High-grade Glioma Patients Research Articles

Non-invasive intracranial pressure monitoring for high-grade gliomas patients treated with radiotherapy: results of the GMaPIC trial.

Patients with high-grade gliomas are at risk of developing increased intracranial hypertension (ICHT) in relation to the increase in volume of their tumor. ICP change cannot be measured by invasive method but can be estimated by using routine clinical signs, in combination with a standard imaging method, magnetic resonance imaging (MRI). A non-invasive monitoring of ICP could be of interest in high-grade glioma, in particular after radiotherapy treatment with as major side effect a cerebral oedema. This prospective clinical study aimed to compare the ICP changes (estimated by a non-invasive method based upon distortion product otoacoustic emissions (DPOAE) monitoring) with volume changes observed on MRI in patients with high-grade gliomas treated with radiotherapy. DPOAE measurements were performed one month after the end of radiotherapy and then every 3 months for one year. At each visit, the patient also underwent MRI as well as an evaluation of clinical signs. The variation in the estimate of intracranial pressure readout measured at each follow-up visit (in absolute value with respect to the baseline measurements) was significantly associated with the variation of T2/FLAIR volume (n=125; p<0.001) with a cut off value of change ICP readout of 40.2 degrees (e.i. an estimated change of 16 mm Hg). The GMaPIC trial confirm the hypothesis that the ICP change estimated by DPOAEs measurement using a non-invasive medical device is correlated with the change of the tumor or edema in high grade glioma after radiotherapy. The device could thus become an easy-to-use and non-invasive intracranial pressure monitoring tool for these patients. Clinicaltrials.gov, identifier (NCT02520492).

“Life…Gets Turned Upside-Down…” Opportunities to Improve Palliative Care for High-Grade Glioma

ContextEarly palliative care referral is recommended broadly in oncology. Yet, few patients with high-grade gliomas (HGG) – highly aggressive brain tumors – receive specialty palliative care consultation. ObjectivesTo delineate unique needs of HGG patients relative to other oncology patients according to perceptions of a diverse sample of US palliative medicine physicians and neuro-oncologists in each of the eight domains of palliative care; and to describe contrasts between physician specialties on indications for and timing of specialty palliative care referrals in HGG. MethodsBetween September 2021 and May 2023, we conducted semi-structured, 40-minute interviews with ten palliative medicine physicians and ten neuro-oncologists. Participants were recruited via purposive sampling for diversity in geographic setting, years in practice, and practice structure. Interviews were audio-recorded, professionally transcribed, and coded by two investigators. Data were analyzed thematically using a qualitative, phenomenological approach. ResultsThe palliative care needs of HGG relative to other cancers across palliative care domains are distinguished by poor prognosis, physical and cognitive deficits, and neuropsychiatric symptoms. Themes on indications for palliative care referral differed between neuro-oncologists and palliative physicians. Neuro-oncologists favored selective referral for clinical indications such as high non-neurologic symptom burden requiring time-intensive management. Palliative physicians favored early referral of most HGG patients, to allow for maximal benefit across HGG trajectory. ConclusionPatients with HGG have unique palliative care needs that affect palliative care delivery across care domains. Bidirectional education, enhanced collaboration, and consensus guidelines may help overcome barriers to specialty palliative care referral.

Amino-acid PET as a prognostic tool after post Stupp protocol temozolomide therapy in high-grade glioma patients

PurposeThis study aimed to evaluate the prognostic performance of amino-acid PET in high-grade gliomas (HGG) patients at the time of temozolomide (TMZ) treatment discontinuation, after the Stupp protocol.MethodsThe analysis included consecutive HGG patients with dynamic [18F]FDOPA PET imaging within 3 months of the end of TMZ therapy, post-Stupp protocol. Static and dynamic PET parameters, responses to RANO criteria for MRI and clinical and histo-molecular factors were correlated to progression-free (PFS).ResultsThirty-two patients (59.4 [54.0;67.6] years old, 13 (41%) women) were included. Static PET parameters peak tumor-to-background ratio and metabolic tumor volume (respective thresholds of 1.9 and 1.5 mL) showed the best 84% accuracies for predicting PFS at 6 months (p = 0.02). These static PET parameters were also independent predictor of PFS in multivariate analysis (p ≤ 0.05).ConclusionIn HGG patients having undergone a Stupp protocol, the absence of significant PET uptake after TMZ constitutes a favorable prognostic factor.

