Diagnosis Of Glioblastoma Research Articles

Naringenin Nanoformulations for Neurodegenerative Diseases.

Glioblastoma (GBM) is a grade-IV astrocytoma, which is the most common and aggressive type of brain tumor, spreads rapidly and has a life-threatening catastrophic effect. GBM mostly occurs in adults with an average survival time of 15 to 18 months, and the overall mortality rate is 5%. Significant invasion and drug resistance activity cause the poor diagnosis of GBM. Naringenin (NRG) is a plant secondary metabolite byproduct of the flavanone subgroup. NRG can cross the blood-brain barrier and deliver drugs into the central nervous system when conjugated with appropriate nanocarriers to overcome the challenges associated with gliomas through naringenin-loaded nanoformulations. Here, we discuss several nanocarriers employed that are as delivery systems, such as polymeric nanoparticles, micelles, liposomes, solid lipid nanoparticles (SLNs), nanosuspensions, and nanoemulsions. These naringenin-loaded nanoformulations have been tested in various in vitro and in vivo models as a potential treatment for brain disorders. This review nanoformulations of NRG can a possible therapeutic alternative for the treatment of neurological diseases are discussed.

Cross-Sectional Study for the Detection of Glioblastoma on Spectroscopy with Histopathology as Gold Standard

Objectives: Glioblastoma (GBM) is one of the most aggressive brain tumors. Patients with GBM typically experience an irreversible return of the disease despite receiving multimodal treatment including surgery, radiation, and chemotherapy. GBMs typically exhibit poor vascularization and fast cell growth, which frequently results in tumor regions with insufficient oxygen supply. This study's goal is to ascertain, using histopathology as the gold standard, the diagnostic accuracy of magnetic resonance spectroscopy (MRS) in the diagnosis of glioblastoma. Methods: 83 participants were engaged in this six-month cross-sectional descriptive study that was carried out at the Department of Radiology, Shifa International Hospital in Islamabad. For each of these individuals, a single voxel approach was used for MR spectroscopy. To locate the lesion, post-contrast conventional MR imaging was first performed. A voxel was then placed on the region of interest. The pathology department at Shifa International Hospital in Islamabad received specimens from patients undergoing intracranial biopsies for histopathological investigation. The results of the MRS were then compared with the histopathology report. Results: The patients' average age was 52.2±12.6 years. 34 females (51%), and 49 males (59%) were present. The average length of the illness was 2.0±1.7 years, and the average lesion size was 54.3±26.9 mm. The results of MR spectroscopy diagnostic accuracy in the diagnosis of glioblastoma were 91.5%, with sensitivity being 90.7%, specificity being 94.4%, positive predictive value being 98.3%, negative predictive value being 73.9%. Conclusion: To sum up, this study showed that magnetic resonance spectroscopy is a valuable tool for glioblastoma diagnosis.

The Impact of Timing of Temozolomide Chemoradiotherapy for Newly Diagnosed Glioblastoma on Patient Overall Survival: A Multi-centre Retrospective Study

Abstract Background The optimal timing of initiating adjuvant temozolomide (TMZ) chemoradiotherapy after surgery in patients with glioblastoma is contentious. This study aimed to determine whether the timing of adjuvant treatment affects their overall survival (OS). Methods Consecutive adult patients with histologically-confirmed newly-diagnosed glioblastoma treated with adjuvant TMZ chemoradiotherapy across all neurosurgical centers in Hong Kong between 2006 and 2020 were analyzed. The surgery-to-chemoradiotherapy (S-CRT) interval was defined as the date of the first surgery to the date of initiation of adjuvant TMZ chemoradiotherapy. Results Four-hundred and seventy-two patients were reviewed. The median S-CRT interval was 41 days (IQR: 33-48) and the mOS was 16.7 months (95% CI: 15.9-18.2). The median age was 58 years (IQR: 50-63). Multivariable Cox regression with restricted cubic splines identified a non-linear relationship between the S-CRT interval and mOS. Post-hoc analysis-derived S-CRT intervals revealed that early CRT (< 5 weeks; adjusted hazard radio (aHR): 1.11; 95% CI 0.90-1.37) or late CRT (> 9 to 12 weeks; aHR 1.07; 95% CI 0.67-1.71) were not significantly associated with OS. Subgroup analyses for extent of resection (EOR) and pMGMT methylation status revealed no significant difference in treatment timing on OS. Conclusion The timing of adjuvant TMZ chemoradiotherapy if commenced within 12 weeks after glioblastoma diagnosis did not influence OS, regardless of EOR or pMGMT methylation status. Clinical judgement should be exercised in optimizing the timing of initiating adjuvant therapy.

