MGMT Promoter Methylation Status Research Articles

Serum lactate dehydrogenase as a prognostic marker for treatment response in IDH wild-type glioblastoma patients undergoing stupp protocol.

Elevated lactate dehydrogenase (LDH), a marker of tumor aggressiveness and metabolic alterations, may predict treatment response and overall survival across various tumors. This study investigates the correlation between serum LDH levels and clinical outcomes in glioblastoma patients treated with radiotherapy (RT) and temozolomide (TMZ). This retrospective study analysed patients with IDH wild-type glioblastoma (IDH-wt GB) treated at the Radiotherapy Department of Azienda Ospedaliero-Universitaria Senese from 2018 to 2023. Clinical data, including hematologic parameters (e.g., LDH), imaging (MRI), and MGMT promoter methylation status, were collected. All patients received RT and TMZ following the Stupp protocol. Serum LDH levels were measured one week before RT, and Radiological Response (RR) was assessed using RANO criteria. Overall survival (OS), progression-free survival (PFS), and RR were primary endpoints. Statistical analyses included Kaplan-Meier, Cox regression, and decision tree analysis for LDH cut-off determination. In a cohort of 147 IDH wild-type glioblastoma patients treated with the Stupp protocol, the median OS was 14 months and median PFS was 8 months. Elevated baseline LDH levels were associated with significantly poorer outcomes, showing a median OS of 9 months versus 20 months and a median PFS of 6 months versus 13 months for lower LDH levels (p < 0.001 and p = 0.0001, respectively). LDH levels also correlated with RR (p = 0,001), Multivariate analysis confirmed high LDH as an independent predictor of worse OS (HR = 2.31) and PFS (HR = 2.60), suggesting its utility as a prognostic biomarker. Elevated LDH levels before starting the Stupp protocol are clinically significant as they predict poorer overall survival and progression-free survival in glioblastoma patients and worse RR. Incorporating LDH measurements into treatment planning can help identify patients at higher risk of poor outcomes, allowing for more tailored and potentially aggressive treatment strategies to improve management and therapeutic responses in glioblastoma.

The prognostic importance of glioblastoma size and shape.

Extent of resection, MGMT promoter methylation status, age, functional level, and residual tumor volume are established prognostic factors for overall survival in glioblastoma patients. Preoperative tumor volume has also been investigated, but the results have been inconclusive. We hypothesized that the surface area and the shape were more representative of the tumor's infiltrative capacities, and thus, the purpose of this study was to assess the prognostic value of tumor size and shape in patients with glioblastoma. In total, 271 patients with primary, unifocal glioblastoma were included from two centers in Norway and Sweden, respectively. All tumors were automatically segmented on preoperative MRI scans and manually validated. Tumor volume was used as a measurement of size, whereas sphericity index and area-to-volume ratio defined the shape complexity of the tumor. Contact surface area of the tumor was considered a measurement of both size and shape. Multivariable Cox proportional hazards models were used to assess the prognostic value of the respective tumor measurements, with previously established prognostic factors as covariates. There were no associations between preoperative tumor volume and overall survival. Contact surface area (HR = 1.013, p = 0.002) and sphericity index (HR = 2.223, p = 0.001) were both significant independent prognostic factors for survival in the multivariable Cox models. Contact surface area was also associated with MGMT promoter methylation (p = 0.039) and extent of resection (p = 0.017). Tumor shape complexity appears to be an independent prognostic factor in glioblastoma patients and may also be associated with MGMT promoter methylation status and extent of surgical resection.

