IDH Wildtype Research Articles

Spermine Synthase : A Potential Prognostic Marker for Lower-Grade Gliomas.

The objective of this study was to assess the relationship between spermine synthase (SMS) expression, tumor occurrence, and prognosis in lower-grade gliomas (LGGs). A total of 523 LGG patients and 1152 normal brain tissues were included as controls. Mann-Whitney U test was performed to evaluate SMS expression in the LGG group. Functional annotation analysis was conducted to explore the biological processes associated with high SMS expression. Immune cell infiltration analysis was performed to examine the correlation between SMS expression and immune cell types. The association between SMS expression and clinical and pathological features was assessed using Spearman correlation analysis. In vitro experiments were conducted to investigate the effects of overexpressing or downregulating SMS on cell proliferation, apoptosis, migration, invasion, and key proteins in the protein kinase B (AKT)/epithelialmesenchymal transition signaling pathway. The study revealed a significant upregulation of SMS expression in LGGs compared to normal brain tissues. High SMS expression was associated with certain clinical and pathological features, including older age, astrocytoma, higher World Health Organization grade, poor disease-specific survival, disease progression, non-1p/19q codeletion, and wild-type isocitrate dehydrogenase. Cox regression analysis identified SMS as a risk factor for overall survival. Bioinformatics analysis showed enrichment of eosinophils, T cells, and macrophages in LGG samples, while proportions of dendritic (DC) cells, plasmacytoid DC (pDC) cells, and CD8+ T cells were decreased. High SMS expression in LGGs may promote tumor occurrence through cellular proliferation and modulation of immune cell infiltration. These findings suggest the prognostic value of SMS in predicting clinical outcomes for LGG patients.

Single-cell transcriptomics reveals IRF7 regulation of the tumor microenvironment in isocitrate dehydrogenase wild-type glioma.

Mutations in isocitrate dehydrogenase (IDH) are important markers of glioma prognosis. However, few studies have examined the gene expression regulatory network (GRN) in IDH-mutant and wild-type gliomas. In this study, single-cell RNA sequencing and spatial transcriptome sequencing were used to analyze the GRN of cell subsets in patients with IDH-mutant and wild-type gliomas. Through gene transcriptional regulation analysis, we identified the M4 module, whose transcription factor activity is highly expressed in IDH wild-type gliomas compared to IDH-mutants. Enrichment analysis revealed that these genes were predominantly expressed in microglia and macrophages, with significant enrichment in interferon-related signaling pathways. Interferon regulatory factor 7 (IRF7), a transcription factor within this pathway, showed the highest percentage of enrichment and was primarily localized in the core region of wild-type IDH tumors. A machine-learning prognostic model identified novel subgroups within the wild-type IDH population. Additionally, IRF7 was shown to promote the proliferation and migration of T98G and U251 cells in vitro, and its knockdown affected glioma cell proliferation in vivo. This study systematically established the regulatory mechanism of IDH transcriptional activity in gliomas at the single-cell level and drew a corresponding cell map. The study presents a transcriptional regulatory activity map for IDH wild-type gliomas, involving single-cell RNA sequencing and spatial transcriptomics to identify gene regulatory networks, machine learning models for IDH subtyping, and experimental validation, highlighting the role of IRF7 in glioma progression.

Neurosurgical application of olaparib from a thermo-responsive paste potentiates DNA damage to prolong survival in malignant glioma.