Discovery of key molecular signatures for diagnosis and therapies of glioblastoma by combining supervised and unsupervised learning approaches

Glioblastoma (GBM) is the most malignant brain cancer and one of the leading causes of cancer-related death globally. So, identifying potential molecular signatures and associated drug molecules are crucial for diagnosis and therapies of GBM. This study suggested GBM-causing ten key genes (ASPM, CCNB2, CDK1, AURKA, TOP2A, CHEK1, CDCA8, SMC4, MCM10, and RAD51AP1) from nine transcriptomics datasets by combining supervised and unsupervised learning results. Differential expression patterns of key genes (KGs) between GBM and control samples were verified by different independent databases. Gene regulatory network (GRN) detected some important transcriptional and post-transcriptional regulators for KGs. The KGs-set enrichment analysis unveiled some crucial GBM-causing molecular functions, biological processes, cellular components, and pathways. The DNA methylation analysis detected some hypo-methylated CpG sites that might stimulate the GBM development. From the immune infiltration analysis, we found that almost all KGs are associated with different immune cell infiltration levels. Finally, we recommended KGs-guided four repurposable drug molecules (Fluoxetine, Vatalanib, TGX221 and RO3306) against GBM through molecular docking, drug likeness, ADMET analyses and molecular dynamics simulation studies. Thus, the discoveries of this study could serve as valuable resources for wet-lab experiments in order to take a proper treatment plan against GBM.

NIMG-07. GLIOBLASTOMA AS A MIMIC OF ACUTE ISCHEMIC STROKE: AN UNDERRECOGNIZED PHENOMENON AND THE IMPACT ON PATIENT OUTCOMES

Abstract BACKGROUND Glioblastoma may present similarly to acute ischemic stroke. This study aims to determine characteristics and outcomes of patients with glioblastoma presenting with stroke-like symptoms. Our objective is to characterize patients with glioblastoma who present as mimics of acute ischemic stroke and identify differences in outcomes when compared to those diagnosed with glioblastoma only. METHODS The 2016-2019 National Inpatient Sample (NIS) database was queried for all patients who had a new diagnosis of glioblastoma. Patients with new glioblastoma who carried an admission diagnosis of acute ischemic stroke, but did not undergo thrombectomy, chemical thrombolysis, or hemicraniectomy were categorized as “GBM-Stroke Mimic”. The characteristics and comorbidities between GBM-Stroke Mimic and new glioblastoma patients were compared. Primary outcomes analyzed were discharge disposition and mortality. RESULTS Of 61,755 patients newly diagnosed with glioblastoma, 1,000 (1.6%) were GBM-Stroke Mimics. GBM-Stroke Mimic patients more commonly presented with aphasia (P < 0.001) and hemiplegia (P < 0.001). Age greater than 65, atrial fibrillation, diabetes mellitus, hypertension, hyperlipidemia, and long-term anticoagulation/antiplatelet therapy were more commonly associated with GBM-Stroke Mimic patients (all P < 0.001). GBM-Stroke Mimic patients were more likely to be discharged to skilled nursing facility, (p < 0.001), and a diagnosis of GBM-Stroke Mimic was an independent risk factor for inpatient death (P < 0.001). CONCLUSION To our knowledge, this is the first study formally investigating the clinical outcomes of glioblastoma when initially diagnosed as stroke. When this misdiagnosis is made, we found an association with increased inpatient mortality, delays of care, and inappropriate resource allocation.

EPID-34. THE EFFECT OF ANTIDEPRESSANT THERAPY ON GLIOBLASTOMA SURVIVAL: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract BACKGROUND Symptoms of depression are highly prevalent among patients with glioblastoma (GBM) and have been associated with poor outcomes. In addition to managing depression symptoms, preclinical and clinical studies suggest that antidepressants may inhibit GBM progression and may be associated with improved outcomes. However, the effect of antidepressants on survival is unknown and results from existing studies are conflicting. OBJECTIVE We conducted a systematic review and meta-analysis to investigate the effect of antidepressant therapy on GBM survival. METHODS We searched PubMed, Embase, Scopus, PsycINFO, and Web of Science from inception to March 2024 for studies assessing the overall survival of patients with GBM treated with antidepressants. Prespecified Hazard ratios (HR), 95% confidence interval (CIs), median overall survival, and patient characteristics were extracted. Results were combined using a restricted maximum-likelihood estimation random-effects model. RESULTS We identified 6 observational studies meeting inclusion criteria with 8269 patients. Of these, 1093 (13%) were treated with antidepressant therapy at some point after their GBM diagnosis. Antidepressant therapy was not significantly associated with overall survival (HR 1.27, 95% CI 0.90-1.79, p=0.17). In a sub-analysis of studies that specified whether SSRIs were utilized, SSRI usage specifically was also not associated with overall survival (HR 1.08, 95% CI 0.58-2.03, p=0.81) We observed considerable heterogeneity (I2 = 92.7%, p<.001). CONCLUSIONS Antidepressants were not significantly associated with overall survival in patients with GBM. However, our meta-analysis was limited by significant heterogeneity observed across studies. The effect of antidepressants on outcomes in patients with GBM remains uncertain. We observed conflicting results in the literature, with some studies suggesting decreased survival. Therefore, the role of antidepressants in patients with GBM warrants further investigation.

