Association of CDKN2A alterations with increased postoperative seizure risk after resection of brain metastases.

OBJECTIVE: Seizures are common and significantly disabling for patients with brain metastases (BMs). Although resection can provide seizure control, a subset of patients with BMs may continue to suffer seizures postoperatively. Genomic BM characteristics may influence which patients are at risk for postoperative seizures. This work explores correlations between genomic alterations and risk of postoperative seizures following BM resection. METHODS: All patients underwent BM resection at a single institution, with available clinical and sequencing data on more than 500 oncogenes. Clinical seizures were documented pre- and postoperatively. A random forest machine learning classification was used to determine candidate genomic alterations associated with postoperative seizures, and clinical and top genomic variables were correlated with postoperative seizures by using Cox proportional hazards models. RESULTS: There were 112 patients with BMs who underwent 114 surgeries and had at least 1 month of postoperative follow-up. Seizures occurred preoperatively in 26 (22.8%) patients and postoperatively in 25 (21.9%). The Engel classification achieved at 6 months for those with preoperative seizures was class I in 13 (50%); class II in 6 (23.1%); class III in 5 (19.2%), and class IV in 2 (7.7%). In those with postoperative seizures, only 8 (32.0%) had seizures preoperatively, and preoperative seizures were not a significant predictor of postoperative seizures (HR 1.84; 95% CI 0.79-4.37; p = 0.156). On random forest classification and multivariate Cox analysis controlling for factors including recurrence, extent of resection, and number of BMs, CDKN2A alterations were associated with postoperative seizures (HR 3.22; 95% CI 1.27-8.16; p = 0.014). Melanoma BMs were associated with higher risk of postoperative seizures compared with all other primary malignancies (HR 5.23; 95% CI 1.37-19.98; p = 0.016). Of 39 BMs with CDKN2A alteration, 35.9% (14/39) had postoperative seizures, compared to 14.7% (11/75) without CDKN2A alteration. The overall rate of postoperative seizures in melanoma BMs was 42.9% (15/35), compared with 12.7% (10/79) for all other primary malignancies. CONCLUSIONS: CDKN2A alterations and melanoma primary malignancy are associated with increased postoperative seizure risk following resection of BMs. These results may help guide postoperative seizure prophylaxis in patients undergoing resection of BMs.

Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity.

Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer's disease (AD). However, we understand very little about the normal functions of fission or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca2+ (mitoCa2+) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca2+. This mitoCa2+ overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.

Global transcriptomic analysis of a murine osteocytic cell line subjected to spaceflight.

Bone loss is a major health concern for astronauts during long-term spaceflight and for patients during prolonged bed rest or paralysis. Growing evidence suggests that osteocytes, the most abundant cells in the mineralized bone matrix, play a key role in sensing mechanical forces applied to the skeleton and integrating the orchestrated response into subcellular biochemical signals to modulate bone homeostasis. However, the precise molecular mechanisms underlying both mechanosensation and mechanotransduction in late-osteoblast-to-osteocyte cells under microgravity (µG) have yet to be elucidated. To unravel the mechanisms by which late osteoblasts and osteocytes sense and respond to mechanical unloading, we exposed the osteocytic cell line, Ocy454, to 2, 4, or 6 days of µG on the SpaceX Dragon-6 resupply mission to the International Space Station. Our results showed that µG impairs the differentiation of osteocytes, consistent with prior osteoblast spaceflight experiments, which resulted in the downregulation of key osteocytic genes. Importantly, we demonstrate the modulation of critical glycolysis pathways in osteocytes subjected to microgravity and discovered a set of mechanical sensitive genes that are consistently regulated in multiple cell types exposed to microgravity suggesting a common, yet to be fully elucidated, genome-wide response to microgravity. Ground-based simulated microgravity experiments utilizing the NASA rotating-wall-vessel were unable to adequately replicate the changes in microgravity exposure highlighting the importance of spaceflight missions to understand the unique environmental stress that microgravity presents to diverse cell types. In summary, our findings demonstrate that osteocytes respond to µG with an increase in glucose metabolism and oxygen consumption.

Pediatric moyamoya MRI score: an imaging-based scale to predict outcomes in surgically treated pediatric patients with moyamoya.