There is increased pan-cancer specific interest in repurposing the poly adenosine diphosphate-ribose polymerase-1 (PARP-1) inhibitor, olaparib, for newly diagnosed or recurrent isocitrate dehydrogenase wild type glioblastoma. We explore whether intra-cavity delivery of olaparib confers a survival benefit in a pre-clinical high-grade glioma model. Primary tumor RNA sequencing data was used to determine PARP-1 as a target in the glioblastoma infiltrative margin. We assessed radiosensitization conferred by olaparib alone and concomitant to genotoxic insults in vitro using clonal growth assays, cell cycle analysis and immunocytochemistry, and in vivo upon post-surgical delivery from a temperature-sensitive polymeric paste. RNA-sequencing confirmed PARP-1 as a viable therapy target in glioblastoma infiltrative disease. Acute exposure of glioma cells to olaparib impaired proliferation and induced late-stage apoptosis associated with DNA damage in vitro, potentiated by radiation. Using high-grade glioma orthotopic allografts, a long-term overall survival benefit was observed upon interstitial olaparib delivery concomitant with radiotherapy, compared to systemic olaparib and standard glioblastoma treatment. Combined delivery of olaparib with either temozolomide or etoposide increased long-term survival, suggestive of olaparib functioning as DNA damage sensitizer. Collectively, our data support a rationale for localized olaparib delivery concomitant with the current clinical regimen for malignant glioma treatment.

P10.09.A BLOOD-BASED CLASSIFICATION OF IDH-STATUS OF NON-ENHANCING GLIOMAS: A MACHINE LEARNING APPROACH

Abstract BACKGROUND Non-invasive determination of IDH mutational status in patients with glioma could offer significant therapeutic opportunities. While IDH wildtype tumors (e.g., GBM) typically show enhancement on MRI, IDH mutant tumors often lack this enhancement. However, relying solely on anatomic radiology may lead to misclassification, and currently, tissue acquisition is the primary method for assessing IDH status in gliomas. This limitation hampers the development of neoadjuvant or intraoperative therapeutic strategies based on IDH status; thus, more minimally invasive methods to determine IDH status are needed. In this study, we assessed immune cell proportions, which vary by glioma subtype, from pre-surgery peripheral blood samples as an alternative method of classifying the IDH status in gliomas without enhancement. MATERIAL AND METHODS First, we employed a highly accurate large language model (GPT-4-Turbo-128k) with over 99% accuracy to read radiology notes and exclude patients with enhancing gliomas. Then, we identified twelve immune cell subtypes from whole blood using deconvolution algorithms based on DNA methylation data. These immune cell subtypes, along with patient age, were integrated into a machine learning model (random forest) to predict IDH status (wildtype vs. mutant), leveraging conditional Generative Adversarial Networks to generate synthetic data and mitigate bias in the datasets. Two independent datasets were included for training and validating the model. RESULTS The random forest model had an area under the ROC curve (AUC) of 0.90 and accurately identified IDH status in 81% of a training set of 287 gliomas (65 wildtype and 222 mutant tumors at varied time points after diagnosis). In an independent validation data set of 99 gliomas (6 wildtype and 93 mutant) from pre-surgery blood samples, the AUC was 0.93, and accuracy predicted IDH status in 92% of cases with a sensitivity of 93% and specificity of 83%. CONCLUSION We could accurately predict IDH status in pre-surgical peripheral blood samples from patients with non-enhancing gliomas. This minimally invasive approach is a promising step toward reducing risk and exploring opportunities for earlier therapies based on IDH status.

Looking Beyond the Surface: Olutasidenib and Ivosidenib for Treatment of mIDH1 Acute Myeloid Leukemia.

Mutations in isocitrate dehydrogenase-1 (IDH1) are recurrent in several malignancies and prevalent in acute myeloid leukemia (AML). Olutasidenib and ivosidenib are inhibitors that target mutant IDH1 (mIDH1) and are FDA approved for the treatment of patients with mIDH1 AML. Olutasidenib and ivosidenib were identified through unique molecular screens and thus are structurally very different molecules. A difference in clinical outcomes has been observed with olutasidenib, which has a longer duration of response than ivosidenib, despite similar rates of response being achieved with the two drugs, such as complete remission (CR) or CR with partial hematologic recovery (CR/CRh). In the absence of a head-to-head trial, this review examines both the extent of differences in clinical outcomes with the two drugs and provides the first comparison of the unique molecular and mechanistic features of each drug, such as molecular structure and binding kinetics, that may contribute to the observed clinical difference in outcomes. Olutasidenib is structurally smaller with a lower molecular weight than ivosidenib (FW 355 vs FW 583) and thus occupies less space in the binding pocket of IDH1 dimers, making it resistant to displacement by IDH1 second-site mutations. In biochemical studies, olutasidenib selectively inhibits mutant but not wild-type IDH1, whereas ivosidenib appears to potently block both mutant and wild-type IDH1. Although they have the same target, olutasidenib and ivosidenib have unique molecular features, which may translate to selectivity differences in their inhibitory activity against IDH1.