DNAR-13. LONG TERM FOLLOW-UP OF A LYNCH SYNDROME-ASSOCIATED GLIOBLASTOMA RESISTANT TO STANDARD-OF-CARE CHEMORADIATION

Abstract BACKGROUND Lynch syndrome is caused by pathogenic germline variants in the DNA mismatch repair (MMR) genes, predisposing individuals to malignancies, including glioblastoma (GBM). MMR-deficient tumors are resistant to monofunctional alkylators such as temozolomide but not to bifunctional alkylators such as the nitrosourea lomustine. Anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitor (ICI) pembrolizumab represents another treatment option, which is approved by the United States Food and Drug Administration (FDA) for the treatment of mismatch repair deficient cancers. METHODS We present a patient with multifocal GBM and Lynch syndrome who experienced rapid progression following standard-of-care chemoradiation, followed by durable responses to lomustine and then to pembrolizumab. RESULTS A 58-year-old man with Lynch syndrome (MSH2 mutation) and prior history of colon cancer presented with seizures. Magnetic resonance imaging (MRI) brain identified right frontal and left parietal masses. Right frontal tumor was resected; pathology was consistent with GBM, IDH wildtype, MGMT-unmethylated. Both lesions were treated with radiation therapy (60 Gy, 30 fractions) with concurrent and adjuvant temozolomide. After two cycles of adjuvant temozolomide, his left parietal tumor progressed and was subtotally resected, followed by four cycles of lomustine (stopped due to myelotoxicity). He remained progression-free for 15 months. Surveillance MRI identified new enhancement involving the left frontal lobe, left periventricular white matter, and right internal auditory canal, concerning for leptomeningeal dissemination. MRI spine identified no additional lesions. Cerebrospinal fluid cytology was negative for tumor cells on two occasions. Patient was treated with pembrolizumab. He remains on treatment with stable disease four months after ICI initiation and 31 months after GBM diagnosis. CONCLUSIONS Patients with MMR-deficient GBM resist standard chemoradiation. Alternatives such as nitrosourea or ICI therapy may achieve durable responses. While data is insufficient to administer these agents as upfront therapy in this specific setting, both should be considered as options for recurrent disease.

NIMG-80. IMPACT OF KETOGENIC DIET ON MOLECULAR METABOLIC IMAGING WITH [18F]FDG AND [18F]DASA-23 POSITRON EMISSION TOMOGRAPHY IN A PATIENT WITH GLIOBLASTOMA

Abstract The standard-of-care for neuroimaging in patients with glioblastoma is contrast-enhanced MRI, which does not provide tumor metabolism information. Although [18F]FDG PET is used to image tumor metabolism in many solid organ cancers, it has limited benefit in atients with brain tumors due to the high level of glucose uptake in normal brain cells. [18F]DASA-23 is a novel PET radiotracer that assesses the levels of pyruvate kinase M2 (PKM2), a protein highly expressed in cancer cells, which undergo aberrant glycolysis. Despite [18F]DASA-23 having a higher tumor-to-background ratio (TBR) of standardized uptake values (SUVs) in the brain compared to [18F]FDG, both may be susceptible to altered carbohydrate metabolism in the setting of a ketogenic diet (KD). We report the case of a patient with glioblastoma on a KD, whose [18F]FDG and [18F]DASA-23 PET brain scans were limited in identifying disease progression (PD). Background was defined as the white matter contralateral to the tumor, at the level of the centrum semiovale, for TBR of SUVmax. A 39-year-old man was diagnosed with right temporal glioblastoma after previous diagnoses of grade 2 gliofibrillary oligodendroglioma (age 20) and grade 3 anaplastic oligodendroglioma (age 22). He began a KD after the glioblastoma diagnosis. 21 months later, TBR on [18F]DASA-23 PET was 1.38. One month later, surveillance brain MRI showed PD. Ten days later, TBR on [18F]FDG PET was 1.03. The patient died 15 months later. Despite MRI-based PD, the TBR of each radiotracer was not markedly elevated, although the [18F]DASA-23 TBR 1-month pre-PD was 34% greater than the [18F]FDG PET TBR 10-days post-PD. This may suggest a limitation of metabolic imaging by PET in the setting of a KD, and provide an opportunity to develop novel PET radiotracers that are not susceptible to the patient’s diet.

