Citations

Abstract IDH-wildtype diffuse astrocytic gliomas with lower-grade histological features alongside specific genomic alterations (e.g., TERT promoter mutation, EGFR amplification, gain Chr7/loss Chr10) are presently diagnosed as glioblastoma, IDH-wildtype (GBM) under WHO 2021 criteria. Previous analyses categorized these into “early/evolving” or “surgically undersampled” GBMs. However, it remains unclear whether these tumors share identical clinical and prognostic features with histologic GBM. Data from IDH-wt molecular GBMs across six institutions were aggregated. Astrocytic IDH-wt tumors of any grade that lacked necrosis or microvascular proliferation on initial histopathology yet exhibited molecular alterations consistent with WHO 2021 GBM diagnosis, were included. Recursive partitioning analysis (RPA) was used to categorize patients into risk groups based on overall survival (OS). Among the 264 patients included, the median age was 60 years (IQR: 51-67), with 162 (61%) being male. Additionally, 210 (80%) were diagnosed since 2016, and 216 (82%) received chemoradiation plus adjuvant temozolomide (GBM-SOC). The median follow-up period was 3.9 years (95% CI: 3.4, 4.6). Identified univariate risk factors for worse survival included older age, biopsy-only status, EGFR amplification, absence of initial adjuvant treatment, low post-operative KPS, and tumor histologic grade of 3. RPA divided patients into four distinct survival groups (p<0.0001). The “best” risk group comprised lower grade (<=2) tumors (n=58, median OS (mOS): 40 months (95% CI: 33, NA)). The “second best” group included Grade 3 patients receiving GBM-SOC without steroids during initial RT (n=139, mOS: 25 months (95% CI: 22, 28)). The “second worst” group encompassed Grade 3 patients who were on steroids during initial RT while receiving GBM-SOC (n=38, mOS: 15 months (95% CI: 13, 20)). The “worst” group contained Grade 3 tumors that had not undergone SOC (n=29, mOS: 9 months (95% CI: 4, 26)). These data show that histologic features and treatment are strong indicators of patient outcomes.

Abstract BACKGROUND Access to in-person evaluations is challenging for patients with glioma due to disease-related disability and distance from specialized neuro-oncology centers. Telehealth is an alternative to in-person evaluations, but acceptability of and therapy compliance with this model has not been prospectively evaluated. METHODS In this single-arm non-randomized pragmatic clinical trial, we compared patient satisfaction with telehealth and in-person assessments among patients with glioma undergoing chemotherapy with temozolomide. Participants acted as their own controls, alternating between telehealth and in-person visits. Patient satisfaction with care delivered was evaluated by Press-Ganey surveys with Likert response scales (1-5, 1=very poor, 5=very good). A digital pill diary (DPD) was implemented to track chemotherapy compliance. RESULTS We accrued 30 patients (median age 59, 38% female) between October 2024 and May 2025. Half of the patients (n=15) reported a primary residence greater than 150 miles from our institution. Surveys from 25 participants were reviewed, with 17/25 completing one or more surveys following an in-person visit, and 21/25 completing one or more surveys following a telehealth visit. Overall average Press-Ganey scores were similar between the two visit modalities with high scores (telehealth=4.8; in-person=4.7). Median scores for specific modalities were similarly highly rated: likelihood of recommending practice to others (telehealth=5.0; in-person=5.0), concern the care provider showed (telehealth=5.0, in-person=4.7), provider’s discussion of treatment options (telehealth=5.0, in-person=5.0), provider effort to include patients in decision-making (telehealth=5.0, in-person=5.0). DPDs used to monitor treatment compliance indicated adherence to all prescribed doses of temozolomide in 75/79 cycles; the other 4 (of 79) treatment cycles were halted per provider instructions. CONCLUSION This interim assessment demonstrates feasibility of treating patients with similar patient satisfaction of care delivered between telehealth and in-person visits. The DPD was effective in tracking chemotherapy administration. Additional results including visit type preference and acute care utilization data are maturing.