SURG-47. SUPRAMAXIMAL RESECTION IMPROVES OVERALL SURVIVAL IN PATIENTS WITH MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract INTRODUCTION Glioblastoma is highly resistant to radio- and chemotherapy and its heterogeneity is a therapeutic challenge. O6-methylguanine–DNA methyltransferase (MGMT) promotor methylation is an established biomarker for favorable effect of chemotherapy. Supramaximal resection has proven predict the best overall survival (OS), but whether this benefit applies equally to patients with different MGMT-promotor methylation status is still to be debated. MATERIAL AND METHODS Population based retrospective study that examined all adult patients in South-Eastern Norway that underwent resection for IDH wildtype glioblastoma between January 2019 and December 2021. Extent of resection (EOR) was classified according to RANO resect classification and MGMT-promotor methylation status by pyrosequencing-qPCR. RESULTS The study included 281 patients. MGMT-promotor methylated patients (MGMT+) had a median OS of 18.4 months compared to 13.1 months in MGMT-unmethylated (MGMT-) patients (p&amp;lt;0.0001). Patients with supramaximal resection had a median OS of 20.4 months compared to 14.9 months (p&amp;lt;0.01) with maximal resection. For patients with supramaximal resection we found no significant difference in median OS (25.5 vs. 18.3 months (p=0.24)) dependent on MGMT-status. Separated analysis between MGMT-status and EOR showed a median survival of 18.3, 13.4 (p&amp;lt;0.001), and 8.5 (p&amp;lt;0.001) months for MGMT-, and 25.5, 18.4 (p=.99), and 9.0 (p&amp;lt;0.001) months for MGMT+ in patients where supramaximal-, maximal-, and submaximal resection was achieved, respectively. CONCLUSIONS Patients with supramaximal resection and MGMT+ have a 50% 2-years survival probability. In patients where supramaximal resection was achieved, survival benefit was not dependent on MGMT-status. There was a significant improved survival in MGMT- patients between supramaximal and maximal resection, that was not present for MGMT+ patients. Intraoperative molecular diagnosis has the potential to guide the surgical strategy dependent on MGMT-promotor methylation status, especially in tumors where supramaximal resection has a higher risk of new neurological deficits.

CCRG-03. DETECTION OF HETEROGENEOUS CELL CYCLE ALTERATIONS UPON TMZ CHEMOTHERAPY TREATMENT THROUGH ADVANCED MACHINE LEARNING

Abstract Glioblastoma (GB), the most aggressive central nervous system tumor, is hallmarked by its frequent relapse under alkylating chemotherapy. GB cells frequently exhibit changes in cell cycle phases during TMZ treatment, with a reduction in the G0-G1 phase and an increase in the S and G2 phases. This indicate both tumor cell re-entry into the cell cycle and a TMZ-induced arrest, contributing to resistance and progression. In this study, we leverage dynamic protein abundance of Ki-67, a proliferation marker peaking during S, G2, and M phases, to analyse cellular responses to TMZ in various cell lines and tissue samples. We designed an image-based machine learning approach for pattern recognition to reconstruct and analyse the cell cycle at the single-cell level. Six primary cell lines were characterized through whole-genome DNA, methylation and RNA sequencing. Functional read-outs were performed with large-scale, time- and concentration-dependent TMZ treatments in cell culture and GB-tissue slice models. Our model successfully reconstructed detailed cell cycle stages, showing that untreated cells were predominantly in the G0-G1 phase. TMZ treatment significantly shifted cells toward the S/G2 phase (p &amp;lt; 0.02) in 3 of 6 cell lines and the pseudo-time reconstruction highlighted dose-dependent cell cycle changes. Cell lines with enhanced stem-like features, defined based on epigenetic and transcriptional data signature, showed no cell cycle changes at high TMZ doses (&amp;gt;150µM), regardless the MGMT promoter methylation status. This heterogeneity in cell cycle response emphasizes the complexity of GB and the need for personalized treatments. Our study provides insights into GB MGMT cell cycle alterations and resistance mechanisms that are independent of MGMT methylation status, a known TMZ response biomarker. Therefore, the observed TMZ-induced cell cycle changes may serve as novel biomarkers for assessing treatment response, paving the way for personalized therapeutic approaches.