QLTI-11. PREDICTORS OF PROLONGED LENGTH OF STAY IN LASER INTERSTITIAL THERMAL THERAPY FOR INTRACRANIAL PATHOLOGIES: A SINGLE CENTER EXPERIENCE

Abstract INTRODUCTION Laser interstitial thermal therapy (LITT) offers a minimally invasive approach for treating intracranial pathologies, often with shorter hospital stays than traditional craniotomies. Yet, some patients still face prolonged length of stay (PLOS), highlighting the need to identify contributing factors and improve post-LITT outcomes. OBJECTIVE To evaluate factors contributing to PLOS following LITT for intracranial pathologies. METHODS A retrospective review was conducted between 2013-2023 for patients undergoing LITT for intracranial pathology at a tertiary care center. PLOS was defined as discharge >2 days. Multivariate logistic regression analyzed variables as contributors to PLOS including ICU LOS (hours), preoperative maximum tumor diameter (cm), lesion location, lesion pathology (high grade glioma (HGG)/glioblastoma (GBM) vs. other), and mFI-11 score (binary ≥ or < 75th percentile). RESULTS The cohort consisted of 288 patients, with 29% (83/288) and 71% (205/288) having PLOS and non-PLOS, respectively. Mean age was similar between the PLOS (63-years) and non-PLOS (60-years) groups (p=0.09). The PLOS group had a 55% male predominance compared to 57% female in the non-PLOS group. Greater mFI-11 scores showed increased risk of PLOS [4.01, (2.11, 7.60), p<0.000]. Lesions having a subcortical location [3.43 (1.70, 6.95), p=0.001] or diagnosis of HGG or GBM [2.87 (1.54, 5.34), p=0.001] had increased risk of PLOS. Importantly, maximum pre-operative diameter did not significantly alter risk of PLOS [1.05 (0.98, 1.13), p=0.151]. CONCLUSION For the first time, we show that patient comorbidities, subcortical lesion location, HGG/GBM pathology, and greater time spent in the ICU portend increased risk of PLOS following LITT. Future work should validate our model with the goal of optimizing post-operative patient management and resource allocation.

DISP-18. RACIAL DISPARITY IN THE UTILIZATION OF MOLECULAR DIAGNOSTIC AS A PROXY FOR SUB-OPTIMAL CLINICAL CARE IN GLIOBLASTOMA PATIENTS

Abstract BACKGROUND Molecular characterization of IDH mutation and MGMT-promoter methylation (MGMTm) are standard-of-care (SOC) diagnostics and essential to diagnosis, treatment, and prognosis of glioblastomas. Here, we determined the extent to which racial disparity occurs in this dimension of oncologic care. METHODS 31,439 glioblastoma patients were derived from the National Cancer Database (NCDB,2018-2021), with 20,736 IDH-wildtype patients with defined MGMT-status. Accessibility to SOC diagnostics was defined as whether patients got IDH/MGMT testing or not. Race/Ethnicity was grouped into Non-Hispanic White (NHW), Non-Hispanic Black, Asian/Pacific Islander, Hispanic, and Others. Receipt of SOC diagnostics and treatments, post-operative outcomes, and overall survival (OS) were explored using multivariable logistic regression, Kaplan-Meier method, and Cox proportional hazards models. RESULTS Relative to NHWs, all racial minority groups were less likely to have undergone IDH or MGMT-testing. These effects remain robust after adjusting for economic status, insurance, and facility type. Patients who received neither IDH nor MGMT-testing were 38% less likely to undergo SOC concurrent chemo-/radiation therapy (cCRT) relative to those having both testing. Further, patients having neither IDH nor MGMT-testing showed significantly higher risk of 30-day mortality (aOR:2.20), 90-day mortality (aOR:1.60), and hazard of death (median OS:8.9-mon,aHR:1.09,p=0.002) than those having both testing (median OS:12.9-mon). Of those tested for both IDH/MGMT, the odds of bearing a methylated MGMT-promoter remained relatively constant across five racial groups. Non-NHW glioblastomas patients were significantly less likely to receive SOC-modality. Of the patients who underwent IDH/MGMT-testing and cCRT, median OSs were 23.7 and 14.4-mon for MGMT-methylated and unmethylated glioblastoma, respectively. No significant difference in hazards of death for racial/ethnic minorities compared to NHWs was detected, regardless of MGMT-methylation status. CONCLUSIONS Our findings suggest that non-NHW glioblastoma patients are less likely to undergo SOC diagnostic (IDH/MGMT) testing, which serves as a proxy for receipt of sub-optimal clinical care. For glioblastoma patients who underwent SOC molecular testing and treatment, survival is similar across racial groups.