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 (>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.

INTEGRATING ALLIED HEALTH PROFESSIONALS DURING THE ONCOLOGICAL TREATMENT PHASE FOR GLIOBLASTOMA PATIENTS: A CASE STUDY AT A UK CANCER CENTRE

Abstract AIMS Primary brain tumour patients should be offered neurological rehabilitation assessment at diagnosis and every stage of follow With only 5% of glioblastoma patients surviving more than 5 years, specialist management that spans across all phases of the Dietz rehabilitation model is required to optimise function, treatment tolerance and Quality-of-life. At Guy’s cancer centre an Allied health multi-disciplinary team (Physiotherapy, Occupational therapy and Speech and language therapy) work alongside the oncologist-led clinic to support this patient group. METHOD Case history A 54-year-old, male, was diagnosed with right parietal Glioblastoma, WHO grade 4, IDH wildtype, MGMT 5.47% methylated (August 2023) on biopsy only. He underwent chemo/radiotherapy - 60gy/90 fractions with Temozolmide (TMZ) on 3/11/2023 Currently C4 of adjuvant TMZ. Dexamethazone 2mg was discontinued on 29/11/2023, he continues with Keppra 500mg twice daily. RESULTS Dietz Intervention approach in phases: PREVENTATIVE Fatigue management was introduced prior to radiotherapy including a physical activity review, advice on pacing, sleep hygiene and relaxation techniques. Given the patient’s history of shift work and altered sleep patterns, managing risks of treatment-related fatigue was of particular importance. Restorative & Supportive: A targeted and periodised exercise programme was initiated, comprising 1:1 gym based physiotherapy sessions. The aims included enhancing exercise confidence, improve balance, endurance, maintain strength, pain management and weight maintenance during chemo/radiotherapy and adjuvant TMZ. Education was deployed on adjusting activity levels based on chemotherapy cycle and day to day side effects, alongside ongoing fatigue management advice around pacing and sleep hygiene. CONCLUSION Learning and Recommendations Implementing tailored rehabilitation interventions early in the patient’s treatment pathway, enables proactive management to mitigate the impact of treatment-related side effects on their QOL. Based on our experience, early engagement with a dedicated therapy team is recommended to foster strong rapport with both the patient and their caregivers. This facilitates timely rehabilitation planning for optimal outcomes.

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

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

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

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

Bihemispheric IDH-Wildtype Glioblastoma with Unilateral FGFR3-TACC3 Fusion in Patient with Breast Cancer History: A Case Report and Literature Review

