTITY

Abstract BACKGROUND The current WHO classification of Central Nervous System tumors recognizes several glioma types driven by the BRAFV600E mutation. These tumors mostly encompass pediatric low-grade gliomas. Nevertheless, a subset of them behaves as anaplastic gliomas and, currently, the unique predictive criterion linked to anaplasia is an elevated mitotic index (more than 2.5 mitoses/mm2). Histologically, the high-grade gliomas harboring BRAFV600E alteration mostly correspond to WHO grade 3 pleomorphic xanthoastrocytoma, IDH wild-type glioblastoma, entering the WHO grade 4 subset like the epithelioid subtype, and the rarer high-grade gliomas with piloïd features. These tumor types share their histomolecular features making differential diagnoses difficult. In this setting, DNA methylation profiling may be very useful to precise the integrative diagnosis. However, some of those high-grade forms failed in our experience to be classified in any methylation class with v11b4 version of the Heidelberg classifier. METHODS To understand the reasons explaining this standard classification failure, we investigated with multi-omics approaches (epigenetics, next-generation sequencing, RNAseq, proteomics and metabolomics) a well clinical characterized cohort of 17 high-grade pediatric intracranial tumors harboring this mutation. RESULTS Interestingly, almost all tumors show similar morphological features and associated passenger molecular alterations mostly CDKN2A homozygous deletion. When using the new v12.5 brain tumor classifier, the methylation profiling of the 2/17 unclassified tumors was clustering with a new MPNST (Malignant Peripheral Nerve Sheath Tumor) methylation entity. The RNAseq and proteomics analyses were showing a different molecular pattern from standard BRAF-mutated high-grade gliomas, even the clinical, radiological and histomolecular characteristics were comparable. CONCLUSION So, methylation profiling should be part of the mandatory molecular assessments to perform when a BRAF-mutated tumor is seen by neuropathologists. Furthermore, the multiomics analyses helped us to define a specific molecular pattern of this new BRAF-driven entity, where frequency and prognosis need to be determined on another larger series.

The relationship between prognosis and temporal muscle thickness in 102 patients with glioblastoma

Temporal muscle thickness measured on 3D MRI has recently been linked to prognosis in glioblastoma patients and may serve as an independent prognostic indicator. This single-center study looked at temporal muscle thickness and prognosis in patients with primary glioblastoma. Overall survival was the major study outcome. For a retrospective analysis from 2010 to 2020, clinical data from 102 patients with glioblastoma at the Department of Oncology Radiotherapy of the First Affiliated Hospital of Dalian Medical University were gathered. Fifty-five cases from 2016 to 2020 contained glioblastoma molecular typing data, of which 45 were IDH wild-type glioblastomas and were analysed separately. TMT was measured on enhanced T1-weighted magnetic resonance images in patients with newly diagnosed glioblastoma.Overall patient survival (OS) was calculated by the Kaplan–Meier method and survival curves were plotted using the log-rank-sum test to determine differences between groups, and multifactorial analyses were performed using a Cox proportional-risk model.The median TMT for 102 patients was 6.775 mm (range: 4.95–10.45 mm). Patients were grouped according to median TMT, and the median overall survival (23.0 months) was significantly longer in the TMT > median group than in the TMT median group (P 0.001; Log-rank test). Analysing 45 patients with IDH wild type alone, the median overall survival (12 months) of patients in the TMT > median group was significantly longer than that of patients in the TMT ≤ median group (8 months) (P < 0.001; Log-rank test).TMT can serve as an independent prognostic factor for glioblastoma.

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.