QLTI-22. TEMOZOLOMIDE CHEMOTHERAPY EFFECTS ON GLIOMA PATIENT FERTILITY AND THEIR OFFSPRING: A RETROSPECTIVE REVIEW

Abstract Gliomas represent ~30% of primary brain tumors. Temozolomide (TMZ) chemotherapy with concurrent radiation or following radiation is the main course of treatment. Avoidance of pregnancy in female patients and partner of male patients is strongly encouraged due to unknown teratogenic and long-term effects to the health and development of fetus. Patients of childbearing age must wrestle with receiving TMZ treatment, potentially impacting fertility, and the desire for biological children in the future. Gamete preservation prior to TMZ induction is the current solution, which is often financially prohibitive, leaving patients to consider natural conception after completion of TMZ. We intend to identify potential difficulties in conception, pregnancy complications, birth abnormalities, and childhood developmental deficiencies that may be correlated to TMZ exposure prior to conception. Included patients conceived and delivered one or two children after completing treatment with TMZ. All patients received antiepileptic drugs (range = 1-4) which have variable known teratogenic effects during pregnancy. We identified 13 patients (7 male, 6 female; median age of 29) with diagnoses of astrocytoma (n=5), oligodendroglioma (n=5), oligoastrocytoma (n=2; diagnosed prior to 2021 WHO classification), and glioblastoma (n=1). Two reported issues with conceiving (1 male and 1 female) and 17 children were born. One child had developmental abnormalities (6%), and all other 16 children were healthy per parental assessment. Complete results of pregnancy complication and childhood development data will be updated at the meeting. Information on teratogenic and developmental effects of TMZ in humans is largely unknown. Animal studies have shown an increase in fetal malformations when exposed to TMZ during pregnancy. Despite the limitations of a retrospective study, our findings suggest that natural conception after the conclusion of TMZ treatment may be safer than suspected. Given the limited sample size, future comprehensive studies are warranted to corroborate these observations.

DISP-17. OUTCOMES, CLINICAL AND MOLECULAR CHARACTERISTICS OF HISPANIC PATIENTS WITH IDH WILDTYPE GLIOBLASTOMA

Abstract BACKGROUND Knowledge about outcomes in Hispanic patients with gliomas is scant and mainly derived from tumor registries. IDH wild-type glioblastomas (GBM) are the most common and aggressive malignant primary brain tumor. Hispanics account for 19% of US population, reaching 29% in Florida and 65% in Miami-Dade County. As a reference center for GBM serving the community of South Florida we provide care for many Hispanic patients. Herein, we aim to describe the clinical and molecular features, including RNA seq analysis of Hispanic vs non-Hispanic patients with IDH wild-type GBM. METHODS Retrospective study of adult patients with diagnosis of IDH Wild-type Glioblastoma, who had NGS testing, treated at University of Miami. RESULTS 179 patients were included, 63 (35%) were Hispanic. 41 (65%) of Hispanic patients were males as compared to 65 (56%) of the non-Hispanics. Median age at diagnosis was 54 years (45-67) for the Hispanic vs 62 (54-72) years for non-Hispanic, p=.002. With a median follow up of 17 months (CI 95% 14-19), median overall survival for Hispanic patients was 22 months (18-25) and 23 months (18-28) for non-Hispanics, p=.99. 42 (23%) patients were enrolled in clinical trials, of whom 21 (50%) were Hispanic, meaning 33% of Hispanic patients enrolled. The molecular characteristics from these patients by next-generation sequencing, including RNA seq, are being analyzed. CONCLUSIONS In our series of IDH wild-type Glioblastomas, Hispanic patients were significantly younger at diagnosis compared to non-Hispanic patients, but there were no differences in overall survival. 33% of Hispanic patients were enrolled in clinical trials. As the latest growing ethnic group in the USA, major efforts have to be made to better understand the disease characteristics and outcomes of this particular population. To our knowledge this will be the first report of the molecular characteristics by NGS from Hispanic patients with GBM.