OBJECTIVE: Moyamoya is a progressive arteriopathy that predisposes patients to stroke due to stenosis of the intracranial internal carotid arteries and their proximal branches. Despite the morbidity caused by this condition, the ability to accurately predict prognosis for individual patients remains challenging. The goal of this study was to develop a systematic scoring method based on parenchymal findings on preoperative brain MRI to predict long-term outcomes for surgically treated pediatric patients with moyamoya. METHODS: A retrospective surgical cohort of pediatric patients (≤ 18 years of age at the time of the initial surgery) with moyamoya from a single center were studied. Radiological variables with existing correlations between outcomes in moyamoya or other vascular diseases were chosen to score preoperative MRI based on easily defined parenchymal findings that could be rapidly assessed and used to make a numeric score. Calculated scores were correlated with clinical outcome measures using the Pearson correlation coefficient and area under the receiver operating characteristic curve (AUROC). RESULTS: A total of 35 children with moyamoya disease or moyamoya syndrome were included in the study, with a median follow-up time of 2.6 years from the time of surgery. The pediatric moyamoya MRI score (PMMS) consists of ischemic changes (0-2; 0 = none, 1 = focal, 2 = diffuse), encephalomalacia (0-2; 0 = none, 1 = focal, 2 = diffuse), and hemorrhage (0-1; 0 = not present, 1 = present). PMMSs were highly correlated with pediatric modified Rankin Scale scores at the last follow-up (r = 0.7, 95% CI 0.44-0.84; p < 0.001) as a six-point scale, and when dichotomized (AUROC = 0.85). CONCLUSIONS: The PMMS was found to be a simple tool based on preoperative MRI data that could be quickly and easily calculated and correlated with disability. This scoring method may aid future development of predictive models of outcomes for children with moyamoya disease and moyamoya syndrome.

Clamshell thoracotomy for en bloc resection of a 3-level thoracic chordoma: technical note and operative video.

The clamshell thoracotomy is often used to access both hemithoraxes and the mediastinum simultaneously for cardiothoracic pathology, but this technique is rarely used for the excision of spinal tumors. We describe the use of a clamshell thoracotomy for en bloc excision of a 3-level upper thoracic chordoma in a 20-year-old patient. The lesion involved T2, T3, and T4, and it invaded both chest cavities and indented the mediastinum. After 2 biopsies to confirm the diagnosis, the patient underwent a posterior spinal fusion followed by bilateral clamshell thoracotomy for 3-level en bloc resection with simultaneous access to both chest cavities and the mediastinum. To demonstrate how the clamshell thoracotomy was used to facilitate the tumor resection, an operative video and illustrations are provided, which show in detail how the clamshell thoracotomy can be used to access both hemithoraxes and the mediastinum.

Arteriovenous malformations in the cerebellopontine angle: assessment of the "backdoor resection" technique and microsurgical results in 38 patients.

OBJECTIVE: Posterior fossa arteriovenous malformations (AVMs) represent 7% to 15% of all intracranial AVMs and are associated with an increased risk of hemorrhage, morbidity, and mortality compared with supratentorial AVMs, thus prompting urgent and definitive treatment. Cerebellopontine angle (CPA) AVMs are a unique group of posterior fossa AVMs incorporating characteristics of brainstem and cerebellar lesions, which are particularly amenable to microsurgical resection. This study reports the clinical, radiological, operative, and outcome features of patients with CPA AVMs in a large cohort. METHODS: The authors conducted a single-surgeon, 2-institution retrospective cohort study of all consecutive patients with CPA AVMs treated with microsurgical resection during a 25-year period. RESULTS: CPA AVMs represented 22% (38 of 176) of all infratentorial AVMs resected by the senior author. Overall, 38 patients (22 [58%] male and 16 [42%] female) met the study inclusion criteria and were analyzed. Most patients presented with hemorrhage (n = 29, 76%). The median age at surgery was 56 (range 6-82) years. Subtypes included 22 (58%) petrosal cerebellar AVMs, 11 (29%) lateral pontine AVMs, and 5 (13%) AVMs involving both the brainstem and cerebellum. Most AVM niduses were small (< 3 cm; n = 35, 92%) and compact (n = 31, 82%). Fourteen (37%) patients harbored flow-related aneurysms. Twenty (53%) patients underwent preoperative embolization. Complete angiographic obliteration was achieved with microsurgery in 35 (92%) patients. Five (13%) patients with poor neurological conditions at presentation died before hospital discharge. Of the 7 (18%) patients with new postoperative neurological deficits, 5 had transient deficits. The median (interquartile range) follow-up was 1.7 (0.5-3.2) years; 32 (84%) patients were alive at last follow-up, and 30 (79%) had achieved a favorable neurological outcome (modified Rankin Scale [mRS] score 0-2). The only independent predictor of unfavorable postoperative outcome (mRS score 3-6) was the preoperative mRS score (p = 0.002). CONCLUSIONS: CPA AVMs are unique posterior fossa lesions, including petrosal cerebellar and lateral pontine AVMs. The "backdoor resection" technique provides a safe and efficient strategy with high obliteration rates and a low risk of treatment-related morbidity. Microsurgical resection should be considered the frontline treatment for most CPA AVMs, except for those with a significant diffuse brainstem component.