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and glioblastoma (GBM). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent GBM and NSCLC. After determining the maximum tolerated dose, adults with recurrent GBM were treated in two expansion cohorts: (a) non-surgical cohort (6/12 patients thus far): EGFRvIII mutation, first recurrence; food-effect study included (b) surgical cohort (6/6 patients), any EGFR mutation, any recurrence; window-of-opportunity study (WOO) included. Among these 12 patients, median age = 60 years; 50% female; 58% ECOG 0). All patients received prior radiation and temozolomide. After the WOO or food-effect study, patients were dosed at 120 mg BID (5 days on, 2 days off), and escalated to 160 mg BID (5 days on, 2 days off) based on tolerability. Common adverse events (>40%) are comparable to other EGFR inhibitors (acneiform rash, diarrhea, fatigue, xerosis, pruritis). Treatment-related grade 3+ adverse events were limited to lymphopenia (n = 1). WSD0922-Fu exposure in the fed state exceeded the fasted state (median plasma Cmax and AUC0-24h are 1.6x and 1.3x, respectively) with a delayed Tmax (6.0 vs 1.8 hours). For the WOO, time between last dose administered to tumor collection ranged between 4 - 13.5 hours. Median tumor WSD0922-Fu concentration was 0.76 µg/g; estimated median unbound tumor concentration was 24.9 ng/g and within expectations for pharmacodynamic effect. Median brain/plasma ratio = 0.59; median unbound brain/unbound plasma = 0.88. Enrollment to the non-surgical cohort is ongoing, so formal efficacy data remain immature. However, examples of clinical efficacy will be shown along with data on recurrence patterns. Phase 2 clinical trial development is in progress.

Abstract The WHO 2021 classification of central nervous system tumors incorporated molecular markers to better define diffuse glioma subgroups. We analyzed array-based copy number, targeted next-generation sequencing, germline genotyping, and Illumina EPIC array methylation data from 404 primary IDH-mutant astrocytomas to further understand the relationship between copy number and outcomes. Loss of chromosome arm 13q was associated with poor overall survival after adjusting for age, sex, tumor grade, and treatment status (hazard ratio [HR]=2.04 (95% confidence interval: 1.25-3.33), p=0.004). Chromosome 13q loss was also significantly associated with the total number of copy number alterations (p<0.001). Loss of arm 11p was associated with poor survival in the adjusted analysis (HR=2.29 (1.38-3.79), p=0.001). Unsupervised clustering of the raw copy number data identified 12 clusters, where each cluster was defined by distinct copy number alteration(s). Clusters that contained 13q loss exhibited worse overall survival compared to other clusters. The clusters were significantly associated with age at diagnosis (p=0.015), tumor grade (p<0.001) and copy number complexity (p<0.001). The clusters with a high proportion of grade 4 tumors and with the highest complexity had the poorest overall survival. These findings highlight the prognostic relevance of chromosome 13q and 11p losses in IDH-mutant astrocytomas and support the integration of additional copy number alterations into molecular classification frameworks of IDH-mutant astrocytomas to improve risk stratification and patient management.

Abstract BACKGROUND Pembrolizumab is FDA approved for solid tumors with high tumor mutation burden (TMB) and may thus have efficacy in hypermutant glioma. This study aimed to identify factors influencing efficacy of pembrolizumab in recurrent glioma. METHODS This retrospective study at Mayo Clinic included patients with adult-type diffuse gliomas who received pembrolizumab (≥2 cycles) for recurrent disease (01/01/2014–05/01/2025). The Mayo Clinic Solid Tumor Panel (MCSTP), which uses the Illumina TruSight Oncology 500 High-Throughput next-generation sequencing (NGS) assay, was also used to assess the molecular characteristics of the recurrent tumors. Responders to pembrolizumab were defined as patients who did not meet RANO 2.0 criteria for progressive disease on first radiographic response assessment. Progression-free survival (PFS) was analyzed using Kaplan-Meier and Cox-Regression analyses. RESULTS Sixty-two patients were identified (median age: 46 years; 65% male; 94% white). All patients received pembrolizumab and had prior alkylating chemotherapy. The median PFS from pembrolizumab initiation was 2.3 months. Twenty-five (40%) patients were responders. Patients with IDH-mutant, 1p/19q co-deleted gliomas (OLIGO, n=13) had a longer PFS (4.3 months) than IDH wildtype gliomas (IDH-WT, n=33, 2.2 months, p=0.012) and IDH-mutant, 1p/19q non-co-deleted (IDH-MUT, n=16, 1.7 months, p=0.0006). The proportion of responders was significantly greater in OLIGO patients (IDH-WT, 33%; IDH-MUT, 19%; OLIGO, 85%, p=0.0008). Overall PFS was not impacted by patient age, sex, or extent of initial resection. Twenty-nine percent of patient tumors tested thus far (6/21) had a high TMB (≥10 mut/Mb). Two-thirds (4/6) of high TMB patients were responders, while only one-third (5/15) of low TMB patients were responders. CONCLUSIONS Patients with recurrent OLIGO may have a longer PFS with pembrolizumab therapy than IDH-WT and IDH-MUT. Furthermore, high TMB may be associated with longer PFS with pembrolizumab therapy in glioma. Additional patients are being assessed using MCSTP (total expected n=43); complete data will be presented.