NIMG-60. SUBTYPING GLIOBLASTOMA FROM JOINT CLUSTERING OF IMAGING AND GENOMIC DATA

Abstract PURPOSE To comprehensively unravel the heterogeneity of glioblastoma, we developed a subtyping method using integrated imaging and genomic data. METHODS We assembled a retrospective cohort of 571 IDH-wildtype glioblastoma patients, obtaining pre-operative multi-parametric MRI (T1, T1-GD, T2, T2-FLAIR, DSC, DTI) scans (available for 462 patients) and targeted next-generation sequencing (NGS) data (available for 355 patients). We extracted 971 radiomic features from these MRI scans, selecting 12 significant dimensions through L21-norm minimization guided by 13 key driver genes from the five most frequently altered pathways in glioblastoma compared to healthy controls (RB1, P53, MAPK, PI3K, and RTK). Subtypes were identified using a joint clustering approach that integrated radiomics and genomics. RESULTS Our method identified three glioblastoma subtypes with distinct risk levels: high-risk (subtype 1), medium-risk (subtype 2), and low-risk (subtype 3), each characterized by their differential overall survival outcomes (Kaplan-Meier analysis, p < 0.05). The intensities of axial diffusivity in enhancing tumor regions and radial diffusivity in non-enhancing cores increased across three subtypes. All subtypes shared a common tendency for more frequent mutation co-occurrence pattern in [TP53,RB1] but exhibited unique molecular characteristics. For example, subtype 1 displayed a relatively high frequency of co-occurring mutations in [TP53,KDR] and [NOTCH2,MDM4]; subtype 2 had six co-occurring pairs [TP53,KDR], [PTPN11,NF1], [RB1,FUBP1], [PTEN,CIC], [PTEN,KRAS], and [NOTCH2,CDKN2A]; subtype 3 showed six co-occurring pairs [PTPN11,NF1], [PDGFRA,NF1], [NTRK1,NOTCH2], [MET,ATRX], [KRAS,KDR], and [FGFR2,DNMT3A] plus four significant patterns of mutual exclusivity in [TP53,PTPN11], [TP53,EGFR], [EGFR,RB1], and [EGFR,NF1]. CONCLUSION Our study discovered distinct glioblastoma subtypes, revealing complex patterns and structures across multiple data modalities without relying on prior clinical assumptions. This is promising to help enhance the precision of diagnosis and treatment of glioblastoma.

BIOM-24. GLIOBLASTOMA DNA ALTERATIONS AND RAPID EARLY PROGRESSION AFTER SURGERY

Abstract Glioblastoma is the most common primary brain cancer with overall poor prognosis. In the weeks following initial resection, approximately 50% of glioblastoma patients will demonstrate rapid early progression (REP) on MRI prior to the start of radiation therapy (RT). REP is associated with worse overall survival (OS), however associations between REP and biomarkers in glioblastoma have yet to be evaluated. A single institution sample of 100 patients (age 61.2 years median, 57 males) with a primary diagnosis of glioblastoma were included in this study. Patients underwent gross or subtotal resection followed by RT within 60 days of their surgery. Patients who received biopsy only were excluded. For this analysis, REP was defined as increased nodular enhancement at the border of the resection cavity between the post-operative MRI and RT planning MRI. DNA mutations were collected from commercial next generation sequencing (NGS) results. Biomarkers with a mutational incidence of >10% were used in the analysis, which included TERT promoter (N=80), EGFR (N=38), PTEN (N=40), TP53 (N=36), CDKN2A/2B (N=41), NF1 (N=16), MTAP (N=24), PIK3CA (N=14), and MGMT methylation status (N=32). Statistical analysis was performed using SPSS Statistics 28.0. Of the patients sampled, 45 met the classification of REP. The presence of EGFR alterations (p=0.001) and MGMT methylation (p=0.016) strongly correlated with REP. After multivariate linear regression, only EGFR alterations significantly correlated with REP (p=0.006). There was no significant correlation between REP or overall survival and mutations in TERT promoter, PTEN, TP53, CDKN2A/2B, NF1, MTAP, and PIK3CA. This is the first study to analyze molecular contributors to REP. We identified that EGFR alterations are most strongly correlated with REP. This suggests that patients with EGFR alterations identified on pathology should move rapidly to adjuvant therapies given their propensity to quickly re-grow after resection.