PATH-44. CLINICAL AND RADIOGRAPHIC PREDICTORS OF PROGNOSIS IN ASTROCYTOMA, IDH-MUTANT, WHO GRADE 4

Abstract BACKGROUND Astrocytoma, IDH-mutant, WHO grade 4, are classified as a separate entity in the 2021 WHO classification of central nervous system tumors and have been poorly characterized in the literature. In this study, we report on the clinical outcomes in a large cohort of newly diagnosed grade 4 IDH-mutant astrocytoma. METHODS We retrospectively identified adult patients with astrocytoma, IDH-mutant, WHO grade 4, treated for their initial diagnosis at Dana-Farber Cancer Institute and Massachusetts General Hospital between 2010 and 2021. Clinical, molecular, and radiological characteristics were recorded, and their association with overall survival (OS) and progression-free survival (PFS) was measured by a log-rank test. If a proportional hazard assumption was violated, we compared the median OS and PFS between groups by the bootstrap method instead. RESULTS We identified 140 patients, with a median age at diagnosis of 37.9 years (range: 19-87) and male predominance (60.7%). MGMT promoter was methylated in 51.4%, and CDKN2A/B homozygous deletion was present in 40 cases (28.6%). Most tumors showed enhancement on the preoperative scan (n=108; 77.1%). Seventy percent of patients had subtotal resection, 25.7% had a gross total resection, and 4.3% had a biopsy. Most patients received standard chemoradiation followed by adjuvant temozolomide (n=103; 73.6%). The median OS was 6.9 years (95% CI: 4.5-9.2), and the median PFS was 3.3 years (95% CI: 2.1-4.4). OS and PFS were not associated with MGMT promoter methylation or the presence of enhancement on the preoperative scan. CDKN2A/B homozygous deletion was associated with worse OS (5.5 vs. 7.8 years, log-rank test-based p-value=0.036) but had no association with PFS (3.4 vs 2.6 years, bootstrap method-based p-value=0.488). CONCLUSIONS In our cohort of astrocytoma, IDH-mutant, WHO Grade 4, CDKN2A/B homozygous deletion had a negative prognostic impact, whereas MGMT promoter methylation status and enhancement on the preoperative scan did not affect survival outcomes.

SURG-21. DEVELOPMENT AND VALIDATION OF A CLINICAL RISK SCORE FOR POSTOPERATIVE OUTCOME IN NEWLY DIAGNOSED GLIOBLASTOMA: A REPORT OF THE RANORESECT GROUP

Abstract BACKGROUND Following resection or biopsy, patients with newly diagnosed glioblastoma frequently enter clinical trials. Nuanced risk assessment is warranted to reduce imbalances between study arms. Here, we aim to make use of our RANO classification for extent of resection (I) to analyze the interactive effects of residual tumor with clinical and molecular factors on outcome and (II) to define a postoperative risk assessment tool. METHODS The RANO resect group retrospectively compiled an international, seven-center training cohort of patients with newly diagnosed glioblastoma. The combined associations of residual tumor with molecular or clinical factors and survival were analyzed, and recursive partitioning analysis was performed for risk modeling. The resulting model was prognostically verified in a separate external validation cohort. RESULTS Our training cohort compromised 1003 patients with newly diagnosed IDH-wildtype glioblastoma, including 744 patients who underwent adjuvant radiochemotherapy (TMZ/RT→TMZ). Residual tumor, MGMT promotor methylation status, age, and KPS 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&amp;lt;0.01). 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 = 258, p&amp;lt;0.01). Compared to previously postulated models, goodness-of-fit measurements were superior for our score. CONCLUSIONS The novel RANO risk score serves as an easy-to-use, yet highly prognostic tool for postoperative patient stratification prior to further therapy. The score may serve to guide patient management and reduce imbalances between study arms in prospective trials.

RADT-09. CHEMORADIOTHERAPY WITH TEMOZOLOMIDE VS. RADIOTHERAPY ALONE IN PATIENTS WITH IDH WILD-TYPE AND TERT PROMOTER MUTATION HISTOLOGICAL GRADE 2/3 GLIOMAS: A POSTHOC ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL

Abstract PURPOSE In 2016, we initiated a signal center prospective randomized trial to compare chemoradiotherapy (CRT) with temozolomide (TMZ) to radiotherapy (RT) alone in patients with IDH wild-type and TERT promoter mutation histological grade 2/3 gliomas. This study demonstrated patients who received CRT had a longer median OS than those who received RT alone and found no statistical difference in PFS between the two groups. Now, we recruited more patients in the CRT group to further explore whether there were differences in PFS between patients treated with CRT and RT. Besides, we explored the effect of MGMT promoter (MGMTp) methylation status on OS and PFS in patients receiving CRT therapy in the STUPP schedule. METHODS We expanded the scope by enrolling 21 participants in the CRT group and extending the follow-up period. OS and PFS were analyzed using the log-rank test, and high-risk factors were explored through Cox regression analysis. RESULTS Patients’ median follow-up is 21.9 months. CRT group has a longer median OS (25.3 vs 17.2 months; P = 0.029, HR = 0.443) and PFS (14.6 vs 8.3 months; P = 0.0008, HR = 0.387) than the RT group. Multivariate analysis identified CRT as a favorable prognostic variable for both OS (P = 0.003) and PFS (P = 0.002). The status of MGMTp methylation did not affect OS (P = 0.560, HR = 1.30) and PFS (P = 0.75, HR = 0.88) in patients with IDH-wt/TERTp-mut receiving TMZ chemotherapy. CRT with TMZ did not significantly increase grade 3 or higher toxicities. CONCLUSIONS The long-term results confirmed that the OS and PFS benefits of the RT plus TMZ regimen exceeded those of the RT alone group in patients with IDH-wt/TERTp-mut gliomas.

