Keough, Michael B.

OBJECTIVE Maximal safe resection of intra-axial brain tumors near the motor cortex is aided by intraoperative motor mapping. Here, the authors compared outcomes in patients undergoing either low-frequency bipolar stimulation (LFBS) or high-frequency monopolar stimulation (HFMS) for cortical and/or subcortical motor mapping during brain tumor resection. METHODS A retrospective analysis of patients undergoing an asleep craniotomy with motor mapping or an awake craniotomy with motor and speech mapping with a single surgeon was performed. Three cohorts were compared: 1) asleep LFBS (AsLFBS), 2) awake LFBS (AwLFBS; motor + speech mapping), and 3) asleep HFMS. HFMS mapping was not used for awake craniotomies. RESULTS A total of 284 patients who underwent 300 craniotomies with motor mapping were identified. No significant differences in permanent neurological deficits (p = 0.377) or extent of resection (EOR) of nonenhancing tumors (p = 0.453) were identified between LFBS or HFMS motor mapping cases. Both EOR (92.7% vs 83.5%, p = 0.035) and permanent neurological deficits (7.6% vs 3.3%) occurred more frequently in enhancing tumors with LFBS, although the latter was not statistically significant. HFMS was associated with higher rates of subcortical motor pathway identification (p = 0.001) and fewer total intraoperative seizures (p = 0.003) compared with LFBS. Previous resection (HR 0.46, p = 0.003) and a higher cortical threshold (HR 0.95, p = 0.023) were significantly associated with longer survival, while preoperative aphasia (HR 2.24, p = 0.022), hospital length of stay (HR 1.1, p = 0.005), an insular-based tumor (HR 3.5, p = 0.021), and a histological diagnosis of glioblastoma (HR 2.9, p = 0.001) were negative predictors. Interestingly, overall FLAIR EOR was significantly associated with a marginally decreased overall survival (HR 1.01, p = 0.011). CONCLUSIONS No significant differences in postoperative neurological deficits were found between LFBS and HFMS paradigms. HFMS may identify subcortical motor fibers more reliably while resulting in significantly fewer intraoperative seizures. Although LFBS was associated with greater EOR of contrast-enhancing tumors, it may also be associated with higher rates of postoperative deficits, perhaps reflecting less reliable identification of subcortical motor fibers.

Abstract Pediatric high-grade gliomas (pHGG) are aggressive primary brain neoplasms with a dismal prognosis, making them the leading cause of brain tumor-related deaths in children. pHGGs occur in specific anatomical locations at specific ages underscoring their origin in neurodevelopment and the critical importance of the brain tumor microenvironment. Many pHGGs originate from oligodendroglial precursor cells (OPC) and, like OPCs, neuronal activity promotes pHGG proliferation. Neuronal activity drives pHGG growth through the secretion of activity-regulated mitogens and electrochemical communication with pHGG cells that integrate into neural circuits. In turn, pHGG increases neuronal excitability and remodels functional neural circuits. The interconnected network of glioma cells and neurons is fundamental to pHGG progression. We developed a two-color in vivo imaging method to study neuron-glioma cell interactions over time in freely behaving mice enabling us to record the frequency, pattern, and synchronicity of calcium transients in neurons, glioma cells, and their coactivity, giving us a comprehensive view of the changes in neuron-glioma circuit dynamics over time. Our imaging paradigm offers a unique ability to study neuron-glioma interactions at the systems level. We have observed increasing neuronal activity and synchronicity throughout the disease. We have also observed that different gliomas exhibit unique patterns of calcium transients and show increased levels of activity and synchronicity as the tumor progresses. We verified our findings through longitudinal in vivo local field potential recordings, finding an increase in all power bands, especially in high-gamma activity over time. Using single nuclei RNA sequencing of mice harboring murine H3K27M-­altered DMG, we observed gene expression changes indicating an increase in synaptogenesis and axonogenesis processes in glioma-associated neurons. Performing in vitro neurite outgrowth assays, we observed increased axonogenesis in hiPSC-derived neurons in the presence of pHGGs compared to other neurons, confirming our snRNA-seq findings. Based on this data, we hypothesize that as gliomas progress, the neuron-glioma malignant circuitry evolves through synaptogenesis and axonogenesis to promote glioma progression.