Early Treatment of Ruptured Cerebral Arteriovenous Malformations: Analysis of Neurological Outcomes and Health Care Costs.

BACKGROUND: The timing of surgical resection is controversial when managing ruptured arteriovenous malformations (AVMs) and varies considerably among centers. OBJECTIVE: To retrospectively analyze clinical outcomes and hospital costs associated with delayed treatment in a ruptured cerebral AVM patient cohort. METHODS: Patients undergoing surgical treatment for a ruptured cerebral AVM (January 1, 2015-December 31, 2020) were retrospectively analyzed. Patients who underwent emergent treatment of a ruptured AVM because of acute herniation were excluded, as were those treated >180 days after rupture. Patients were stratified by the timing of surgical intervention relative to AVM rupture into early (postbleed days 1-20) and delayed (postbleed days 21-180) treatment cohorts. RESULTS: Eighty-seven patients were identified. The early treatment cohort comprised 75 (86%) patients. The mean (SD) length of time between AVM rupture and surgical resection was 5 (5) days in the early cohort and 73 (60) days in the delayed cohort ( P < .001). The cohorts did not differ with respect to patient demographics, AVM size, Spetzler-Martin grade, frequency of preoperative embolization, or severity of clinical presentation ( P ≥ .15). Follow-up neurological status was equivalent between the cohorts ( P = .65). The associated mean health care costs were higher in the delayed treatment cohort ($241 597 [$99 363]) than in the early treatment cohort ($133 989 [$110 947]) ( P = .02). After adjustment for length of stay, each day of delayed treatment increased cost by a mean of $2465 (95% CI = $967-$3964, P = .002). CONCLUSION: Early treatment of ruptured AVMs was associated with significantly lower health care costs than delayed treatment, but surgical and neurological outcomes were equivalent.

Chronic hyperactivation of midbrain dopamine neurons causes preferential dopamine neuron degeneration.

Parkinson's disease (PD) is characterized by the death of substantia nigra (SNc) dopamine (DA) neurons, but the pathophysiological mechanisms that precede and drive their death remain unknown. The activity of DA neurons is likely altered in PD, but we understand little about if or how chronic changes in activity may contribute to degeneration. To address this question, we developed a chemogenetic (DREADD) mouse model to chronically increase DA neuron activity, and confirmed this increase using ex vivo electrophysiology. Chronic hyperactivation of DA neurons resulted in prolonged increases in locomotor activity during the light cycle and decreases during the dark cycle, consistent with chronic changes in DA release and circadian disturbances. We also observed early, preferential degeneration of SNc projections, recapitulating the PD hallmarks of selective vulnerability of SNc axons and the comparative resilience of ventral tegmental area axons. This was followed by eventual loss of midbrain DA neurons. Continuous DREADD activation resulted in a sustained increase in baseline calcium levels, supporting an important role for increased calcium in the neurodegeneration process. Finally, spatial transcriptomics from DREADD mice examining midbrain DA neurons and striatal targets, and cross-validation with human patient samples, provided insights into potential mechanisms of hyperactivity-induced toxicity and PD. Our results thus reveal the preferential vulnerability of SNc DA neurons to increased neural activity, and support a potential role for increased neural activity in driving degeneration in PD.

Multi-omic screening of invasive GBM cells in engineered biomaterials and patient biopsies reveals targetable transsulfuration pathway alterations.

While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multi-omics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Amongst oncologic ROS, hydrogen peroxide specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine gamma lyase (CTH), which converts cystathionine to the non-essential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.

A comparison of incidental and symptomatic unruptured brain arteriovenous malformations in children.