CTNI-85. FINAL RESULTS FROM N2M2/NOA-20

Abstract BACKGROUND MGMT promoter methylation determines benefit from temozolomide (TMZ). Trials aiming at replacing TMZ with targeted agents in not molecularly selected patient populations have failed. Solid evaluation of the MGMT promotor methylation status is critical. METHODS The phase I/IIa umbrella trial NCT Neuro Master Match (N2M2) in patients with newly diagnosed glioblastoma aimed at showing safety, feasibility, and preliminary efficacy of targeted compounds in addition to radiotherapy. In five subtrials (alectinib, idasanutlin, palbociclib, vismogedib and temsirolimus) patients were included according to the best matching molecular alteration. Patients without matching alterations were randomized between atezolizumab, asunercept or TMZ as standard of care. Primary objective of the phase I parts of the trial was dose finding or dose validation. In the phase IIa trials, centrally determined progression-free survival at six months (PFS-6) is used as endpoint for efficacy with interim analyses for futility (H0: p=0.231). RESULTS From May 2018 through July 2022, 301 patients were enrolled and 228 treated in 13 German NOA sites. MGMT was determined locally and confirmed centrally by pyrosequencing as well as methylation arrays. The TMZ subtrial showed a PFS-6 of 18.52% (10/54 patients) (p=0.8311) and a median overall survival (mOS) of 12.1 months. Asunercept: PFS-6 of 15.4% (4/26) (p=0.8825) and mOS of 13.0 months. Atezolizumab: PFS-6 of 21.4% (9/42) (p=0.660) and mOS of 11.7 months. Palbociclib with patients demonstrating CDK4 amplification or CDKN2A/B codeletion: PFS-6 of 24.4% (10/41) (p=0.4823) and mOS of 12.6 months. Temsirolimus with patients demonstrating mTOR activation: PFS-6 of 39.1% (18/46) (p=0.0109) and mOS of 15.4 months. For the other arms, phase IIa has not been reached. CONCLUSIONS There is clinical activity of temsirolimus in patients with tumors harboring an activated mTOR pathway although this is not positively prognostic without mTOR inhibition; there is no clinical activity for asunercept and atezolizumab in not molecularly selected patients nor palbociclib in molecularly selected patients. Potential biomarkers will be discussed.

Dynamic susceptibility contrast‑enhanced perfusion magnetic resonance imaging parameters for predicting MGMT promoter methylation and prognostic value in newly diagnosed patients with glioblastoma.

O6-methylguanine DNA methyltransferase (MGMT) promoter methylation is an important clinical biomarker of newly diagnosed glioblastoma. Previous radiological studies using dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion have aimed to predict MGMT methylation status non-invasively in gliomas with radiological characteristics. The possibility of predicting MGMT methylation status using DSC-MRI perfusion with a radiological approach remains controversial. The present study aimed to evaluate the usefulness of MRI perfusion parameters as non-invasive markers to predict MGMT methylation status and prognosis in newly diagnosed glioblastoma patients. Thus, 50 patients with histologically confirmed primary glioblastoma, IDH-wildtype who underwent tumor resection at Osaka University Hospital (Suita, Japan) between January 2017 and January 2023 were included in this study. The mean cerebral blood volume (CBV) ratio (rCBV) and cerebral blood flow (CBF) ratio (rCBF) for tumors with MGMT methylation (mean rCBV:2.09 and mean rCBF:3.08) were significantly higher compared with those for tumors without MGMT methylation (mean rCBV:1.33 and mean rCBF:1.85; P<0.05). While patients with MGMT methylation had longer progression-free survival (PFS) compared with those without MGMT methylation (P<0.05), there was no significant difference in OS with or without MGMT methylation (P=0.06). By contrast, there was no association between MRI perfusion parameters and OS or PFS in patients with glioblastoma. Furthermore, the association between CBV, CBF, MGMT promotor methylation status, OS, and PFS were explored. There was no significant prognostic difference between low vascularity tumors (rCBV <1.3 or rCBF <1.8) with or without MGMT methylation. On the other hand, high vascularity tumors (rCBF ≥1.8) with MGMT promotor methylation were associated to longer OS and PFS compared with those without. However, there was no association between MGMT methylation status and OS or PFS in patients with high rCBV (rCBV ≥1.3). The present study indicated that CBV and CBF could be used to predict the MGMT methylation status in glioblastomas. However, the prognostic value of tumor vascularity and MGMT methylation status may be limited.