DSC-PWI presurgical differentiation of grade 4 astrocytoma and glioblastoma in young adults: rCBV percentile analysis across enhancing and non-enhancing regions

PurposeThe presurgical discrimination of IDH-mutant astrocytoma grade 4 from IDH-wildtype glioblastoma is crucial for patient management, especially in younger adults, aiding in prognostic assessment, guiding molecular diagnostics and surgical planning, and identifying candidates for IDH-targeted trials. Despite its potential, the full capabilities of DSC-PWI remain underexplored. This research evaluates the differentiation ability of relative-cerebral-blood-volume (rCBV) percentile values for the enhancing and non-enhancing tumor regions compared to the more commonly used mean or maximum preselected rCBV values.MethodsThis retrospective study, spanning 2016–2023, included patients under 55 years (age threshold based on World Health Organization recommendations) with grade 4 astrocytic tumors and known IDH status, who underwent presurgical MR with DSC-PWI. Enhancing and non-enhancing regions were 3D-segmented to calculate voxel-level rCBV, deriving mean, maximum, and percentile values. Statistical analyses were conducted using the Mann-Whitney U test and AUC-ROC.ResultsThe cohort consisted of 59 patients (mean age 46; 34 male): 11 astrocytoma-4 and 48 glioblastoma. While glioblastoma showed higher rCBV in enhancing regions, the differences were not significant. However, non-enhancing astrocytoma-4 regions displayed notably higher rCBV, particularly in lower percentiles. The 30th rCBV percentile for non-enhancing regions was 0.705 in astrocytoma-4, compared to 0.458 in glioblastoma (p = 0.001, AUC-ROC = 0.811), outperforming standard mean and maximum values.ConclusionEmploying an automated percentile-based approach for rCBV selection enhances differentiation capabilities, with non-enhancing regions providing more insightful data. Elevated rCBV in lower percentiles of non-enhancing astrocytoma-4 is the most distinguishable characteristic and may indicate lowly vascularized infiltrated edema, contrasting with glioblastoma’s pure edema.

Delineating the Biomarker Potential and Therapeutic Significance of MicroRNAs in IDH-wildtype Glioblastoma as Defined by the WHO CNS5 Criteria

The World Health Organization (WHO) CNS5 classification, updated in 2021, has brought about a significant transformation in the diagnosis and treatment of IDH-wildtype glioblastoma, a subgroup of aggressive brain tumors. This new system, which incorporates molecular markers alongside traditional tissue analysis, provides a more refined approach that facilitates the identification of distinct glioblastoma subtypes with unique genetic profiles. Examples of these subtypes include IDH-mutant astrocytoma, IDH-mutant and 1p/19q-deleted oligodendroglioma, and IDH-wildtype glioblastoma. Despite advancements in genetics and targeted therapies, the treatment of these malignant tumors remains an ongoing quest. Therefore, the need for more specific diagnostic and therapeutic approaches is undeniable. MicroRNAs (miRNAs) are emerging as molecules that molecular biology has brought to the medical world in this context. These tiny molecules act as master regulators of gene expression and hold immense potential for glioblastoma diagnosis, prognosis prediction, and biomarker development. Recent research has highlighted the potential of miRNAs as therapeutic strategies, attracting scientific interest to this point. This review examines the current relationships of miRNAs in the context of IDH-wildtype glioblastoma within the framework of the WHO CNS5 classification. Utilizing extensive databases, this article investigates the intricate relationship between genetic abnormalities defined in the latest WHO classification and dysregulated miRNAs. By analyzing proposed molecular biomarkers and associated miRNA dysregulation, we aim to pave the way for the development of personalized miRNA-based therapies for this aggressive cancer type.

Safety and Efficacy of Laser Interstitial Thermal Therapy as Upfront Therapy in Primary Glioblastoma and IDH-Mutant Astrocytoma: A Meta-Analysis.

Although primary studies have reported the safety and efficacy of LITT as a primary treatment in glioma, they are limited by sample sizes and institutional variation in stereotactic parameters such as temperature and laser power. The current literature has yet to provide pooled statistics on outcomes solely for primary brain tumors according to the 2021 WHO Classification of Tumors of the Central Nervous System (WHO CNS5). In the present study, we identify recent articles on primary CNS neoplasms treated with LITT without prior intervention, focusing on relationships with molecular profile, PFS, and OS. This meta-analysis includes the extraction of data from primary sources across four databases using the Covidence systematic review manager. The pooled data suggest LITT may be a safe primary management option with tumor ablation rates of 94.8% and 84.6% in IDH-wildtype glioblastoma multiforme (GBM) and IDH-mutant astrocytoma, respectively. For IDH-wildtype GBM, the pooled PFS and OS were 5.0 and 9.0 months, respectively. Similar to rates reported in the prior literature, the neurologic and non-neurologic complication rates for IDH-wildtype GBM were 10.3% and 4.8%, respectively. The neurologic and non-neurologic complication rates were somewhat higher in the IDH-mutant astrocytoma cohort at 33% and 8.3%, likely due to a smaller cohort size.