Abstract Introduction/Objective Adult IDH-wild type glioblastomas comprise a heterogeneous spectrum of neoplasms, characterized by poor prognosis and resistance to the chemoradiotherapy. For WHO integrated diagnosis classification and to establish treatment options, molecular analysis is necessary. Herein, we present a case of a glioblastoma, IDH-wildtype with involvement of both cerebral hemispheres and an uncharacteristic in-frame fusion limited to one hemisphere. Methods/Case Report The patient is a 52-year-old woman with past medical history of metastatic breast cancer who presented with headache and worsening facial pain. Brain magnetic resonance imaging brain demonstrated a right frontal lobe lesion with vasogenic edema. The patient was treated with Gamma Knife radiosurgery. Scans revealed enlargement and a new left frontal lobe lesion. Bihemispheric tumor resection and GammaTile placement was undertaken. Results (if a Case Study enter NA) Histologically, the tumor was composed of hypercellular astrocytes, microvascular proliferation, and necrosis with no evidence of metastatic disease. Immunohistochemistically, neoplastic cells showed glial fibrillary acidic protein expression and elevated Ki-67 proliferation index. Molecular examination revealed in the right hemisphere lesion post-radiation (1) FGFR3::TACC3 (exon 17::exon 11) fusion and (2) TERT promoter, while the left hemisphere lesion which did not receive radiation showed clinically relevant variants in (1) TERT promoter, (2) TP53, (3) NF1, and (3) PIK3CA without identification of a fusion. An integrated diagnosis of glioblastoma, IDH- wildtype, CNS WHO grade 4 was established bilaterally. Conclusion The fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil 3 (TACC3) fusion is identified as a rare molecular feature in glioblastomas with an estimated prevalence of 4%. Clinical trials suggest that F3T3-positive tumors have a better prognosis than those without the translocation. The identification of the oncogenic FGFR3-TACC3 fusion highlights the possibility of identifying patients potentially responsive to targeted therapy with FGFR kinase inhibitors. The significance of the molecular differences in the right and left hemisphere lesions is uncertain; glioblastomas are heterogeneous tumors with intra-and intertumoral heterogeneity but it may suggest independent origins.

PRECISE-GBM: A RADIOGENOMIC MACHINE LEARNING BASED STUDY TO IDENTIFY PREDICTIVE RADIOMICS FOR EVALUATION OF CANCER IMMUNE SIGNATURE IN IDHW GLIOBLASTOMA

Abstract AIMS The aim of the study is to identify machine learning model based on radiological biomarkers that can predict immune status within tumor microenvironment of IDH wildtype glioblastoma. METHOD This is a retrospective multicenter machine learning based study utilizing open access anonymized matched radiogenomic data of TCGA-GBM, CPTAC, Ivy GAP and REMBRANDT datasets. REMBRANDT data acted as hold out dataset. Imaging data consisted of MRI based radiomics features extracted from deep learning based segmented tumors and transcriptomic (RNA seq/microarray) data consisted of immune scores extracted using CIBERSORTx. Outliers were identified and filtered using principal component analysis. Combat and neuroCombat were utilized for data harmonization for each data type respectively. Radiomic feature selection was performed using LASSO technique with cross validation. Support vector machine (SVM) was trained and tested with 80:20 radiomics data split and a median based binary label of immune score (low and high). Validation of the trained model was performed with hold out dataset. Data query and analysis was performed using python and R statistical software. RESULTS One hundred one patients were included in the study with 15 being on the hold out set. Trained SVM model predicted the immune score label with AUC of 0.79 and balanced accuracy of 0.76 (recall 0.75, F1 score 0.75, precision 0.75) in the test data. In the holdout set, the model predicted the immune score with AUC of 0.70 with specificity of 75% in predicting the cold immune cases. The radiomic signature that acted as the label for this model were a group of first order and second order radiomic features. CONCLUSION Radiogenomic SVM model non-invasively predicts immune status in wildtype glioblastoma microenvironment with good accuracy. This model has potential to be utilized in a prospective glioblastoma clinical trial for immunotherapy.

Anatomy-guided resections for paralimbic tumors in the temporo-insular region: combining tumor and epilepsy surgery concepts.