Abstract OBJECTIVE Despite advancements in therapy and improved survival rates for patients with primary central nervous system lymphoma (PCNSL), the optimal management strategy for recurrent or refractory PCNSL (r/r PCNSL) remains undefined. In such cases, repeat brain biopsy is often performed to confirm disease recurrence, though its diagnostic and therapeutic value is uncertain. This study evaluates whether repeat brain biopsy provides new, actionable diagnostic insights that influence treatment decisions. METHODS A retrospective analysis was conducted on patients with a confirmed diagnosis of PCNSL who underwent repeat brain biopsy for suspected recurrent or refractory disease between 2005 and 2023. Patients with a history of other CNS neoplasms, demyelinating disorders, or active systemic disease were excluded. RESULTS Twenty patients met inclusion criteria (55% female), with a mean age at biopsy of 56 years in the PCNSL group and 61 years in the r/r PCNSL group. While the overall distribution of presenting symptoms did not significantly differ (p = 0.2), gait instability, weakness, and cognitive decline were more common in r/r PCNSL. PCNSL more often presented with single lesions, while r/r PCNSL had predominantly multiple lesions (p < 0.05). Periventricular enhancement was significantly more frequent in r/r PCNSL (p < 0.05), though other radiologic features were comparable. Repeat biopsy confirmed DLBCL in 90% of cases; no infections or alternate malignancies were identified. Diagnostic clarification was the primary indication for repeat biopsy. Chemotherapy regimens were altered in 50% of post-biopsy cases, without a corresponding difference in overall survival (p = 0.79). Procedure-related morbidity was observed in three patients (15%). CONCLUSIONS The second biopsy in most cases reaffirmed the original diagnosis of diffuse large B cell lymphoma. Although biopsy results led to treatment adjustments; these changes did not affect overall survival.

Abstract BACKGROUND Bevacizumab is an anti-angiogenic monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) used in the treatment of various cancers including recurrent glioblastoma (rGBM) and is particularly useful in mitigating cerebral edema and radiation necrosis. Complications associated with bevacizumab that are of concern for patients requiring urgent surgical procedures include: impaired wound healing, increased bleeding risk and infection. Recent bevacizumab use (e.g. <28 days) is considered a contraindication to surgical procedures. Therapeutic plasma exchange (TPE) is a procedure that nonspecifically removes substances from plasma such as immunoglobulins. We reviewed our institutional experience with the use of TPE to remove bevacizumab for patients who required urgent neurosurgical intervention. METHODS Single center retrospective study from: 01/01/2022 to 12/31/2024 (first patient treated for this indication was in 2022). Inclusion criteria: patients who underwent perioperatively TPE to remove bevacizumab. Data collected from electronic medical record included age, gender, pertinent medical history, indication for bevacizumab and TPE for its removal, TPE procedure parameters, and clinical outcomes. RESULTS Four patients met study inclusion criteria, all were male. Three patients had a diagnosis of rGBM, one patient had a diagnosis of metastatic melanoma. All patients had received bevacizumab within 21 days of TPE (range 8-21). All subjects underwent 3 daily, 1 plasma volume TPE. Eleven of 12 procedures used the Fenwal Amicus® Separator. Neurosurgical outcomes were favorable. In one patient, bevacizumab levels measured by ELISA decreased from 1087.63 ng/mL to 145.35 ng/mL after the third procedure. No post-surgical wound complications (e.g., wound dehiscence, bleeding, infection) were observed in four patients requiring urgent neurosurgery despite recent administration of bevacizumab. CONCLUSIONS TPE was successful and well-tolerated by subjects in this study. Perioperative bevacizumab removal by TPE may be considered to reduce the risk of wound healing complications associated with bevacizumab.

Abstract Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) is under evaluation as a liquid biopsy tool across multiple neuro-oncologic indications, including diagnosing lesions of uncertain etiology, delineating progression from pseudoprogression, and confirming suspected leptomeningeal disease (LMD). We evaluated the real-world performance of CSF cfDNA sequencing for identification of variant alleles (VA) using targeted panel sequencing (PredicineCARE) and/or copy number alterations (CNA) using low-pass whole-genome sequencing (LPWGS; PredicineSCORE) in a diverse cohort across three aforementioned indications. From 82 adult patients, 93 samples (92.4% from lumbar puncture and 7.6% from ventriculoperitoneal shunt taps) were analyzed. For CNS progression, gliomas were most frequently evaluated (60%); for LMD, metastatic disease was most common (86.7%). Median CSF volume utilized for analysis was 4.60 mL (range: 0.40-7.50 mL). Median cfDNA yield was 0.29 ng/mL (range: 0.00–1037.74 ng/mL). For lesions of uncertain etiology (n=40 patients, 1 sample/patient), VAs were identified in 10 samples (25%); an additional 10 samples had sufficient cfDNA for LPWGS (25%). 50% of samples in this indication had insufficient cfDNA for testing. For suspected progression (n=26 patients, 35 samples), VAs were identified in 6 samples (17.1%); an additional 14 samples underwent LPWGS (40%); 15 had insufficient cfDNA for further testing (42.9%). For suspected LMD (n=16 patients, 18 samples), VAs were quantifiable in 4 samples (22.2%); LPWGS could be performed in an additional 9 (50%); 5 had insufficient cfDNA (27.8%). Across indications, identification of known tumor-associated alterations in CSF, including those confirmed previously by tissue, served as a non-surgical diagnostic adjunct. In some patients, targetable mutations could be identified via CSF. Conversely, absence of such alterations and/or low cfDNA yields may lower suspicion for active neuro-oncologic disease, when evaluated alongside clinical history. Despite modest cell-free DNA yield, CSF cfDNA evaluation provides valuable information to aid clinical decision-making across neuro-oncologic indications.