Leptomeningeal metastases in isocitrate dehydrogenase-wildtype glioblastomas revisited: Comprehensive analysis of incidence, risk factors, and prognosis based on post-contrast fluid-attenuated inversion recovery.

The incidence of leptomeningeal metastases (LM) has been reported diversely. This study aimed to investigate the incidence, risk factors, and prognosis of LM in patients with isocitrate dehydrogenase (IDH)-wildtype glioblastoma. A total of 828 patients with IDH-wildtype glioblastoma were enrolled between 2005 and 2022. Baseline preoperative MRI including post-contrast fluid-attenuated inversion recovery (FLAIR) was used for LM diagnosis. Qualitative and quantitative features, including distance between tumor and subventricular zone (SVZ) and tumor volume by automatic segmentation of the lateral ventricles and tumor, were assessed. Logistic analysis of LM development was performed using clinical, molecular, and imaging data. Survival analysis was performed. The incidence of LM was 11.4%. MGMTp unmethylation (odds ratio [OR] = 1.92, P = .014), shorter distance between tumor and SVZ (OR = 0.94, P = .010), and larger contrast-enhancing tumor volume (OR = 1.02, P < .001) were significantly associated with LM. The overall survival (OS) was significantly shorter in patients with LM than in those without (log-rank test; P < .001), with median OS of 12.2 and 18.5 months, respectively. The presence of LM remained an independent prognostic factor for OS in IDH-wildtype glioblastoma (hazard ratio = 1.42, P = .011), along with other clinical, molecular, imaging, and surgical prognostic factors. The incidence of LM is high in patients with IDH-wildtype glioblastoma, and aggressive molecular and imaging factors are correlated with LM development. The prognostic significance of LM based on post-contrast FLAIR imaging suggests the acknowledgment of post-contrast FLAIR as a reliable diagnostic tool for clinicians.

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.

The role of neoadjuvant clinical trials in patients with newly diagnosed glioblastoma.

e14022 Background: Novel cytotoxic drugs are commonly first studied in patients with solid tumors who have recurrent disease. If high response rates and durable remissions are observed, further studies are conducted in previously untreated cancers where the novel agent can be combined with radiation or administered as neoadjuvant therapy (NAT) to reduce tumor size before surgery or radiation and to limit systemic dissemination. While NAT can provide critical information on response rates and survival in previously untreated patients, it can add toxicities and delay the administration of standard therapies. Neoadjuvant chemotherapy is now standard-of-care in many systemic cancers but is rarely considered in patients with glioblastoma (GBM). This literature review was conducted to describe factors leading to NAT playing an increasingly important role in systemic cancers and a diminishing role in patients with GBM. Methods: Prospective trials published between 1980 and 2023 where patients with newly diagnosed systemic cancers and GBM received NAT prior to radiation were identified in PubMed. Results: During these 43 years, over 5,000 NAT trials in patients with systemic cancers were published. As a result of these studies, NAT is now considered standard therapy for 28 different cancers. In contrast, during the same years only 51 prospective studies were reported evaluating the efficacy of NAT in newly diagnosed GBM. These clinical trials accrued a total of 2,047 patients and evaluated the efficacy of nitrosoureas, temozolomide, platinum-based agents, and targeted therapies. These studies peaked before 2005, when combining temozolomide and radiation was shown to improve survival, and declined thereafter. NAT temozolomide was studied in 12 trials (641 patients) resulting in a median response rate of 35% (range 8.7-51%) and a median overall survival of 12.5 (range 6-22) months. NAT trials in patients with GBM were not associated with unexpected toxicities, major reductions in survival, or poor patient accrual. Conclusions: As in other solid tumors, NAT in patients with GBM is relatively safe and feasible. Enthusiasm for this approach has been limited by the paucity of active agents in recurrent glioblastoma that could be subsequently evaluated in newly diagnosed patients. However, the neoadjuvant setting is ideally suited to rapidly screening novel cytotoxic agents for efficacy as it allows: 1) radiographic response rates in previously untreated patients to be the primary endpoint, 2) small sample sizes, and 3) efficacy results in 2-3 months when patients are transitioned to standard care. Given the well documented safety and feasibility history of using NAT in patients with solid tumors and GBM, this approach has the ability to rapidly identify potentially active, novel cytotoxic agents, especially in patients with MGMT unmethylated, IDH wildtype GBM who are unlikely to benefit from temozolomide.