OBJECTIVE: Patients with unruptured brain arteriovenous malformations (AVMs) may present with headaches, seizures, and/or neurological deficits. A smaller number of cases may be discovered incidentally. These lesions remain incompletely understood due to their sparse reporting. Herein, the authors describe the largest series to date comparing the presentation, angioarchitecture, and management of incidental versus symptomatic unruptured AVMs in children. METHODS: The authors performed a retrospective analysis of patients who presented with brain AVMs from 1998 to 2022 at the University of California, San Francisco. Inclusion criteria were age ≤ 18 years at the time of presentation and an angiographically proven unruptured AVM that had been diagnosed postnatally. RESULTS: Of 76 children with unruptured AVMs, 66 (86.8%) presented with headaches, seizures, and/or neurological deficit. Ten AVMs (13.1%) were incidentally discovered through unrelated disease workup (50%), cranial trauma (40%), or research study participation (10%). Compared with patients with symptomatic unruptured AVMs, patients with incidental unruptured AVMs had a smaller mean ± SD maximum nidus diameter (2.82 ± 1.1 vs 3.98 ± 1.52 cm, p = 0.025) and fewer had deep venous drainage (20% of patients vs 61%, p = 0.036). They also presented at an earlier age (10 ± 5.2 vs 13.5 ± 4 years, p = 0.043) and with longer duration to first treatment (541 ± 922 vs 196 ± 448 days, p = 0.005). During the observation period, 1 patient developed recurring headaches and demonstrated AVM nidus growth. Four AVMs greater than 3 cm in size or in a deep location were treated with radiosurgery. Six other AVMs were treated with resection, with 2 receiving preoperative embolization. Eight AVMs (80%) were obliterated on last follow-up. Postprocedural complications included 2 transient neurological deficits after resection and 1 case of delayed seizure development after radiosurgery. The mean follow-up period was 5.7 ± 5.7 years without any hemorrhage episodes. CONCLUSIONS: A substantial proportion of pediatric patients with unruptured AVMs are discovered incidentally. With earlier presentation and more elementary angioarchitecture than symptomatic unruptured AVMs, these incidental lesions provide a snapshot into the natural history of AVM before symptom development or rupture.

You Take the Low Road: Differential Outcomes After Tangential and Transcortical Approaches to Medial Temporal Brain Arteriovenous Malformations.

OBJECTIVE: Microsurgical resection of medial temporal brain arteriovenous malformations (AVMs) is typically conducted through 2 approaches: the orbitozygomatic-tangential and subtemporal-transcortical. Relative indications and outcomes for these techniques have not been formally compared. METHODS: The cerebrovascular database of a quaternary center was reviewed for patients with medial temporal AVMs treated between January 1, 1997, and July 31, 2021. Demographic characteristics, lesion characteristics, surgical approaches, and outcomes were retrospectively analyzed and compared. Postoperative outcome testing was performed using the Montreal Cognitive Assessment and Global Quality of Life Scale. RESULTS: Fifty-nine patients were assessed. Mean (standard deviation) age was 31 (18) years; 30 (51%) patients were male. Of the AVMs, 29 (49%) were left-sided and 30 (51%) were right-sided. The tangential approach was selected in 20 (34%) cases, whereas the transcortical technique was preferred in 39 (66%). Improved modified Rankin Scale status was significantly associated with the tangential resection technique both in the early postoperative period (P = 0.02) and at last follow-up (P = 0.01). Differences between the tangential and transcortical approaches were not significant with respect to new postoperative deficits (5/20 [25%] vs. 12/39 [31%], P = 0.87) or the presence of residual AVM on follow-up angiography (1/20 [6%] vs. 5/39 [14%], P = 0.65). CONCLUSIONS: The orbitozygomatic-tangential strategy was associated with favorable functional and quality-of-life outcomes after medial temporal AVM resection. These benefits are likely to be attributable to minimization of temporal retraction, avoidance of brain transgression, and avoidance of traction on the vein of Labbé, rendering the orbitozygomatic-tangential approach the preferred option for cases that are anatomically amenable to either strategy.

Factors Associated with Unfavorable Clinical Presentations in Patients with Ruptured BrainArteriovenous Malformations.