A phase 0/1 trigger trial of BDTX-1535 in patients with recurrent high-grade glioma (HGG) with EGFR alterations or fusions.

2069 Background: This Phase 0/1 clinical trial evaluates the pharmacokinetic (PK), pharmacodynamic (PD), and clinical response of recurrent high-grade glioma (HGG) patients with EGFR alterations and/or fusions to the ATP-competitive, irreversible EGFR inhibitor, BDTX-1535. Methods: Recurrent HGG patients with EGFR alterations (Arm A) or EGFR fusions (Arm B) received 5 days of BDTX-1535 (200 mg) prior to planned resection at 2-4 hours following the final dose. In the Phase 0 component of the study, total and unbound drug concentrations were measured in tumor tissue (Gadolinium enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug concentration above 5-fold biochemical IC50 in Gadolinium (Gd)-nonenhancing tumor, determined eligibility for Phase 1. PD response was assessed by quantification of percentage of positive pEGFR, pERK and MIB-1 cells in the surgical tumor tissue compared to baseline pre-treatment tissue. Patients with tumors exceeding the PK threshold for unbound drug concentration were eligible for expansion phase therapeutic dosing of BDTX-1535. Results: A total of 7 patients with recurrent glioblastoma (Arm A) were enrolled in the Phase 0 component of the study. Two patients were excluded from PK analysis due to pseudoprogression. The mean unbound concentrations of BDTX-1535 in Gd-enhancing and nonenhancing tumor regions were 16.0 nM and 10.5 nM respectively. Four of five (80%) evaluable patients exceeded the PK threshold. The suppression of pEGFR and MIB1 was observed in 40% and 60% of patients, respectively. No serious adverse events were observed among patients in the Phase 1 component of the study and a clinical readout is planned in Q2 2024. Conclusions: BDTX-1535 is well-tolerated in recurrent HGG patients, achieves pharmacologically relevant concentrations in Gd-nonenhancing tumor tissue and is associated with suppression of EGFR signaling. Clinical trial information: NCT06072586 .

Amide proton transfer-weighted and arterial spin labeling imaging may improve differentiation between high-grade glioma recurrence and radiation-induced brain injury

Rationale and objectivesThe management of tumor recurrence (TR) and radiation-induced brain injury (RIBI) poses significant challenges, necessitating the development of effective differentiation strategies. In this study, we investigated the potential of amide proton transfer-weighted (APTw) and arterial spin labeling (ASL) imaging for discriminating between TR and RIBI in patients with high-grade glioma (HGG). MethodsA total of 64 HGG patients receiving standard treatment were enrolled in this study. The patients were categorized based on secondary pathology or MRI follow-up results, and the demographic characteristics of each group were presented. The APTw, rAPTw, cerebral blood flow (CBF) and rCBF values were quantified. The differences in various parameters between TR and RIBI were assessed using the independent-samples t-test. The discriminative performance of these MRI parameters in distinguishing between the two conditions was assessed using receiver operating characteristic (ROC) curve analysis. Additionally, the Delong test was employed to further evaluate their discriminatory ability. ResultsThe APTw and CBF values of TR were significantly higher compared to RIBI (P < 0.05). APTw MRI demonstrated superior diagnostic efficiency in distinguishing TR from RIBI (area under the curve [AUC]: 0.864; sensitivity: 75.0 %; specificity: 81.8 %) when compared to ASL imaging. The combined utilization of APTw and CBF value further enhanced the AUC to 0.922. The Delong test demonstrated that the combination of APTw and ASL exhibited superior performance in the identification of TR and RIBI, compared to ASL alone (P = 0.048). ConclusionAPTw exhibited superior diagnostic efficacy compared to ASL in the evaluation of TR and RIBI. Furthermore, the combination of APTw and ASL exhibits greater discriminatory capability and diagnostic performance.

Tumor treating fields for newly diagnosed high-grade glioma based on the criteria of 2021 WHO CNS5: A retrospective analysis of Chinese patients in a single center.