Subventricular zone-associated classification in isocitrate dehydrogenase-wildtype glioblastomas: improved prognostic value through integration of FLAIR with contrast-enhanced imaging.

Controversy surrounds the prognostic value of contrast-enhanced T1-weighted (T1CE) imaging-based subventricular zone (SVZ) classification in isocitrate dehydrogenase (IDH)-wildtype glioblastomas (GBMs). In this study, the authors aimed to assess the potential of incorporating FLAIR imaging into T1CE imaging-based classification for improving prognostic accuracy. A retrospective analysis was conducted on 281 patients with IDH-wildtype GBM. T1CE imaging-based classification was performed, and T2-weighted/FLAIR imaging was integrated to evaluate its prognostic estimation ability. Based on the relationship between the tumors and SVZ, patients were categorized into SVZ+ and SVZ- cohorts based on T1CE and T2-weighted/FLAIR imaging findings. Kaplan-Meier and Cox proportional hazards regression analyses were used to assess progression-free survival (PFS) and overall survival (OS), respectively. Patients were then categorized into three subgroups based on their combined classifications: group 1 (SVZ+ on T1CE and T2-weighted/FLAIR imaging), group 2 (SVZ- on T1CE but SVZ+ on T2-weighted/FLAIR imaging), and group 3 (SVZ- on T1CE and T2-weighted/FLAIR imaging). Subgroup analysis was used to evaluate differences in clinical and molecular factors as well as in prognoses. The T1CE imaging-based classification failed to stratify OS between SVZ+ and SVZ- cohorts (16.0 vs 20.0 months, p = 0.36). Survival analysis revealed similar prognoses for patients in groups 1 and 2, and patients in group 2 exhibited worse OS compared with those in group 3 (19.0 vs 23.5 months, p = 0.024). Logistic regression identified lower Karnofsky Performance Status (KPS) (p = 0.011), tumor diameter (p = 0.002), and telomerase reverse transcriptase (TERT) promoter mutation (p = 0.003) to be associated with a higher incidence of group 2 GBMs. Additionally, T2-weighted/FLAIR imaging-based classification provided significant prognostic value (17.0 vs 23.5 months p = 0.021) and was found to be an independent prognostic factor in the Cox multivariate analysis (HR 1.79, 95% CI 1.08-2.96; p = 0.024). This study underscores the limitations of T1CE imaging-based SVZ-associated classification in predicting prognosis for IDH-wildtype GBMs. The authors therefore propose an integrated approach that involves T2-weighted/FLAIR imaging that can provide improved prognostic ability. Notably, the presence of TERT promoter mutation was identified as a critical factor in nonenhancing tumor infiltration into the SVZ. Further validation through extensive cohort studies is recommended to confirm these findings.

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.

Development and validation of a clinical risk score for postoperative outcome in newly diagnosed glioblastoma: A report of the RANO Resect group.