CDKN2A Homozygous Deletion Is a Stronger Predictor of Outcome than IDH1/2-Mutation in CNS WHO Grade 4 Gliomas.

Background: We primarily investigated the prognostic role of CDKN2A homozygous deletion in CNS WHO grade 4 gliomas. Additionally, we plan to examine traditional prognostic factors for grade 4 gliomas and validate the findings. Materials: We conducted a retrospective analysis of the glioma cohorts at our institute. We reviewed medical records spanning a 15-year period and examined pathological slides for an updated diagnosis according to the 2021 WHO classification of CNS tumors. We examined the IDH1/2 mutation and CDKN2A deletion using NGS analysis with ONCOaccuPanel®. Further, we examined traditional prognostic factors, including age, WHO performance status, extent of resection, and MGMT promoter methylation status. Results: The mean follow-up duration was 27.5 months (range: 4.1-43.5 months) and mean overall survival (OS) was 20.7 months (SD, ±1.759). After the exclusion of six patients with a poor status of pathologic samples, a total of 136 glioblastoma cases diagnosed by previous WHO classification criteria were newly classified into 29 (21.3%) astrocytoma, IDH-mutant, and CNS WHO grade 4 cases, and 107 (78.7%) glioblastoma, IDH-wildtype, and CNS WHO grade 4 cases. Among them, 61 (56.0%) had CDKN2A deletions. The high-risk group with CDKN2A deletion regardless of IDH1/2 mutation had a mean OS of 16.65 months (SD, ±1.554), the intermediate-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 21.85 months (SD, ±2.082), and the low-risk group without CDKN2A deletion and with IDH1/2 mutation had a mean OS of 33.38 months (SD, ±2.946). Multifactor analysis showed that age (≥50 years vs. <50 years; HR 4.645), WHO performance (0, 1 vs. 2; HR 5.002), extent of resection (gross total resection vs. others; HR 5.528), MGMT promoter methylation, (methylated vs. unmethylated; HR 5.078), IDH1/2 mutation (mutant vs. wildtype; HR 6.352), and CDKN2A deletion (absence vs. presence; HR 13.454) were associated with OS independently. Conclusions: The present study suggests that CDKN2A deletion plays a powerful prognostic role in CNS WHO grade 4 gliomas. Even if CNS WHO grade 4 gliomas have mutant IDH1/2, they may have poor clinical outcomes because of CDKN2A deletion.

Analysis of Gliomas DNA Methylation: Assessment of Preanalytical Variables

Precision oncology is driven by biomarkers. For glioblastoma multiforme (GBM), the most common malignant adult primary brain tumor, O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation is an important prognostic and treatment clinical biomarker. Time-consuming preanalytical steps such as biospecimen storage, fixation, sampling, and processing are sources of data irreproducibility, and all these preanalytical variables are confounded by intratumor heterogeneity of MGMT promoter methylation. To assess the effect of preanalytical variables on GBM DNA methylation, tissue storage/sampling (CryoGrid), sample preparation multisonicator (PIXUL), and 5-methylcytosine DNA immunoprecipitation (Matrix-MeDIP-qPCR/seq) platforms were used. MGMT promoter methylation status assayed by MeDIP-qPCR was validated with methylation-specific PCR. MGMT promoter methylation levels in frozen and formalin-fixed paraffin-embedded sample pairs were not statistically different, confirming the reliability of formalin-fixed paraffin-embedded for MGMT promoter methylation analysis. Warm ex vivo ischemia (up to 4 hours at 37 °C) and 3 cycles of repeated sample thawing and freezing did not statistically impact 5-methylcytosine at MGMT promoter, exon, and enhancer regions, indicating the resistance of DNA methylation to common variations in sample processing conditions that might be encountered in research and clinical settings. Twenty-six percent to 34% of specimens exhibited intratumor heterogeneity in the MGMT DNA promoter methylation. These data demonstrate that variations in sample fixation, ischemia duration and temperature, and DNA methylation assay technique do not have a statistically significant impact on MGMT promoter methylation assessment. However, intratumor methylation heterogeneity underscores the value of multiple biopsies at different GBM geographic tumor sites in the evaluation of MGMT promoter methylation status. Matrix-MeDIP-seq analysis revealed that MGMT promoter methylation status clustered with other differentially methylated genomic loci (eg, HOXA and lncRNAs) that are resilient to variation in the above preanalytical conditions. These observations offer new opportunities to develop more granular data-based epigenetic GBM biomarkers. In this regard, the high-throughput CryoGrid-PIXUL-Matrix toolbox could be useful.