High-grade glioma (HGG) is known to be characterized by a high degree of malignancy and a worse prognosis. The classical treatment is safe resection supplemented by radiotherapy and chemotherapy. Tumor treating fields (TTFields), an emerging physiotherapeutic modality that targets malignant solid tumors using medium-frequency, low-intensity, alternating electric fields to interfere with cell division, have been used for the treatment of new diagnosis of glioblastoma, however, their administration in HGG requires further clinical evidence. The efficacy and safety of TTFields in Chinese patients with HGG were retrospectively evaluated by us in a single center. We enrolled and analyzed 52 patients with newly diagnosed HGG undergoing surgery and standard chemoradiotherapy regimens from December 2019 to June 2022, and followed them until June 2023. Based on whether they used TTFields, they were divided into a TTFields group and a non-TTFields group. Progression-free survival (PFS) and overall survival (OS) were compared between the two groups. There were 26 cases in the TTFields group and 26 cases in the non-TTFields group. In the TTFields group, the median PFS was 14.2 months (95% CI: 9.50-18.90), the median OS was 19.7 months (95% CI: 14.95-24.25) , the median interval from surgery to the start of treatment with TTFields was 2.47 months (95% CI: 1.47-4.13), and the median duration of treatment with TTFields was 10.6 months (95% CI: 9.57-11.63). 15 (57.69%) patients experienced an adverse event and no serious adverse event was reported. In the non-TTFields group, the median PFS was 9.57 months (95% CI: 6.23-12.91) and the median OS was 16.07 months (95% CI: 12.90-19.24). There was a statistically significant difference in PFS (p = 0.005) and OS (p = 0.007) between the two groups. In this retrospective analysis, TTFields were observed to improve newly diagnosed HGG patients' median PFS and OS. Compliance was much higher than reported in clinical trials and safety remained good.

Retraction Note: Neurocognitive impairment and patient-proxy agreement on health-related quality of life evaluations in recurrent high-grade glioma patients.

Retraction Note: Neurocognitive impairment and patient-proxy agreement on health-related quality of life evaluations in recurrent high-grade glioma patients.

Survival analysis and associated factors of highgrade glioma patients

High-grade gliomas are the most common primary brain tumors in adults, and they usually have a quick fatal course. Average survival is 18 months, mainly, because of tumor resistance to Stupp protocol. To determine high-grade glioma patient survival and the effect of persuasion variables on survival. We conducted a longitudinal descriptive study in which 80 untreated recently diagnosed high-grade glioma patients participated. A survey was conducted regarding their exposure to some risk factors, degree of genetic instability in peripheral blood using micronucleus quantification on binuclear lymphocytes, micronuclei in reticulocytes and sister-chromatid exchanges in lymphocytes. In the statistical analysis, this study constructed life tables, used the Kaplan-Meier, and the log-rank test, and in the multivariate analysis, a Cox proportional hazards model was constructed. Eighty patients' clinical, demographic and lifestyle characteristics were analyzed, as well as their survival rates and the average survival time is 784 days (interquartile range: 928). Factors like age, exposure at work to polycyclic hydrocarbons and the number of sister-chromatid exchanges in lymphocytes in the first sampling was significantly survivalrelated in the multivariate analysis. We determined that only three of the analyzed variables have an important effect on survival time when it comes to high-grade glioma patients.

Accurate and rapid molecular subgrouping of high-grade glioma via deep learning-assisted label-free fiber-optic Raman spectroscopy.

Molecular genetics is highly related with prognosis of high-grade glioma. Accordingly, the latest WHO guideline recommends that molecular subgroups of the genes, including IDH, 1p/19q, MGMT, TERT, EGFR, Chromosome 7/10, CDKN2A/B, need to be detected to better classify glioma and guide surgery and treatment. Unfortunately, there is no preoperative or intraoperative technology available for accurate and comprehensive molecular subgrouping of glioma. Here, we develop a deep learning-assisted fiber-optic Raman diagnostic platform for accurate and rapid molecular subgrouping of high-grade glioma. Specifically, a total of 2,354 fingerprint Raman spectra was obtained from 743 tissue sites (astrocytoma: 151; oligodendroglioma: 150; glioblastoma (GBM): 442) of 44 high-grade glioma patients. The convolutional neural networks (ResNet) model was then established and optimized for molecular subgrouping. The mean area under receiver operating characteristic curves (AUC) for identifying the molecular subgroups of high-grade glioma reached 0.904, with mean sensitivity of 83.3%, mean specificity of 85.0%, mean accuracy of 83.3%, and mean time expense of 10.6 s. The diagnosis performance using ResNet model was shown to be superior to PCA-SVM and UMAP models, suggesting that high dimensional information from Raman spectra would be helpful. In addition, for the molecular subgroups of GBM, the mean AUC reached 0.932, with mean sensitivity of 87.8%, mean specificity of 83.6%, and mean accuracy of 84.1%. Furthermore, according to saliency maps, the specific Raman features corresponding to tumor-associated biomolecules (e.g. nucleic acid, tyrosine, tryptophan, cholesteryl ester, fatty acid, and collagen) were found to contribute to the accurate molecular subgrouping. Collectively, this study opens up new opportunities for accurate and rapid molecular subgrouping of high-grade glioma, which would assist optimal surgical resection and instant post-operative decision-making.