2060 Background: Following resection or biopsy, patients with newly diagnosed glioblastoma frequently enter clinical trials. To standardize terminology for extent of resection, we proposed the RANO classification acknowledging four prognostic resection classes reflecting different amounts of residual tumor. Here, we aim to make use of our classification to (I) analyze the interactive effects of residual tumor with clinical and molecular factors on outcome (II) to define a prognostic postoperative risk score. Methods: The RANO resect group retrospectively compiled an international, seven-center training cohort of newly diagnosed glioblastoma. Predictors of outcome were identified by uni- and multivariate Cox’s proportional hazard regression. The combined effects of residual tumor with prognostic molecular and clinical factors on survival were assessed by recursive partitioning analysis (significance level: p≤ 0.05). Terminal regression tree nodes were combined into risk classes guided by Kaplan-Meier survival analyses and log-rank tests. The risk classes were converted into a numerical score which was prognostically verified in an external validation cohort. Results: Our training cohort compromised 1003 patients with newly diagnosed IDH-wildtype glioblastoma, including 744 patients who underwent adjuvant radiochemotherapy per EORTC-NCIC (TMZ/RT→TMZ). Residual tumor per RANO classification, MGMT promotor methylation status, age (as continuous variable; optimal cutoff: ≤65 years), and KPS (as continuous variable; optimal cutoff: ≥80) were prognostic of overall survival and forwarded into regression tree analysis. By combining eleven terminal nodes and individually weighting the prognostic factors, an additive scale (range, 0-9 points) integrating these four variables distinguished patients with low (0-2 points), intermediate (3-5 points), and high risk (6-9 points) for poor postoperative outcome (median overall survival: 24 vs. 16 vs. 6 months; p &lt; 0.01). Adjustment of the regression tree for adjuvant therapy was applied, and the presence of the three risk groups was confirmed in the subgroups of patients treated with or without RT/TMZ→TMZ. The prognostic value of the risk score was verified in a external single-center validation cohort of newly diagnosed glioblastoma ( n = 231, p &lt; 0.01). When we compared our risk score to previously postulated risk models, our score was superior in concordance between predicted with observed survival (c-index; development cohort: 0.7, validation cohorts: 0.6). Conclusions: The novel RANO risk score integrates molecular and clinical factors to serve as an easy-to-use, yet highly prognostic tool to stratify patients after resection or biopsy of newly diagnosed glioblastoma. The score may serve to guide patient management and reduce imbalances between study arms in prospective interventional trials.

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.

Prognostic Impact of TERT Promoter Mutations in Adult-Type Diffuse Gliomas Based on WHO2021 Criteria.

Mutation in the telomerase reverse transcriptase promoter (TERTp )is commonly observed in various malignancies, such as central nervous system (CNS) tumors, malignant melanoma, bladder cancer, and thyroid carcinoma. These mutations are recognized as significant poor prognostic factors for these tumors. In this investigation, a total of 528 cases of adult-type diffuse gliomas diagnosed at a single institution were reclassified according to the 2021 WHO classifications of CNS tumors, 5th edition (WHO2021). The study analyzed clinicopathological and genetic features, including TERTp mutations in each tumor. The impact of known prognostic factors on patient outcomes was analyzed through Kaplan-Meier survival and Cox regression analysis. TERTp mutations were predominantly identified in 94.1% of oligodendrogliomas (ODG), followed by 66.3% in glioblastoma, IDH-wildtype (GBM-IDHwt), and 9.2% of astrocytomas, IDH-mutant (A-IDHm). When considering A-IDHm and GBM as astrocytic tumors (Group 1) and ODGs (Group 2), TERTp mutations emerged as a significant adverse prognostic factor (p = 0.013) in Group 1. However, within each GBM-IDHwt and A-IDHm, the presence of TERTp mutations did not significantly impact patient prognosis (p = 0.215 and 0.268, respectively). Due to the high frequency of TERTp mutations in Group 2 (ODG) and their consistent prolonged survival, a statistical analysis to evaluate their impact on overall survival was deemed impractical. When considering MGMTp status, the combined TERTp-mutated and MGMTp-unmethylated group exhibited the worst prognosis in OS (p = 0.018) and PFS (p = 0.034) of GBM. This study confirmed that the classification of tumors according to the WHO2021 criteria effectively reflected prognosis. Both uni- and multivariate analyses in GBM, age, MGMTp methylation, and CDKN2A/B homozygous deletion were statistically significant prognostic factors while in univariate analysis in A-IDHm, grade 4, the Ki-67 index and MYCN amplifications were statistically significant prognostic factors. This study suggests that it is important to classify and manage tumors based on their genetic characteristics in adult-type diffuse gliomas.