Abstract Background Imaging-based glioma monitoring is confounded by treatment-related changes. D-2-hydroxyglutarate (D-2-HG), produced by the isocitrate dehydrogenase (IDH) mutation, is detectable in cerebrospinal fluid (CSF), which can be sampled from cranial or lumbar compartments. We evaluated CSF D-2-HG as a serially accessible biomarker for IDH-mutant gliomas, including the optimal compartment for longitudinal sampling. Methods Lumbar and cranial CSF samples were collected from patients with IDH-mutant gliomas or IDH-wild-type central nervous system pathologies via surgical field collection, lumbar punctures, and CSF access devices. CSF D-2-HG was quantified via our CLIA-certified gas chromatography mass spectrometry assay. Results D-2-HG was significantly higher in cranial than lumbar CSF from IDH-mutant glioma patients. Consistent with low D-2-HG abundance in lumbar CSF, lumbar samples could not discriminate IDH-mutant gliomas from IDH-wild-type lesions. In contrast, cranial CSF D-2-HG was significantly higher in IDH-mutant gliomas than wild-type lesions, providing an adequate baseline for initial evaluations of monitoring capabilities. Across 75 samples from 7 consecutive patients with grade 4 IDH-mutant astrocytomas, serial cranial CSF D-2-HG decreased with cytoreduction, remained unchanged with stable disease, and increased with disease progression, but not pseudoprogression. Conclusions Serial cranial CSF D-2-HG shows promise as a monitoring biomarker for IDH-mutant gliomas.

OBJECTIVE Spinal ultrasound is used to investigate occult dysraphism in neonates with sacrococcygeal dimples. Inappropriate imaging studies may be performed despite the Choosing Wisely Canada guidelines. The objective of this study was to assess the appropriateness of spinal ultrasounds performed in 2 Canadian provinces and to compare the diagnostic accuracy of spinal ultrasound and MRI in predicting the need for neurosurgical intervention. METHODS This multicenter retrospective cohort study identified spinal ultrasounds in neonates younger than 6 months of age from January 1, 2017, to December 30, 2018, in Alberta and British Columbia, Canada. The authors collected data on patient demographic characteristics, reasons for requested imaging, the presence of any imaging abnormalities, and the ultimate need for intraspinal surgery. Ultrasounds were deemed appropriate if the Choosing Wisely guidelines were followed for ordering. The authors compared high-risk findings on spinal ultrasound and MRI to the need for surgery using sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV). RESULTS A total of 1043 ultrasounds were ordered in 1042 neonates, most commonly by pediatricians (49%), family doctors (27%), and neonatologists (16%). Three hundred eighty-three ultrasounds (37%) were deemed inappropriately ordered. Sixty-nine infants (7%) of the cohort received an MRI and 11 (1%) ultimately underwent neurosurgical intervention. None of the patients who had an inappropriately ordered ultrasound underwent surgery. Spinal ultrasound, compared to surgery, had a sensitivity of 36%, specificity of 98%, PPV of 17%, and NPV of 99%. Spinal MRI, compared to surgery, had a sensitivity of 73%, specificity of 76%, PPV of 38%, and NPV of 94%. CONCLUSIONS Although spinal ultrasound has an acceptable specificity in predicting surgery, it remains a poor screening test (36% sensitivity). Given that approximately 37% of spinal ultrasounds were inappropriately ordered in this study period, the authors estimate that if physicians followed the Choosing Wisely Guidelines more closely, it would result in an estimated potential cost savings of CAD$1,856,769 over a decade for Canada with minimal surgical impact and a very low risk of missing surgically relevant spinal dysraphism.

OBJECTIVE 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 3 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 evaluated prognostic factors associated with 90-day survival after SRS, aiming to improve patient selection. METHODS The authors retrospectively analyzed a cohort of 1546 patients who underwent Gamma Knife SRS for brain metastases at their institution between 2015 and 2023. One hundred seventy patients who survived less than 90 days after SRS were identified and case matched to 170 patients who survived over 90 days. Measured variables included patient demographic characteristics, tumor characteristics, treatment history, functional status, and control of the primary cancer. The authors modeled post-SRS 90-day survival using binomial and multivariate logistic regression. RESULTS Multivariate analysis highlighted Karnofsky Performance Score (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 poor survival, whereas CNS progression before SRS (OR 0.22, p < 0.001) and control of systemic cancer (OR 0.556, p = 0.002) were associated with survival < 90 days. 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%. CONCLUSIONS Key predictors of 90-day survival after SRS for brain metastases include functional status (KPS), control of systemic cancer, CNS progression status, and focal neurological deficits. These findings are complementary factors that can assist in making decisions and SRS patient selection.