Abstract Imaging-based monitoring of gliomas is hampered by treatment-related changes, as well as the insidious growth of gliomas harboring the isocitrate dehydrogenase (IDH) mutation. The IDH mutation results in elevated D-2-hydroxyglutarate (D-2-HG), which is detectable in cerebrospinal fluid (CSF) that can be accessed longitudinally from multiple compartments, including cranially via CSF access devices. As such, we evaluated the early utility of CSF D-2-HG as a serially accessible biomarker for IDH-mutant gliomas. A CLIA-approved gas chromatography mass spectrometry assay was developed for CSF D- and L-2-HG. Lumbar and cranial CSF samples were collected from patients with IDH-mutant gliomas or IDH-wild-type brain tumors and non-tumor pathologies via surgical field collection, lumbar punctures, Ommaya reservoirs, and ventriculoperitoneal shunts. First, to confirm the ability of CSF D-2-HG to detect IDH-mutant gliomas, concentrations were compared between IDH-mutant gliomas and wild-type lesions. Cranial, but not lumbar, CSF D-2-HG distinguished primary IDH-mutant gliomas from IDH-wild type lesions (cranial AUC= 0.89, 95% confidence interval (CI)= 0.80-0.97); lumbar AUC= 0.52, 95% CI=0.28-0.76). Indeed, CSF D-2-HG was significantly higher in cranial than lumbar samples from IDH-mutant glioma patients (median lumbar=0.20 μM, cranial = 1.72 μM; p<0.0001), confirming a significantly elevated abundance of CSF D-2-HG only in cranial CSF from IDH-mutant gliomas. Then, response to cytoreduction was evaluated, demonstrating that cranial CSF D-2-HG levels decreased to 0.54x of baseline with resection in seventeen patients (p=0.0129). Changes in tumor-to-CSF contact impacted the serial evaluation of CSF D-2-HG prior to versus after chemoradiation in some patients. Nevertheless, in patients with grade 4 IDH-mutant astrocytomas, serial cranial CSF D-2-HG increased with disease progression and differentiated stability from pseudoprogression when tumor-CSF contact was sufficient. In conclusion, serial cranial CSF D-2-HG shows promise as a monitoring biomarker in patients with IDH-mutant gliomas, although anatomic variables must be considered in parallel to CSF D-2-HG evaluation.

Abstract Glioblastomas (GBMs) are aggressive brain tumors that pose therapeutic challenges. Microperfusion (MP) probes offer a unique method for real-time sampling of extracellular biomarkers and drug responses within the tumor microenvironment. Compared to microdialysis probes, MP probes can sample large molecules without a molecular weight cut-off, making them particularly valuable for drug quantification and novel biomarker detection. In this study, MP was used to measure the GDF-15 (24.8 kDa) levels in TP53 wild-type, MDM2-amplified GBM treated with Brigimadlin, using orthotopic mouse models. Patient-derived xenograft (GBM108) was implanted intracranially in mice, and tumor growth was monitored by bioluminescent imaging or MRI. A single MP probe was placed in the tumor for the Brigimadlin group and compared with the vehicle group. MP samples were collected over four-hour daily sessions across a baseline day and three treatment days. Brigimadlin treatment led to an increase in GDF-15 within the tumor catheter during treatment days (mean: 225.3 pg), compared to stable levels in the vehicle control group (mean: 66.4 pg), consistent with activation of the p53 pathway. In a separate study of blood–brain barrier (BBB) permeability, FITC-Dextran analysis revealed a decline in BBB permeability from 0.4 μg/mL at 24 hours post-implantation to a stable 0.02 μg/mL by 72 hours, reflecting sustained but reduced permeability. MP enabled quantification of GDF-15 dynamics in vivo, highlighting its potential in clinical settings. An investigational device exemption has been secured for an upcoming clinical trial deploying intraoperative use of cerebral microperfusion catheters.