Molecular Profile as an Outcome Predictor in Glioblastoma along with MRI Features and Surgical Resection: A Scoping Review.

Glioblastoma (GBM) is one of the most aggressive malignant tumors of the brain. We queried PubMed for articles about molecular predictor markers in GBM. This scoping review aims to analyze the most important outcome predictors in patients with GBM and to compare these factors in terms of absolute months of survival benefit and percentages. Performing a gross total resection for patients with GBM undergoing optimal chemo- and radiotherapy provides a significant benefit in overall survival compared to those patients who received a subtotal or partial resection. However, compared to IDH-Wildtype GBMs, patients with IDH-Mutant 1/2 GBMs have an increased survival. MGMT promoter methylation status is another strong outcome predictor for patients with GBM. In the reviewed literature, patients with methylated MGMT promoter lived approximately 50% to 90% longer than those with an unmethylated MGMT gene promoter. Moreover, KPS is an important predictor of survival and quality of life, demonstrating that we should refrain from aggressive surgery in important brain areas. As new therapies (such as TTFs) emerge, we are optimistic that the overall median survival will increase, even for IDH-Wildtype GBMs. In conclusion, molecular profiles are stronger outcome predictors than the extent of neurosurgical resection for GBM.

The Role of Amide Proton Transfer (APT)-Weighted Imaging in Glioma: Assessment of Tumor Grading, Molecular Profile and Survival in Different Tumor Components.

Amide Proton Transfer-weighted (APTw) imaging is a molecular MRI technique used to quantify protein concentrations in gliomas, which have heterogeneous components with varying cellularity and metabolic activity. This study aimed to assess the correlation between the component-specific APT signal of the neoplasm and WHO grade, molecular profile and survival status. Sixty-one patients with adult-type diffuse gliomas were retrospectively analyzed. APT values were semi-automatically extracted from tumor solid and, whenever present, necrotic components. APT values were compared between groups stratified by WHO grade, IDH-mutation, MGMT promoter methylation and 1- and 2-year survival status using Wilcoxon rank-sum test, adjusting for multiple comparisons. Overall survival (OS) was analyzed in the subgroup of 48 patients with grade 4 tumors using Cox proportional-hazards models. Random-effects models were used to assess inter-subject heterogeneity of the mean APT values in each tumor component. APT values of the solid component significantly differed between patients with grades 2-3 and 4 tumors (mean 1.58 ± 0.50 vs. 2.04 ± 0.56, p = 0.028) and correlated with OS after 1 year (1.81 ± 0.58 in survivors vs. 2.17 ± 0.51 in deceased patients, p = 0.030). APT values did not differ by IDH-mutation, MGMT methylation, and 2-year survival status. Within grade 4 glioma patients, higher APT kurtosis of the solid component was a negative prognostic factor (hazard ratio = 1.60, p = 0.040). Mean APT values of the necrosis showed high inter-subject variability, although most necrotic tumors were grade 4 and IDH wildtype. In conclusion, APTw imaging in the solid component provided metrics associated with glioma grade and survival status but showed weak correlation with IDH-mutation and MGMT promoter methylation status, in contrast to previous works. Further research is needed to understand APT signal variability within the necrotic component of high-grade gliomas.

Optimizing Glioblastoma, IDH-wildtype Treatment Outcomes : A Radiomics and Support Vector Machine -Based Approach to Overall Survival Estimation.