P.099 Transfer RNA fragments in patient plasma extracellular vesicles as biomarkers of high grade glioma

Background: High-grade gliomas (HGG) present challenges with short post-surgery survival and high progression rates. Extracellular vesicles (EVs) in the tumor microenvironment (TME) contribute to a pro-tumorigenic setting. Investigating Transfer RNA fragments (TfRNA) in HGG patient plasma EVs reveals potential biomarkers and therapeutic targets, shedding light on the molecular landscape for enhanced diagnostic and therapeutic strategies. This study examines TfRNA in 10 HGG patients at diagnosis, offering insights into the molecular landscape for improved management strategies. Methods: The study involved the collection of plasma samples from HGG patients and controls. EVs were isolated from these samples and subsequently analyzed for tfRNA. Results: Analysis of plasma EVs highlighted distinct differences in TfRNA fragments between High-Grade Glioma (HGG) and control samples. HGG EVs showed a global reduction in tRNA content, higher 5’ tfRNA proportions, and increased nuclear tfrna compared to controls. A notable biological marker, elevated in HGG, holds potential as a diagnostic indicator. Conclusions: Our study concludes that High-Grade Gliomas (HGG) demonstrate a global reduction in tfRNA content in plasma extracellular vesicles compared to non-cancer controls, echoing findings in other cancers. Despite this, specific tfRNA molecules in HGG show significant differential expression or sorting into EVs, indicating their potential as future biomarkers or therapeutic targets.

P.100 Plasma extracellular vesicle sampling from high grade gliomas demonstrates a small RNA signature indicative of disease and identifies lncRNA RPPH1 as a novel biomarker

Background: High grade gliomas (HGGs) and cells of the tumour microenvironment secrete extracellular vesicles (EVs) into the plasma that contain genetic and protein cargo which function in paracrine signalling. Isolation of these EVs and their cargo could lead to an important tool that can inform on diagnosis and disease-course of HGGs. Methods: EVs were isolated using Vn96 capture from plasma obtained longitudinally from HGG patients. sRNA was enriched from the EVs, followed by next-generation sequencing, multidimensional scaling, differential expression, and in silico functional enrichment analyses. Results: Over 750 differentially expressed sRNA were identified between HGG and controls. Pathway analysis revealed miRNA highly enriched in both EV and HGG pathways demonstrating the validity of results in capturing a signal from HGG. Other sRNA included several novel HGG plasma-EV biomarkers including lncRNA RPPH1, RNY4, and RNY5. Furthermore, in paired longitudinal patient sampling, RPPH1 informed on surgical resection (decreased on resection) and importantly increased again with clinically defined progression. TCGA analysis demonstrated increased expression of RPPH1 in HGG tissue and additionally, higher expression of RPPH1 was associated with a worse disease-specific prognosis. Conclusions: The present study supports the role of plasma-EV sRNA sampling (and particularly RPPH1) as part of a multi-pronged approach to HGG disease course surveillance.

Correlation between rCBV Delineation Similarity and Overall Survival in a Prospective Cohort of High-Grade Gliomas Patients: The Hidden Value of Multimodal MRI?

