Burns, Terry C.

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 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.

Abstract BACKGROUND Pembrolizumab elicits durable responses in many solid tumors, yet activity in gliomas has been limited. Lymphopenia has been reported in association with reduced survival and a shorter time to progression on checkpoint inhibition in other solid tumors. We evaluated whether low absolute lymphocyte count (ALC) is related to worse outcomes in pembrolizumab-treated patients with gliomas. METHODS In this single-center retrospective study, we identified adults with gliomas who received ≥1 dose of pembrolizumab and had available lymphocyte counts at our center between 05/01/2018 and 1/31/2025. Patients’ demographics, dexamethasone use, baseline ALC (before initiation of pembrolizumab), and clinical outcomes were collected. Overall Survival (OS) was estimated using Kaplan–Meier analysis from the date of starting pembrolizumab to the date of death. RESULTS Ninety patients met eligibility criteria (glioblastoma [GBM] n = 44, astrocytoma n = 20, oligodendroglioma n = 13, meningioma n = 8, other n = 5); 62% were male and 31% (n = 28) harbored IDH-mutant tumors. Across all histological subtypes, baseline ALC<750 cells/mm³ was associated with significantly shorter OS compared to baseline ALC≥750 cells/mm³ (3.7 vs 7.7 months, P = 0.0063) with similar dexamethasone exposure (63% vs 52%). In the recurrent GBM subgroup (n = 43; MGMT-methylated 26%), ALC≥750 cells/mm³ correlated with longer OS (8.5 vs 3.4 months, P = 0.0065) with a slightly lower proportion of patients on dexamethasone in high ALC group (52% vs 75%). Conversely, among patients with IDH-mutant gliomas (n = 28), no significant difference in OS was observed based on ALC levels (7.8 vs. 7.3 months, P = 0.58) with similar dexamethasone use (57% and 43% in high and low ALC groups, respectively). CONCLUSION Baseline lymphopenia preceding pembrolizumab treatment is associated with shorter OS in patients with GBM, but not in IDH-mutant gliomas. These associations require further validation in additional patient cohorts.

Abstract Brain metastases significantly impact neurocognitive function and overall survival. Stereotactic radiosurgery (SRS) is a cornerstone of treatment for patients with limited metastases and expected survival beyond three months. Despite current guidelines, up to 20% of patients with brain metastases undergoing SRS have been reported to die within 90 days. This study retrospectively evaluates prognostic factors associated with 90-day survival after SRS, aiming to improve patient selection. We retrospectively analyzed a cohort of 1,546 patients who underwent Gamma Knife SRS for brain metastases at our institution between 2015 and 2023. One hundred seventy patients who survived fewer than 90 days post-SRS were identified and case-matched to 170 patients who survived over 90 days. Measured variables included patient demographics, tumor characteristics, treatment history, functional status, and control of the primary cancer. We modeled post-SRS 90-day survival using binomial and multivariate logistic regression. Multivariate analysis highlighted Karnofsky Performance Status (KPS) < 70 (OR: 17.4, p < 0.001), prior whole brain radiation (OR: 6, p = 0.004), and focal neurological deficits (OR: 3.02, p = 0.003) as significant predictors of early deaths, while CNS progression before SRS (OR: 0.22, p < 0.001) and control of systemic cancer (OR: 0.556, p = 0.002) were associated with a less than 90-day survival. The predictive model demonstrated acceptable performance with an area under the curve (AUC) of 0.85, accuracy of 80%, sensitivity of 87%, and specificity of 71%. Key predictors of 90-day survival following SRS for brain metastases include functional status (KPS), control of systemic cancer, CNS progression status, and focal neurologic deficits. These findings are complementary factors that can assist in making decisions and SRS patient selection.