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.

A longer time to relapse is associated with a larger increase in differences between paired primary and recurrent IDH wild-type glioblastomas at both the transcriptomic and genomic levels

Glioblastoma (GBM) is the most common malignant brain tumor in adults, which remains incurable and often recurs rapidly after initial therapy. While large efforts have been dedicated to uncover genomic/transcriptomic alternations associated with the recurrence of GBMs, the evolutionary trajectories of matched pairs of primary and recurrent (P-R) GBMs remain largely elusive. It remains challenging to identify genes associated with time to relapse (TTR) and construct a stable and effective prognostic model for predicting TTR of primary GBM patients. By integrating RNA-sequencing and genomic data from multiple datasets of patient-matched longitudinal GBMs of isocitrate dehydrogenase wild-type (IDH-wt), here we examined the associations of TTR with heterogeneities between paired P-R GBMs in gene expression profiles, tumor mutation burden (TMB), and microenvironment. Our results revealed a positive correlation between TTR and transcriptomic/genomic differences between paired P-R GBMs, higher percentages of non-mesenchymal-to-mesenchymal transition and mesenchymal subtype for patients with a short TTR than for those with a long TTR, a high correlation between paired P-R GBMs in gene expression profiles and TMB, and a negative correlation between the fitting level of such a paired P-R GBM correlation and TTR. According to these observations, we identified 55 TTR-associated genes and thereby constructed a seven-gene (ZSCAN10, SIGLEC14, GHRHR, TBX15, TAS2R1, CDKL1, and CD101) prognostic model for predicting TTR of primary IDH-wt GBM patients using univariate/multivariate Cox regression analyses. The risk scores estimated by the model were significantly negatively correlated with TTR in the training set and two independent testing sets. The model also segregated IDH-wt GBM patients into two groups with significantly divergent progression-free survival outcomes and showed promising performance for predicting 1-, 2-, and 3-year progression-free survival rates in all training and testing sets. Our findings provide new insights into the molecular understanding of GBM progression at recurrence and potential targets for therapeutic treatments.

Prognostic relevance of radiological findings on early postoperative MRI for 187 consecutive glioblastoma patients receiving standard therapy

Several prognostic factors are known to influence survival for patients treated with IDH-wildtype glioblastoma, but unknown factors may remain. We aimed to investigate the prognostic implications of early postoperative MRI findings. A total of 187 glioblastoma patients treated with standard therapy were consecutively included. Patients either underwent a biopsy or surgery followed by an early postoperative MRI. Progression-free survival (PFS) and overall survival (OS) were analysed for known prognostic factors and MRI-derived candidate factors: resection status as defined by the response assessment in neuro-oncology (RANO)-working group (no contrast-enhancing residual tumour, non-measurable contrast-enhancing residual tumour, or measurable contrast-enhancing residual tumour) with biopsy as reference, contrast enhancement patterns (no enhancement, thin linear, thick linear, diffuse, nodular), and the presence of distant tumours. In the multivariate analysis, patients with no contrast-enhancing residual tumour or non-measurable contrast-enhancing residual tumour on the early postoperative MRI displayed a significantly improved progression-free survival compared with patients receiving only a biopsy. Only patients with non-measurable contrast-enhancing residual tumour showed improved overall survival in the multivariate analysis. Contrast enhancement patterns were not associated with survival. The presence of distant tumours was significantly associated with both poor progression-free survival and overall survival and should be considered incorporated into prognostic models.