Glioblastoma multiforme (GBM), particularly the IDH-wildtype type, represents a significant clinical challenge due to its aggressive nature and poor prognosis. Despite advancements in medical imaging and its modalities, survival rates have not improved significantly, demanding innovative treatment planning and outcome prediction approaches. This study utilizes a Support Vector Machine (SVM) classifier using radiomics features to predict the overall survival (OS) of GBM, IDH-wildtype patients to short (< 12 Months) and long (>=12 Months) survivors. A dataset comprising multi-parametric MRI (mpMRI) scans from 574 patients was analyzed. Radiomic features were extracted from T1, T2, FLAIR, and T1-Gd sequences. Low variance features were removed, and Recursive Feature Elimination (RFE) was used to select the most informative features. The SVM model was trained using a k-fold cross-validation approach. Furthermore, clinical parameters such as age, gender, and MGMT promoter methylation status were integrated to enhance prediction accuracy. The model showed reasonable results in terms of cross-validated AUC of 0.84 (95% CI: 0.80-0.90) with (p-value < 0.001) effectively categorizing patients into short and long survivors. Log-rank test (Chi-square statistics) analysis for the developed model was 0.00029 along with the 1.20 Cohen's d effect size. Most importantly, clinical data integration further refined the survival estimates, providing a more fitted prediction that considers individual patient characteristics by Kaplan-Meier curve with p-value<0.0001. The proposed method significantly enhances the predictive accuracy of OS outcomes in GBM, IDH-wildtype patients. By integrating detailed imaging features with key clinical indicators, this model offers a robust tool for personalized treatment planning, potentially improving OS.

Adaptive fine-tuning based transfer learning for the identification of MGMT promoter methylation status.

Background.Glioblastoma Multiforme (GBM) is an aggressive form of malignant brain tumor with a generally poor prognosis.O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been shown to be a predictive bio-marker for resistance to treatment of GBM, but it is invasive and time-consuming to determine methylation status. There has been effort to predict the MGMT methylation status through analyzing MRI scans using machine learning, which only requires pre-operative scans that are already part of standard-of-care for GBM patients.Purpose.To improve the performance of conventional transfer learning in the identification of MGMT promoter methylation status, we developed a 3D SpotTune network with adaptive fine-tuning capability. Using the pretrained weights of MedicalNet with the SpotTune network, we compared its performance with a randomly initialized network for different combinations of MR modalities.Methods.Using a ResNet50 as the base network, three categories of networks are created: (1) A 3D SpotTune network to process volumetric MR images, (2) a network with randomly initialized weights, and (3) a network pre-trained on MedicalNet. These three networks are trained and evaluated using a public GBM dataset provided by the University of Pennsylvania. The MRI scans from 240 patients are used, with 11 different modalities corresponding to a set of perfusion, diffusion, and structural scans. The performance is evaluated using 5-fold cross validation with a hold-out testing dataset.Results.The SpotTune network showed better performance than the randomly initialized network. The best performing SpotTune model achieved an area under the Receiver Operating Characteristic curve (AUC), average precision of the precision-recall curve (AP), sensitivity, and specificity values of 0.6604, 0.6179, 0.6667, and 0.6061 respectively.Conclusions.SpotTune enables transfer learning to be adaptive to individual patients, resulting in improved performance in predicting MGMT promoter methylation status in GBM using equivalent MRI modalities as compared to a randomly initialized network.

Preoperative prediction of MGMT promoter methylation in glioblastoma based on multiregional and multi-sequence MRI radiomics analysis

O6-methylguanine-DNA methyltransferase (MGMT) has been demonstrated to be an important prognostic and predictive marker in glioblastoma (GBM). To establish a reliable radiomics model based on MRI data to predict the MGMT promoter methylation status of GBM. A total of 183 patients with glioblastoma were included in this retrospective study. The visually accessible Rembrandt images (VASARI) features were extracted for each patient, and a total of 14676 multi-region features were extracted from enhanced, necrotic, “non-enhanced, and edematous” areas on their multiparametric MRI. Twelve individual radiomics models were constructed based on the radiomics features from different subregions and different sequences. Four single-sequence models, three single-region models and the combined radiomics model combining all individual models were constructed. Finally, the predictive performance of adding clinical factors and VASARI characteristics was evaluated. The ComRad model combining all individual radiomics models exhibited the best performance in test set 1 and test set 2, with the area under the receiver operating characteristic curve (AUC) of 0.839 (0.709–0.963) and 0.739 (0.581–0.897), respectively. The results indicated that the radiomics model combining multi-region and multi-parametric MRI features has exhibited promising performance in predicting MGMT methylation status in GBM. The Modeling scheme that combining all individual radiomics models showed best performance among all constructed moels.