The accuracy of target delineation in radiation treatment planning of high-grade gliomas (HGGs) is crucial to achieve high tumor control, while minimizing treatment-related toxicity. Magnetic resonance imaging (MRI) represents the standard imaging modality for delineation of gliomas with inherent limitations in accurately determining the microscopic extent of tumors. The purpose of this study was to assess the survival impact of multi-observer delineation variability of multiparametric MRI (mpMRI) and [18F]-FET PET/CT. Thirty prospectively included patients with histologically confirmed HGGs underwent a PET/CT and mpMRI including diffusion-weighted imaging (DWI: b0, b1000, ADC), contrast-enhanced T1-weighted imaging (T1-Gado), T2-weighted fluid-attenuated inversion recovery (T2Flair), and perfusion-weighted imaging with computation of relative cerebral blood volume (rCBV) and K2 maps. Nine radiation oncologists delineated the PET/CT and MRI sequences. Spatial similarity (Dice similarity coefficient: DSC) was calculated between the readers for each sequence. Impact of the DSC on progression-free survival (PFS) and overall survival (OS) was assessed using Kaplan-Meier curves and the log-rank test. The highest DSC mean values were reached for morphological sequences, ranging from 0.71 +/- 0.18 to 0.84 +/- 0.09 for T2Flair and T1Gado, respectively, while metabolic volumes defined by PET/CT achieved a mean DSC of 0.75 +/- 0.11. rCBV variability (mean DSC0.32 +/- 0.20) significantly impacted PFS (p = 0.02) and OS (p = 0.002). Our data suggest that the T1-Gado and T2Flair sequences were the most reproducible sequences, followed by PET/CT. Reproducibility for functional sequences was low, but rCBV inter-reader similarity significantly impacted PFS and OS.

Additive Value of Magnetic Resonance Simulation Before Chemoradiation in Evaluating Treatment Response and Pseudoprogression in High-Grade Gliomas

BackgroundA dedicated MRI Simulation(MRsim) for radiation treatment(RT) planning in high-grade glioma(HGG) patients can detect early radiological changes, including tumor progression after surgery and before standard of care chemoradiation. This study aimed to determine the impact of using post-op MRI vs. MRsim as the baseline for response assessment and reporting pseudo-progression on follow-up imaging at one month(FU1) after chemoradiation. MethodsHistologically confirmed HGG patients were planned for six weeks of RT in a prospective study for adaptive RT planning. All patients underwent post-op MRI, MRsim, and follow-up MRI scans every 2-3 months. Tumor response was assessed by three independent blinded reviewers using Response Assessment in Neuro-Oncology(RANO) criteria when baseline was either post-op MRI or MRsim. Interobserver agreement was calculated using light's kappa. Results30 patients (median age 60.5 years; IQR 54.5-66.3) were included. Median interval between surgery and RT was 34 days (IQR 27–41). Response assessment at FU1 differed in 17 patients (57%) when the baseline was post-op MRI vs. MRsim, including true progression vs. partial response(PR) or stable disease(SD) in 11 (37%) and SD vs. PR in 6 (20%) patients. True progression was reported in 19 patients (63.3%) on FU1 when the baseline was post-op MRI vs 8 patients (26.7%) when the baseline was MRsim (p=.004). Pseudo-progression was observed at FU1 in 12 (40%) vs. 4 (13%) patients, when the baseline was post-op MRI vs. MRsim (p=.019). Interobserver agreement between observers was moderate (κ = 0.579; p<0.001). ConclusionsOur study demonstrates the value of acquiring an updated MR closer to RT in patients with HGG to improve response assessment, and accuracy in evaluation of pseudo-progression even at the early time point of first follow-up after RT. Earlier identification of patients with true progression would enable more timely salvage treatments including potential clinical trial enrolment to improve patient outcomes.

SUPRAMAX-study: supramaximal resection versus maximal resection for glioblastoma patients: study protocol for an international multicentre prospective cohort study (ENCRAM 2201)

IntroductionA greater extent of resection of the contrast-enhancing (CE) tumour part has been associated with improved outcomes in glioblastoma. Recent results suggest that resection of the non-contrast-enhancing (NCE) part might...

The plasma miRNome and venous thromboembolism in high-grade glioma: miRNA Sequencing of a nested case-control cohort.