RADT-40. EVALUATION OF SMALLER CLINICAL TARGET VOLUMES AND PATTERNS OF PROGRESSION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA TO INFORM FUTURE DIRECTIONS IN RADIATION TREATMENT PLANNING

Abstract BACKGROUND NRG Oncology Group guidelines recommend a clinical target volume (CTV) including generous expansions and incorporation of T2/FLAIR to account for potential tumor infiltration for glioblastoma patients, though smaller CTV expansions may be feasible. We retrospectively reviewed a large cohort of GBM patients to characterize patterns of recurrence and to assess the potential for smaller CTV margins. METHODS 312 consecutive adult patients with histologically confirmed diagnosis of glioblastoma treated with radiation therapy and temozolomide at a single institution were included in this study. All relevant clinical and pathological data was retrieved from local electronic medical records. MRIs from four timepoints 1) Pre-operative, 2) post-operative, 3) post-radiation and 4) time of progression were reviewed and fused with each other with rigid registration. We created a gross tumor volume including the resection cavity and residual enhancing tumor (GTV-GAD) and a GTV which included the GAD-GTV and pre-radiation T2/FLAIR signal (GTV-FLAIR). Multiple CTV expansions were applied to the GAD-GTV and FLAIR-GTV to evaluate coverage of subsequent progressive disease. RESULTS We evaluated 312 patients with a median age of 59.8 (range 20-93), 59% male, 61% KPS ≥ 90, 49% underwent gross total resection (51% subtotal resection/biopsy), 43% methylated and 57% unmethylated. CTV expansions of 2 cm, 1.5 cm, 1 cm, 0.5 cm, and 0 cm from GTV-GAD would have covered the epicenter of recurrent tumor in 90.7%, 88.1%, 84.6%, 77.5%, and 53.5% of cases respectively. CTV expansions from GTV-FLAIR of 2 cm, 1.5 cm, 1 cm, 0.5 cm, and 0 cm would have covered the epicenter of recurrent tumor in 93.5%, 92.6%, 91.3%, 88.1%, and 78.8% of cases respectively. On multivariable analysis, GAD-GTV and FLAIR-GTV volume were not associated with progression-free or overall survival(P>0.05). CONCLUSION Based upon our analysis, smaller treatment volumes could represent an opportunity to reduce treatment-related morbidity without compromising clinical outcomes.

CTNI-79. ASSESSING SYSTEMIC AND LOCAL LEVELS OF LIDOCAINE DURING SURGERY FOR GLIOBLASTOMA

Abstract The objective of this study is to assess the pharmacokinetics of lidocaine penetration into tumor tissue during glioblastoma surgery. In-vitro studies of glioblastoma have demonstrated co-culture with lidocaine inhibits glioblastoma proliferation via inhibition of TRPM7 channels. TRPM7 is a transmembrane ion channel that modulates proliferation and migration in several human cancers. Scalp block with lidocaine during glioblastoma surgery has been associated with improved survival in human studies. Twelve patients were enrolled in this study. The study group received an intravenous bolus dose of 1.5 mg/kg IBW of lidocaine at induction of anesthesia followed by 2 mg/kg IBW/hr infusion of lidocaine. Craniotomy was performed in the standard fashion. A total of 3 fresh tumor specimens were collected hourly from each patient after confirmation of glioblastoma diagnosis by frozen section. Plasma samples were simultaneously collected for analysis. Lidocaine concentration was measured using mass spectroscopy. The maximum concentration of lidocaine (Cmax), time from bolus to maximum concentration (Tmax), and area under curve from 0-3 hours (AUC) were calculated for each patient. Patients were followed for survival and adverse events. The median tumor specimen Cmax, Tmax, and AUC values were 333 ng/dL (range 226-555), 179 min (range 126-211), and 20665 ng*min/dL (range 8003-55,426), respectively. Peak lidocaine concentration was reached in 6 of 12 cases. Median Cmax and Tmax for plasma samples were 1195 ng/dL (range 951-1475) and 191 min (range 156-211), respectively. Median overall survival was 308 days (range 74-413). Two grade 3 adverse events occurred which were deemed to be unlikely to be related to the study intervention. In conclusion, lidocaine infiltrates tumor tissue when administered intravenously during glioblastoma surgery. Concentrations do not reach levels previously demonstrated to inhibit tumor growth in in vitro studies (roughly 2*108 ng/dL lidocaine). Alternative mechanisms may explain previously observed improved outcomes with lidocaine administration in human studies.