MGMT promoter methylation in prognosis of patients with newly diagnosed IDH1 wildtype Glioblastoma

The objective of this study was to analyse the prognosis values of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation on the overall survival in patients with newly diagnosed isocitrate dehydrogenase 1 (IDH1) wild-type glioblastoma multiforme (GBM). A retrospective observational study was conducted on 108 IDH1 wild-type glioblastoma patients who underwent tumour resection at neurosurgical centres, including Hanoi Medical University Hospital and Viet Duc University Hospital, from October 2017 to December 2021. The MGMT status was assessed using methylation-specific Polymerase Chain Reaction (MSP). Multivariable Cox proportional hazards models and Kaplan-Meier survival analysis were performed. Of 108 patients, 79.6% had methylated MGMT. The median overall survival of patients with IDH1 wild-type GBM was 8.47 months (95%Confidence Interval (CI) =6.93-11.07). Patients with Methylated MGMT had a lower mortality risk (Hazard Ratio (HR) =0.63, 95%CI=0.41-0.98) than those without Methylated MGMT. Patients aged &lt;55 HR=0.55, CI=0.35-0.85)&gt;=55 years old. Having tumours on both sides of the hemisphere was associated with a higher risk of mortality (HR=3.18, 95%CI=1.68-6.00) compared to patients with tumours on the right side of the hemisphere. To conclude, our data underline the impact of the MGMT promoter methylation status in the treatment response of IDH1-wildtype GBM. In addition, age, tumour size and hemisphere were also significant prognostic factors in the overall survival of patients.

A prognostic matrix gene expression signature defines functional glioblastoma phenotypes and niches.

Interactions among tumor, immune, and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Here, through computational genomics and proteomics approaches, we analyzed the functional and clinical relevance of CMP expression in GBM at bulk, single cell, and spatial anatomical resolution. We identified genes encoding CMPs whose expression levels categorize GBM tumors into CMP expression-high (M-H) and CMP expression-low (M-L) groups. CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells, and immune checkpoint gene expression. Anatomical and single-cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene CMP expression signature, termed Matrisome 17 (M17) signature that further refines the prognostic value of CMP genes. The M17 signature is a significantly stronger prognostic factor compared to MGMT promoter methylation status as well as canonical subtypes, and importantly, potentially predicts responses to PD1 blockade. The matrisome gene expression signature provides a robust stratification of GBM patients by survival and potential biomarkers of functionally relevant GBM niches that can mediate mesenchymal-immune cross talk. Patient stratification based on matrisome profiles can contribute to selection and optimization of treatment strategies.

HGG-08. DIFFUSE HEMISPHERIC GLIOMA, H3 G34-MUTANT: A MULTI-INSTITUTIONAL EXPERIENCE

Abstract BACKGROUND Diffuse hemispheric glioma (DHG), H3 G34-mutant, is a rare, aggressive brain tumor molecularly defined by mutations in the H3-3A gene. Our study explored the association between patient outcomes and key molecular findings, resection extent, and temozolomide (TMZ) use. METHODS Multi-institutional chart and molecular analysis of 32 patients with H3 G34-mutant DHG. RESULTS The median patient age was 14 (10-28 years), with a M/F ratio of 1.4. The 1-year, 2-year, and 5-year PFS were 40.4% (23.7%, 57.1%), 22.1% (9.0%, 38.7%), and 11.0% (1.9%, 33.7%), respectively. The 1-year, 2-year, and 5-year OS were 82.5% (63.2%, 92.3%), 49.3% (28.7%, 66.3%), and 29.6% (9.1%, 50.6%), respectively. Patients who underwent a gross total resection (GTR) had improved PFS (p=0.0105) and OS (p=0.0184) compared to non-GTR patients. 22 patients (68.8%) received concurrent and/or adjuvant TMZ and had improved PFS (p=0.0278) compared to patients who did not receive front-line TMZ. Disease recurrence in relation to the radiation therapy (RT) field was analyzed in 17 patients; 5 recurred locally within the high-dose RT field, 5 recurred distantly, and 7 had both local and distant recurrences. There was no significant association between MGMT promoter methylation status (18 evaluable cases), PDGFRA amplification (N=6), and CDKN2A homozygous deletion (N=10) and survival outcomes. MGMT promoter methylation was not associated with increased TMZ efficacy (N=8 with MGMT silencing, N=4 without). CONCLUSIONS In our cohort, MGMT promoter methylation was not a favorable prognostic factor, in distinction from prior reports in adult and pediatric high-grade gliomas. Resection extent and the use of TMZ were associated with improved survival outcomes. As most treatment failures occurred within the high-dose RT field, extended fields do not appear warranted. Our findings may guide prognostic and therapeutic decisions in patients with H3 G34-mutant DHG and support the need for prospective efforts to improve outcomes in this patient population.

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.