Abstract BACKGROUND Awake craniotomy with speech mapping remains a gold standard for achieving maximal safe resection of diffuse gliomas located in eloquent cortex. Significant practice variability exists with regards to patient selection, speech mapping paradigms, aggressiveness of resection, and use of other adjuncts. We report our experience with speech mapping procedures for patients with diffuse gliomas, comparing cases performed with and without intraoperative MRI. METHODS A single-surgeon retrospective review of 148 consecutive awake craniotomy procedures, from 2008-2024, was performed. We recorded baseline patient characteristics, speech mapping findings, post-operative course, and volumetric extents of resection. Multivariate regression analyses were performed for factors predictive of permanent aphasia and residual tumor volume. RESULTS Speech mapping was performed in 95% of cases, with positive speech areas found in 49% of cases. Intraoperative MRI cases (75% of total) had significantly greater extent of resection (87.4% vs. 78.6%, p=0.03) despite equivalent pre-operative volumes. Post-operative new/worsened aphasia was 15% for mild and 5% for moderate symptoms, and this was associated with reduced rates of return to work (54% vs 78%, p=0.04). Predictors of recovery from aphasia were extent of resection (OR 1.1, p=0.006) and 90-day disease progression (OR 0.06, p=0.04). Predictors of residual tumor volume were pre-operative tumor volume (β 0.3, p&lt;0.001), identification of after-discharge potentials during speech mapping (β -9.7, p&lt;0.001), and pre-operative functional status (β -0.3, p=0.02). Overall survival was impacted by presence of contrast enhancement (p=0.0002), tissue diagnosis (p&lt;0.0001), and WHO grade (p&lt;0.0001). CONCLUSIONS Awake craniotomy with speech mapping remains a valuable strategy for achieving maximal safe resection of diffuse gliomas, with the majority of patients returning to baseline level of functioning. New/worsened aphasia is the biggest risk of surgery, which significantly impacts patient quality of life. Intraoperative MRI can be considered as an adjunctive tool for awake speech mapping during glioma surgery.

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 &lt; 0.05). Periventricular enhancement was significantly more frequent in r/r PCNSL (p &lt; 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 Pediatric high-grade gliomas (pHGG) are aggressive primary brain neoplasms with a dismal prognosis, making them the leading cause of brain tumor-related deaths in children. pHGGs occur in specific anatomical locations at specific ages underscoring their origin in neurodevelopment and the critical importance of the brain tumor microenvironment. Many pHGGs originate from oligodendroglial precursor cells (OPCs) and, like OPCs, neuronal activity promotes the proliferation of pHGGs. Neuronal activity drives pHGG growth through electrochemical communication with pHGG cells. In turn, pHGGs increase neuronal excitability and remodel functional neural circuits. The interconnected network of glioma cells and neurons is fundamental to pHGG progression. Using single-nuclei RNA sequencing of mice harboring murine H3K27M-altered Diffused Midline Glioma (DMG), we observed gene expression changes indicating an increase in axonogenesis processes in glioma-associated neurons (GANs), primarily driven by EphA signaling. EphA4, EphA5, and EphA7 are overexpressed in GANs while the ligand, EphrinA1, is overexpressed in H3K27M gliomas. Performing in vitro neurite outgrowth and co-culture assays, we observed increased axonogenesis in neurons in the presence of DMG cells and DMG-conditioned media. We developed a two-color in vivo imaging method to study neuron-glioma interactions over time in freely behaving mice enabling us to record the frequency, pattern, and synchronicity of calcium transients in neurons, glioma cells, and their coactivity, giving us a comprehensive view of the changes in neuron-glioma circuit dynamics over time. We have observed increasing neuronal activity and synchronicity throughout the disease. We have also observed that gliomas also exhibit increased levels of activity and synchronicity as the tumor progresses. We verified our findings through longitudinal in vivo local field potential recordings, finding an increase in all power bands, especially in high-gamma activity over time. Ongoing experiments will test how glioma-induced axonogenesis contributes to the observed evolution of malignant circuit dynamics over time. Taken together, our data shows as gliomas progress, the neuron-glioma malignant circuitry evolves through axonogenesis driven by EphA signaling.

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&lt;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 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) &lt; 70 (OR: 17.4, p &lt; 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 &lt; 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.