Methylthioadenosine phosphorylase and p16 as surrogate diagnostic markers for CDKN2A homozygous deletion in brain tumors

Objective: To examine whether immunohistochemistry of methylthioadenosine phosphorylase (MTAP) and p16 could be used to predict the CDKN2A status in various brain tumors. Methods: A total of 118 cases of IDH-mutant astrocytomas, 16 IDH-wildtype glioblastoma, 17 polymorphic xanthoastrocytoma (PXA) and 20 meningiomas diagnosed at Xuanwu Hospital, Capital Medical University, Beijing, China from November 2017 to October 2023 were collected and analyzed. The CDKN2A status was detected by using fluorescence in situ hybridization or next-generation sequencing. Expression of MTAP and p16 proteins was detected with immunohistochemistry. The association of loss of MTAP/p16 expression with CDKN2A homozygous/heterozygous deletion was examined. Results: Among the 118 cases of IDH-mutant astrocytoma, 13 cases showed homozygous deletion of CDKN2A. All of them had no expression of MTAP while 9 cases had no expression of p16. Among the 16 cases of IDH wild-type glioblastoma, 6 cases showed homozygous deletion of CDKN2A. All 6 cases had no expression of MTAP, while 3 of these cases had no expression of p16 expression. Among the 17 PXA cases, 4 cases showed homozygous deletion of CDKN2A, and the expression of MTAP and p16 was also absent in these 4 cases. Among the 20 cases of meningiomas, 4 cases showed homozygous deletion of CDKN2A. Their expression of MTAP and p16 was also absent. Among the four types of brain tumors, MTAP was significantly correlated with CDKN2A homozygous deletion (P<0.05), with a sensitivity of 100%. However, it was only significantly correlated with the loss of heterozygosity (LOH) of CDKN2A in astrocytomas (P<0.001). P16 was associated with CDKN2A homozygous deletion in IDH-mutant astrocytoma and PXA (P<0.001), but not with the LOH of CDKN2A. Its sensitivity and specificity were lower than that of MTAP. Conclusions: MTAP could serve as a predictive surrogate for CDKN2A homozygous deletion in adult IDH-mutant astrocytoma, PXA, adult IDH-wildtype glioblastoma and meningioma. However, p16 could only be used in the first two tumor types, and its specificity and sensitivity are lower than that of MTAP.

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.

Extent of Resection Thresholds in Molecular Subgroups of Newly Diagnosed Isocitrate Dehydrogenase-Wildtype Glioblastoma.

Maximizing the extent of resection (EOR) improves outcomes in glioblastoma (GBM). However, previous GBM studies have not addressed the EOR impact in molecular subgroups beyond IDH1/IDH2 status. In the current article, we evaluate whether EOR confers a benefit in all GBM subtypes or only in particular molecular subgroups. A retrospective cohort of newly diagnosed GBM isocitrate dehydrogenase (IDH)-wildtype undergoing resection were prospectively included in a database (n = 138). EOR and residual tumor volume (RTV) were quantified with semiautomated software. Formalin-fixed paraffin-embedded tumor tissues were analyzed by targeted next-generation sequencing. The association between recurrent genomic alterations and EOR/RTV was evaluated using a recursive partitioning analysis to identify thresholds of EOR or RTV that may predict survival. The Kaplan-Meier methods and multivariable Cox proportional hazards regression methods were applied for survival analysis. Patients with EOR ≥88% experienced 44% prolonged overall survival (OS) in multivariable analysis (hazard ratio: 0.56, P = .030). Patients with alterations in the TP53 pathway and EOR <89% showed reduced OS compared to TP53 pathway altered patients with EOR>89% (10.5 vs 18.8 months; HR: 2.78, P = .013); however, EOR/RTV was not associated with OS in patients without alterations in the TP53 pathway. Meanwhile, in all patients with EOR <88%, PTEN -altered had significantly worse OS than PTEN -wildtype (9.5 vs 15.4 months; HR: 4.53, P < .001). Our results suggest that a subset of molecularly defined GBM IDH-wildtype may benefit more from aggressive resections. Re-resections to optimize EOR might be beneficial in a subset of molecularly defined GBMs. Molecular alterations should be taken into consideration for surgical treatment decisions in GBM IDH-wildtype.