Patients with high-grade gliomas are at high risk of venous thromboembolism (VTE). MicroRNAs (miRNAs) are small non-coding RNAs with multiple roles in tumour biology, haemostasis and platelet function. Their association with VTE risk in high-grade glioma has not been comprehensively mapped so far. We thus conducted a nested case-control study within 152 patients with WHO grade IV glioma that had been part of a prospective cohort study on VTE risk factors. At inclusion a single blood draw was taken, and patients were thereafter followed for a maximum of 2 years. During that time, 24 patients (16%) developed VTE. Of the other 128 patients, we randomly selected 24 age- and sex-matched controls. After quality control, the final group size was 21 patients with VTE during follow-up and 23 without VTE. Small RNA next-generation sequencing of plasma was performed. We observed that hsa-miR-451a was globally the most abundant miRNA. Notably, 51% of all miRNAs showed a correlation with platelet count. The analysis of miRNAs differentially regulated in VTE patients-with and without platelet adjustment-identified potential VTE biomarker candidates such as has-miR-221-3p. Therewith, we here provide one of the largest and deepest peripheral blood miRNA datasets of high-grade glioma patients so far, in which we identified first VTE biomarker candidates that can serve as the starting point for future research.

A Shifting Paradigm Toward Family-Centered Care in Neuro-Oncology: A Longitudinal Quasi-Experimental Mixed-Methods Feasibility Study.

Family-centered intervention can help families facing illness-related issues. We investigated the feasibility of Family and Network Conversations (FNCs) in high-grade glioma patients and their families. Quasi-experimental feasibility study with longitudinal mixed-methods design. Patients and families were invited to three FNCs over 1 year. They completed questionnaires at four time points and expressed their perspectives on the intervention through telephone interviews. Nurses' perspectives were collected in a focus group. Twenty-one patients and 47 family members were included. On average, patients were 66 years old, mainly male, married, living with caregivers, with unifocal cancer. On average, caregivers were 47 years old, mainly female, being spouses or children of the patient. Quantitative and qualitative data did not always match and expanded each other. Nurse-delivered FNCs holistically addressed families' needs while strengthening family's dialogue and union. Nurses felt empowered, underling that advanced competencies were required. Nurse-delivered FNCs are feasible to provide family-centered care, but they should be tailored to each family's needs.

Abstract 953: Integration of functional precision medicine assay for high grade glioma management: A single institution experience

Abstract Despite the advances in precision oncology, genomic approaches have not significantly improved outcomes for high grade gliomas (HGGs) as once was anticipated. Recurrent HGG pose even greater therapeutic challenge. The integration of functional precision medicine (FPM), in which drugs screens are performed on live tissue, into clinical routine practice presents a promising alternative by offering personalized treatments based on the unique characteristics of the patient’s tumor. Here, we present our institutional experience of integrating a spheroid-based drug screening assay (3D PredictTM Glioma) in the treatment management of HGG patients to evaluate its feasibility and efficacy as a therapeutic tool in a clinical setting. We also sought to determine factors that related to assay success. Tissue from intracranial lesions of patients with presumed HGG and planned surgical resection at our institution were collected for ex vivo 3D cell culture and challenged with 12 drug agents to determine patient-specific response parameters. The impact of potential variables, such as ki67, tumor pathology, and shipment timing, on the assay’s success was evaluated. Clinical correlation was established between ex vivo response and clinical response in HGG patients. 57 samples, including 24 upfront HGGs, 32 recurrent HGGs, and one medulloblastoma, were sent for spheroid formation and drug testing. In total, 57.9% (33/57) or 23% (13/57) of the assays were successful and resulted in complete or partial functional profiling data, respectively. We conducted a multivariable analysis of our cohort to determine which variables (i.e. tumor volume sent, ki-67 proliferation index, tumor percentage determined by DNA sequencing by Tempus Lab, recurrent status, sample shipment time) were predictive of assay success. The only variable significantly associated with assay success was tumor percentage with samples comprised of &amp;gt;70% tumor leading to assay success, 40%-70% leading to 60% chance of success, and &amp;lt;40% having 0% success. Among 46 patients with partial or complete assay success, 26 patients (56.5%) had a targetable mutation and 17/26 yielded a moderate or full response to one or more of their corresponding targeted drugs in the assay. Treatments were newly administered or altered from prior treatments in 40/57 patients (70%) based on FPM results. Our study demonstrates the technical feasibility of incorporating FPM approaches in the development of treatment regimens for patients with HGG. Success was correlated to tumor percentage present in the sample which indicates intraoperative communication between surgeon and pathologist can lead to improved assay results. Our institutional protocol demonstrates that Integrating FPM into routine clinical practice is possible and can serve as a valuable guide in the refinement of therapeutic recommendations for HGG patients. Citation Format: Grace Guzman, Sahana Bettadapura, William Jeremy Shelton-Correa, Taylor Brooks, Melissa Rayner, Christopher Wardell, Analiz Rodriguez. Integration of functional precision medicine assay for high grade glioma management: A single institution experience [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 953.