Tumors in the temporo-mesial region often extend into the insula and vice versa. The present study investigated the results of a surgical strategy that combines principles of tumor and epilepsy surgery. We retrospectively analyzed 157 consecutive patients with intrinsic brain tumors in the temporo-mesial region, with varying degrees of extensions into the insula (44 patients, 28.0%). The surgical strategy utilized "anatomy-guided resection," targeting specific anatomical compartments infiltrated by the tumor (e.g., temporal pole, anterior temporo-mesial region = uncus and hippocampal head, posterior temporo-mesial, insula) rather than treating the tumor as a single mass. The most frequent histologies were ganglioglioma CNS WHO grade 1 (55 patients, 35.0%) and IDH1 wildtype glioblastoma (36 patients, 22.9%). Tumor infiltration was most commonly found in the anterior temporo-mesial compartment (145 patients, 92.4%). An anterior temporal lobectomy was part of the surgical strategy in 131 cases (83.4%). Seventy-six patients (48.4%) with drug-resistant epilepsy underwent a formal presurgical epilepsy work-up, including depth electrode placement in three cases. Complete resections were achieved in 117 patients (74.5%), with supramarginal resections performed in 89 cases (56.7%). Four patients experienced non-temporary neurological complications (CTCAE grade 3-5). At 6 months, 127 of 147 assessable patients (86.4%) were free from seizures or auras (ILAE class 1), excluding early postoperative seizures (<30 days). At 24 months, 122 of 144 assessable cases (84.7%) remained seizure-free (ILAE class 1). Kaplan-Meier estimates for 5-year overall survival were 98.5% for non-recurrent glioneuronal tumors. The 2-year overall survival estimates were 96.0% for 24 primary diffuse CNS WHO grade 2 and 3 gliomas and 55.2% for 30 patients undergoing first surgeries for glioblastomas/astrocytomas CNS WHO grade 4. Combining both epilepsy and tumor surgery concepts in the surgical treatment of intrinsic brain tumors involving the mesial temporal lobe, often extending into the insula, led to more extensive resections, improved seizure outcomes, and potentially even better patient survival outcomes.

Health-Related Quality of Life and Treatment Satisfaction of Patients with Malignant IDH Wild-Type Gliomas and Their Caregivers.

(1) Background: Clinical aspects like sex, age, Karnofsky Performance Scale (KPS) and psychosocial distress can affect the health-related quality of life (HR-QoL) and treatment satisfaction of patients with malignant isocitrate dehydrogenase wild-type (IDHwt) gliomas and caregivers. (2) Methods: We prospectively investigated the HR-QoL and patient/caregiver treatment satisfaction in a cross-sectional study with univariable and multiple regression analyses. Questionnaires were applied to investigate the HR-QoL (EORTC QLQ-C30, QLQ-BN20) and treatment satisfaction (EORTC PATSAT-C33). (3) Results: A cohort of 61 patients was investigated. A higher KPS was significantly associated with a better HR-QoL regarding the functional scales of the EORTC QLQ-C30 (p < 0.004) and a lower symptom burden regarding the EORTC QLQ-BN20 (p < 0.001). The patient treatment satisfaction was significantly poorer in the patients older than 60 years in the domain of family involvement (p = 0.010). None of the investigated aspects showed a significant impact on the treatment satisfaction of caregivers. (4) Conclusions: We demonstrated that in patients with IDHwt gliomas, the KPS was the most important predictor for a better HR-QoL in functional domains. Data on the HR-QoL and treatment satisfaction in patients with IDHwt gliomas and their caregivers are rare; therefore, further efforts should be made to improve supportive care in this highly distressed cohort.

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.

Fractal dimension and lacunarity measures of glioma subcomponents are discriminative of the grade of gliomas and IDH status.