Epidemiology of malignant brain tumors in Genova, Italy. 1993–2017

We present an updated analysis on the incidence of primary brain tumors in the Metropolitan Area of Genova, the capital of the northwestern Italian region Liguria.The number of cases and incidence rates for all malignant brain tumors, glioblastoma, malignant brain tumors other than glioblastoma, and brain tumors not otherwise specified were calculated for each of seven three-year and one-eighth four-year periods in which the quarter century 1993–2017 was divided. The rates were age-adjusted (AAR) using the 2013 European standard population, presented per 100,000 person-years and the average percentage change over the three-year period was calculated.The number of cases of all malignant brain tumors and glioblastoma was higher in males than in females in each three-year period and in the entire quarter century 1993–2017. During the latter, the average three-year percentage change in AARs for all brain tumors was minimal [0.6 (95% C.I. = -1.0/2.1) %] while for glioblastoma there was a change of 5.3 (95% C.I. = -0.4/11.3) %. The partially concurrent decline in the incidence rates of malignant brain tumors other than glioblastoma or not otherwise specified suggests that the observed increase in the incidence rate of glioblastoma during 1993–2017 may have been at least partially linked to the improvement during the same period in sensitivity and specificity of the diagnosis of glioblastoma, depleting the reservoirs of other malignant or unspecified brain tumors. Research into possibly increased environmental risk factors (e.g., population exposure to ionizing radiation) for glioblastoma in Genova remains warranted.

Leveraging machine learning for preoperative prediction of supramaximal ablation in laser interstitial thermal therapy for brain tumors.

Maximizing safe resection in neuro-oncology has become paramount to improving patient survival and outcomes. Laser interstitial thermal therapy (LITT) offers similar survival benefits to traditional resection, alongside shorter hospital stays and faster recovery times. The extent of ablation (EOA) achieved using LITT is linked to patient outcomes, with greater EOA correlating with improved outcomes. However, the preoperative predictors for achieving supramaximal ablation (EOA ≥ 100%) are not well understood. By leveraging machine learning (ML) techniques, this study aimed to identify these predictors to enhance patient selection and therefore outcomes. The objective was to explore preoperative predictors for supramaximal EOA using ML in patients with glioblastoma. A retrospective study was conducted on the medical records of 254 patients undergoing LITT from 2013 to 2023 at a single tertiary center. Cohort criteria included age ≥ 18 years, diagnosis of glioblastoma, single-trajectory ablation, and a complete dataset. The study assessed preoperative clinical and radiographic factors, using EOA ≥ 100% as the endpoint. Five ML models were used: logistic regression, random forest (RF), gradient boosting, Gaussian naive Bayes, and support vector machine. Training and testing cohorts were subsequently assessed across ML models with fivefold cross-validation. Models were optimized using hyperparameter tuning. Performance was primarily quantified using the area under the curve (AUC) of the receiver operating characteristic curve. The final cohort consisted of 72 patients. Among the ML models, RF achieved the highest AUC (mean ± SD 0.94 ± 0.06). The leading models identified that lower preoperative volume, history of prior radiation therapy, history of prior craniotomy, preoperative neurological deficits, history of preoperative seizures, and distance from intracranial heat sinks were predictive of successful ablations in patients. Additionally, RF had the best mean metrics: accuracy 0.88, precision 0.87, specificity 0.87, and sensitivity 0.89. This is the first study to investigate the role of ML for optimizing ablation volumes in LITT. These ML models suggest that low preoperative volumes, previous craniotomy, previous radiation therapy, no previous neurological deficits, larger catheter-heat sink distance, and the presence of preoperative seizures are important prognostic factors for predicting successful supramaximal ablations with LITT.

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

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

Prognosis prediction via histological evaluation of cellular heterogeneity in glioblastoma

Glioblastomas (GBMs) are the most aggressive types of central nervous system tumors. Although certain genomic alterations have been identified as prognostic biomarkers of GBMs, the histomorphological features that predict their prognosis remain elusive. In this study, following an integrative diagnosis of 227 GBMs based on the 2021 World Health Organization classification system, the cases were histologically fractionated by cellular variations and abundance to evaluate the relationship between cellular heterogeneity and prognosis in combination with O-6-methylguanine-DNA methyltransferase gene promoter methylation (mMGMTp) status. GBMs comprised four major cell types: astrocytic, pleomorphic, gemistocytic, and rhabdoid cells. t-distributed stochastic neighbor embedding analysis using the histological abundance of heterogeneous cell types identified two distinct groups with significantly different prognoses. In individual cell component analysis, the abundance of gemistocytes showed a significantly favorable prognosis but confounding to mMGMTp status. Conversely, the abundance of epithelioid cells was correlated with the unfavorable prognosis. Linear model analysis showed the favorable prognostic utility of quantifying gemistocytic and epithelioid cells, independent of mMGMTp. The evaluation of GBM cell histomorphological heterogeneity is more effective for prognosis prediction in combination with mMGMTp analysis, indicating that histomorphological analysis is a practical and useful prognostication tool in an integrative diagnosis of GBMs.