Abstract 6372: Germline pathogenic variants are enriched in pediatric central nervous system tumor patients and associate with somatic functional consequences

Abstract The genetic contribution of rare pathogenic germline variation to central nervous system (CNS) tumor formation in pediatric patients without a family history of cancer remains unclear. We sought to characterize the prevalence, spectrum, and clinical significance of pathogenic germline variation in cancer predisposition genes (CPGs) in 838 patients profiled in the Pediatric Brain Tumor Atlas (PBTA) by whole genome sequencing (n=821) or whole exome sequencing (n=17). Rare variants in 214 CPGs were annotated as pathogenic (P) or likely pathogenic (LP) consistent with American College of Medical Genetics criteria using AutoGVP, our open-source automated pathogenicity assessment tool. To assess enrichment of P/LP variants in the PBTA, we compared the frequency of CPG P/LP variants in cases to a tumor-free control cohort from Penn Medicine BioBank (PMBB; n=6,295). Somatic alterations, mutational signatures, and gene set enrichment analyses from matched tumor sequencing were integrated to characterize functional consequences associated with germline pathogenic variation. We observed 215 germline P/LP variants within 76 distinct CPGs in 189 (22.6%) PBTA patients. CPG P/LP variants were most prevalent among patients with a plexiform neurofibroma diagnosis (9/14, 64.3%), and least prevalent among patients with craniopharyngioma (3/39, 7.8%). We detected syndrome-associated P/LP variants in 45/58 (77.6%) patients with a clinically reported cancer predisposition syndrome and incidentally in another 37 patients. CPG P/LP variants were significantly enriched in the PBTA cohort relative to the PMBB control cohort (OR=2.0, p=1.0E-12, CI=1.6-2.4), and NF1 harbored the most significant excess P/LP variant burden (OR=30.7, p=4.57E-13, CI=11.2-105.1). We observed a significant enrichment of mismatch repair (MMR) gene P/LP variants in patients with high-grade gliomas (HGG) and tumors from MMR P/LP carriers exhibited significantly higher MMR-deficiency mutational signature exposures relative to tumors from non-carrier HGG patients (SBS14: W=478, p=1.71E-05). Overall, 90/215 (41.9%) of identified germline P/LP variants co-occurred with at least one corresponding somatic alteration in matched tumors, including oncogenic SNV (n=5), copy number variation (n=28), loss of heterozygosity (n=54), differential gene expression (n=23), and proximal alternative splicing (n=19). In summary, rare germline P/LP variants are enriched in PBTA patients and are associated with somatic events in the same gene, resulting in gene- and pathway-specific functional consequences. Our work emphasizes a role for pathogenic germline variation in pediatric CNS tumor development and frequent under-identification of cancer predisposition syndromes, underscoring the importance of germline sequencing in personalized patient care strategies. Citation Format: Ryan J. Corbett, Rebecca Kaufman, Shelly W. McQuaid, Zalman Vaksman, Saksham Phul, Miguel A. Brown, Jennifer L. Mason, Heena Desai, Ryan Hausler, Ammar S. Naqvi, Antonia Chroni, Zhuangzhuang Geng, Bo Zhang, Chuwei Zhong, Yuankun Zhu, Allison P. Heath, Marilyn Li, Penn Medicine BioBank, Phillip B. Storm, Adam C. Resnick, Kara N. Maxwell, Miriam Bornhorst, Kristina A. Cole, Angela J. Waanders, Suzanne P. MacFarland, Jo Lynne Rokita, Sharon J. Diskin. Germline pathogenic variants are enriched in pediatric central nervous system tumor patients and associate with somatic functional consequences [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6372.