Since the overall glioma mass and its subcomponents-enhancing region (malignant part of the tumor), non-enhancing (less aggressive tumor cells), necrotic core (dead cells), and edema (water deposition)-are complex and irregular structures, non-Euclidean geometric measures such as fractal dimension (FD or "fractality") and lacunarity are needed to quantify their structural complexity. Fractality measures the extent of structural irregularity, while lacunarity measures the spatial distribution or gaps. The complex geometric patterns of the glioma subcomponents may be closely associated with the grade and molecular landscape. Therefore, we measured FD and lacunarity in the glioma subcomponents and developed machine learning models to discriminate between tumor grades and isocitrate dehydrogenase (IDH) gene status. 3D fractal dimension (FD3D) and lacunarity (Lac3D) were measured for the enhancing, non-enhancing plus necrotic core, and edema-subcomponents using preoperative structural-MRI obtained from the The Cancer Genome Atlas (TCGA) and University of California San Francisco Preoperative Diffuse Glioma MRI (UCSF-PDGM) glioma cohorts. The FD3D and Lac3D measures of the tumor-subcomponents were then compared across glioma grades (HGGs: high-grade gliomas vs. LGGs: low-grade gliomas) and IDH status (mutant vs. wild type). Using these measures, machine learning platforms discriminative of glioma grade and IDH status were developed. Kaplan-Meier survival analysis was used to assess the prognostic significance of FD3D and Lac3D measurements. HGG exhibited significantly higher fractality and lower lacunarity in the enhancing subcomponent, along with lower fractality in the non-enhancing subcomponent compared to LGG. This suggests that a highly irregular and complex geometry in the enhancing-subcomponent is a characteristic feature of HGGs. A comparison of FD3D and Lac3D between IDH-wild type and IDH-mutant gliomas revealed that mutant gliomas had ~2.5-fold lower FD3D in the enhancing-subcomponent and higher FD3D with lower Lac3D in the non-enhancing subcomponent, indicating a less complex and smooth enhancing subcomponent, and a more continuous non-enhancing subcomponent as features of IDH-mutant gliomas. Supervised ML models using FD3D from both the enhancing and non-enhancing subcomponents together demonstrated high-sensitivity in discriminating glioma grades (~97.9%) and IDH status (~94.4%). A combined fractal estimation of the enhancing and non-enhancing subcomponents using MR images could serve as a non-invasive, precise, and quantitative measure for discriminating glioma grade and IDH status. The combination of 2-hydroxyglutarate-magnetic resonance spectroscopy (2HG-MRS) with FD3D and Lac3D quantification may be established as a robust imaging signature for glioma subtyping.

Patterns of intersectional tumor volumes in T2-weighted MRI and [18F]FET PET in adult glioma: a prospective, observational study

Brain tumor volumes as assessed by magnetic resonance imaging (MRI) do not always spatially overlap with biological tumor volumes (BTV) measured by [18F]Fluoroethyltyrosine positron emission tomography ([18F]FET PET). We prospectively investigated volumetric patterns based on the extent of tumor volume overlap between the two modalities. Eighty-six patients with newly diagnosed glioma who had undergone MRI and [18F]FET PET between 2007 and 2009 were included in this prospective study and (re-)classified according to CNS WHO 2021 (Classification of Tumors of the Central Nervous System by the World Health Organization). Four different patterns of volume overlap were defined mathematically according to the extent of overlap between MRI-based T2 tumor volume (non-enhancing tumor volume, nCEV) and BTVs. Progression-free (PFS) and overall survival (OS) were determined. Seventy patients were diagnosed with isocitrate dehydrogenase wildtype (IDHwt) glioblastoma and 16 with IDH-mutant glioma, respectively. The most common pattern was characterized by a larger non-contrast-enhancing tumor volume (nCEV) that enclosed all or most of the BTV and was observed in 46 patients (54%) (pattern 1). This pattern was more frequent in IDH-mutant gliomas than in IDH-wildtype glioblastoma (81% versus 47%, p = 0.02). In multivariate analyses, pattern 1 was associated with prolonged PFS (HR 0.59; 95 CI 0.34-1.0; p = 0.05), but not OS (HR 0.66; 95 CI 0.4–1.08; p = 0.1). For OS, presence of an IDH mutation (p = 0.05) and lower age (p = 0.03) were associated with prolonged OS. The spatial relation between nCEV and BTV varies within and between glioma entities. Most frequently, a larger nCEV encases the BTV. Some patients show spatially dissociated nCEVs and BTVs. Not accounting for this phenomenon in surgery or radiotherapy planning might lead to undertreatment.

N-Acetyl-L-Cysteine (NAC) Blunts Axitinib-Related Adverse Effects in Preclinical Models of Glioblastoma.

Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH-wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo-angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib-dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells. We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N-Acetyl-L-Cysteine (NAC) might be used to reduce senescence-associated adverse effects of axitinib treatment without altering its anti-tumor activity. We demonstrate that the use of the antioxidant molecule N-Acetyl-Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib-dependent toxicity. Overall, we found that NAC co-treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib-dependent toxicity.

The Role of Systemic Therapies in the Treatment of Grades 1-4 Gliomas.

The primary treatment for gliomas typically involves tumor resection followed by adjuvant radiotherapy, with increasing emphasis on chemotherapy and molecularly targeted drugs. This study aimed to review and summarize the literature on the systemic therapy of malignant gliomas.Chemotherapy may be considered in grades 2 and 3 gliomas, especially when mutations in 1p19q-codeletion are detected. The beneficial impact of adding chemotherapy to radiotherapy (PCV: procarbazine, lomustine, vincristine) has also been demonstrated. In grade 4 glioblastoma multiforme (GBM), wild-type isocitrate dehydrogenase (IDH) status showed the best treatment outcomes with temozolomide (TMZ) in patients with O-6-methylguanine-DNA methyltransferase (MGMT)promoter methylation. Prolonging adjuvant TMZ therapy improves treatment outcomes compared to the standard 6-cycle adjuvant therapy. Bevacizumab (BEV) monotherapy can improve progression-free survival and maintain the initial quality of life. Despite advancements in GBM treatment, outcomes remain unsatisfactory, with a median survival of 14-16 months. Further research is still needed regarding the systemic treatment of central nervous system gliomas.

Pre‑operative mean platelet volume is associated with overall survival in patients with IDH‑wildtype glioblastoma undergoing maximal safe resection.

Glioblastoma (GBM) is the most common, fast-growing, and aggressive malignant primary CNS tumor, with a survival time of ~15 months despite the use of surgery and adjuvant treatments. In recent years, there has been a growing interest in exploring the potential contribution of hemostasis and platelet activation in GBM biology. The present study assessed the association between the pre-operative coagulation profile [as indicated by prothrombin time (PT) ratio and activated partial thromboplastin time (aPTT) ratio], overall platelets (PLT) count and the mean platelet volume (MPV) with tumoral characteristics and overall survival in patients with isocitrate dehydrogenase-wildtype (IDH-wt) GBM.

Prospective longitudinal analysis of imaging-based spatiotemporal tumor habitats in glioblastoma, IDH-wild type: implication in patient outcome using multiparametric physiologic MRI

BackgroundPhysiologic MRI-based tumor habitat analysis has the potential to predict patient outcomes by identifying the spatiotemporal habitats of glioblastoma. This study aims to prospectively validate the cut-off for tumor progression obtained from tumor habitat analysis based on physiologic MRI in ascertaining time-to-progression (TTP) and the site of progression in glioblastoma patients following concurrent chemoradiotherapy (CCRT).MethodsIn this prospective study (ClinicalTrials.gov ID: NCT02613988), we will recruit patients with IDH-wild type glioblastoma who underwent CCRT and obtained immediate post-operative and three serial post-CCRT MRI scans within a three-month interval, conducted using diffusion-weighted imaging and dynamic susceptibility contrast imaging. Voxels from cerebral blood volume and apparent diffusion coefficient maps will be grouped using k-means clustering into three spatial habitats (hypervascular cellular, hypovascular cellular, and nonviable tissue). The spatiotemporal habitats of the tumor will be evaluated by comparing changes in each habitat between the serial MRI scans (post-operative and post-CCRT #1, #2, and #3). Associations between spatiotemporal habitats and TTP will be analyzed using cox proportional hazard modeling. The site of progression will be matched with spatiotemporal habitats.DiscussionThe perfusion- and diffusion-derived tumor habitat in glioblastoma is expected to stratify TTP and may serve as an early predictor for tumor progression in patients with IDH wild-type glioblastoma.Trial registrationClinicalTrials.gov ID: NCT02613988.