Abstract 5137: BRAF mutations in primary central nervous system tumors

Abstract Background: BRAF alterations are present in a variety of primary central nervous system (CNS) tumors from 3% in glioblastomas to 60% in pleomorphic xanthoastrocytomas. BRAF V600E mutation is the most common BRAF alteration found in tumors and has been successfully targeted by combining BRAF/MEK inhibitors in different tumor types, including gliomas. We aimed to describe the clinical and genomic features of primary CNS tumors harboring BRAF alterations and real-world data on BRAF-targeted therapy including our experience sequencing BRAF-directed therapies (BDI) in gliomas. Methods: Single-center retrospective analysis of patients with diagnosis of primary CNS tumors with NGS testing. Clinical, histological and molecular characteristics were analyzed. Results: 44 patients with BRAF mutant primary CNS tumors were included, 28 (64%) were male. 24 (55%) had histology consistent with high-grade glioma (HGG), 14 (32%) low grade glioma (LGG), 4 (9%) low grade neuroepithelial tumors and 2 (4%) others. Missense mutations were found in 77%, followed by amplifications (9%), fusions (9%) and in/del alterations (5%). V600E was the most common mutation (63%), followed by class 2 (16%) and 3 (7%) mutations and amplifications (9%). Co-occurring mutations were found in CDKN2A/B (22), TERT (20) and MTAP (12), median TMB was 2 mut/mb and only 2 patients had high TMB. 4 patients had commuted IDH1 (3 R132H), non-concurring with a V600E mutation. For patients with HGG, median age at diagnosis was 47 years and 16 (66%) were male. Lesions were more frequent in left hemisphere (70%) and temporal lobe (54%). V600E was found in 50% of cases, KIAA1549-BRAF fusion was found in 1 case. Median follow-up was 40 months (95% CI 11-68) and median overall survival (OS) was 22 months (3.4-40) for the whole population, and 56 (4-109) months for patients treated with BDI (n=4). All 4 patients had an OS &amp;gt;30 months. In the LGG cohort, median age at diagnosis was 34 years (IQR 24-46), 8 (57%) were male. 50% of the lesions were in the left side and 21% of the tumors were in the posterior fossa. 78% had a V600E mutation, with no statistical difference with HGG cohort (p=.082). Median follow up was 11 months, median OS was not reached. For 5 patients treated at recurrence with BDI, median PFS was 15 months (3-27).5 patients were treated with plixorafenib (PLX8394) on clinical trial achieving disease control (PR +SD) in 4 cases. Upon progression, 4 were rechallenged with dabrafenib + trametinib and 1 with another BDI. 4 patients had a partial response with duration of response &amp;gt;6 months in 3 cases. Conclusion: BRAF mutant CNS tumors are a heterogeneous disease. Longer survival was observed in the small group of HGG patients treated with BDI compared to SoC (56 months vs 22months). BDI rechallenge showed durable responses in heavily pretreated patients. Further molecular characterization of these patients is ongoing. The best therapeutical sequencing strategy for BDI remains uncertain. Citation Format: Juan B. Blaquier, Fulvio D'Angelo, Dalissa Tejera, Ruham A. Nasany, Gaurav Saigal, Antonio Iavarone, Macarena I. de la Fuente. BRAF mutations in primary central nervous system tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5137.

Simulation-based caregiving skills training for family members of high-grade glioma patients.

Because family caregivers of patients with a high-grade glioma experience high levels of distress and feel unprepared to perform the complex caregiving tasks associated with the disease and its treatment, we pilot-tested a caregiving skills intervention that integrates hands-on caregiving with coping skill training. In this single-arm trial, caregivers participated in a 4-session research nurse-led intervention involving simulation-based caregiving skills training at the hospital and psychoeducation delivered via videoconference. We collected measures of patients' and caregivers' psychological symptoms; caregivers' caregiving self-efficacy and role adjustment; and patients' cancer-related symptoms (MDASI) at baseline and again postintervention. We tracked feasibility data. We approached 29 dyads of which 10 dyads (34%) consented. All patients (mean age: 60 years, 89% male) and caregivers (mean age: 58 years, 80% female, 80% spouses) completed the baseline and 7 dyads completed the follow-up assessments (attrition was related to patient's hospice transfer). Seven caregivers completed all 4 sessions and rated the program as beneficial. Paired t-tests revealed a significant improvement in caregiving self-efficacy at 6 weeks postintervention (t = -3.06, P = .02). Although improvements in caregiver role adjustment and patient and caregiver symptoms were not observed, no decreases in symptom burden or role adjustment were found during the follow-up period. This novel supportive care program appears to be safe, feasible, acceptable, and perceived as useful for caregivers of patients with high-grade glioma. Based on feasibility indicators and a signal of intervention efficacy, a randomized controlled trial is warranted.