BACKGROUND: Rupture of brain arteriovenous malformations (bAVMs) carries potentially devastating consequences. For patients presenting with ruptured bAVMs, several clinical grading systems have been shown to predict long-term patient morbidity and may be taken into consideration when making clinical decisions. Unfortunately, use of these scoring systems is typically limited to their prognostic value and offer little to patients in therapeutic benefit. Tools are needed not only to predict prognosis for patients experiencing ruptured bAVMs but to gain insight into what characteristics predispose patients to poor long-term outcomes before they rupture. Our objective was to find clinical, morphologic, and demographic variables that correlate with unfavorable clinical grades on presentation in patients with ruptured bAVMs. METHODS: We retrospectively reviewed a cohort of patients with ruptured bAVMs. Linear regression models were used to test whether Glasgow Coma Scale (GCS) and Hunt-Hess scores on presentation(outcomes) were associated with patient and arteriovenous malformation (AVM) characteristics (predictors) individually. RESULTS: GCS and Hunt-Hess were assessed following bAVM rupture for 121 brain cases. The median age at rupture was 28.5 years, and 62 (51%) were female. Smoking history was associated with worse GCS; current and past smokers had GCS scores 1.33 points lower on average than nonsmokers (95% confidence interval [CI] -2.59 to -0.07, P = 0.039) and had worse Hunt-Hess scores (0.42, 95% CI 0.07-0.77, P = 0.019). Associated aneurysms were associated with worse GCS (-1.60, 95% CI -3.16 to -0.05, P = 0.043) and trended towards worse Hunt-Hess scores (0.42 points, 95% CI -0.01 to 0.86, P = 0.057). CONCLUSIONS: Patient smoking status and presence of an AVM associated aneurysm were shown to have modest correlations with unfavorable clinical grades (Hunt-Hess, GCS) on presentation, with unfavorable clinical grades being associated with long-term patient prognosis following bAVM rupture. Further investigation using AVM-specific grading scales and external data are needed to determine the utility of these and other variables in clinical practice for patients with bAVM.

Patient Frailty Influences Outcome After Open, But Not Minimally Invasive, Transforaminal Interbody Fusion: A Case Series of 115 Patients With Lumbar Degenerative Disease.

BACKGROUND: For transforaminal lumbar interbody fusion (TLIF), there are equally good open and minimally invasive surgery (MIS) options. OBJECTIVE: To determine if frailty has a differential effect on outcome for open vs MIS TLIF. METHODS: We performed a retrospective review of 115 TLIF surgeries (1-3 levels) for lumbar degenerative disease performed at a single center; 44 MIS transforaminal interbody fusions and 71 open TLIFs were included. All patients had at least a 2-year follow up, and any revision surgery during that time was recorded. The Adult Spinal Deformity Frailty Index (ASD-FI) was used to separate patients into nonfrail (ASD-FI < 0.3) and frail (ASD-FI > 0.3) cohorts. The primary outcome variables were revision surgery and discharge disposition. Univariate analyses were performed to reveal associations in demographic, radiographic, and surgical data with the outcome variables. Multivariate logistic regression was used to assess independent predictors of outcome. RESULTS: Frailty uniquely predicted both reoperation (odds ratio 8.1, 95% CI 2.5-26.1, P = .0005) and discharge to a location other than home (odds ratio 3.9, 95% CI 1.2-12.7, P = .0239). Post hoc analysis indicated that frail patients undergoing open TLIF had a higher revision surgery rate (51.72%) compared with frail patients undergoing MIS-TLIF (16.7%). Nonfrail patients undergoing open and MIS TLIF had a revision surgery rate of 7.5% and 7.7%, respectively. CONCLUSION: Frailty was associated with increased revision rate and increased probability to discharge to a location other than home after open transforaminal interbody fusions, but not MIS transforaminal interbody fusions. These data suggest that patients with high frailty scores may benefit from MIS-TLIF procedures.

Occipital Artery to Middle Cerebral Artery Direct Bypass: A Salvage Revascularization Technique for Ischemic Moyamoya Disease.

OBJECTIVE: The main treatment for moyamoya disease (MMD) is revascularization surgery. Most bypasses use the superficial temporal artery (STA) as the donor vessel. However, even if the STA-middle cerebral artery (MCA) bypass is functioning, the affected hemisphere can continue to be symptomatically malperfused. We sought to assess the efficacy of salvage direct revascularization surgery using the occipital artery (OA) as a donor vessel in patients with ischemic MMD who experience continued cerebral malperfusion despite previous successful STA-MCA bypass. METHODS: We retrospectively analyzed the cerebrovascular databases of 2 surgeons and described patients in whom the OA was used as the donor vessel for direct revascularization. RESULTS: Seven patients were included (5 women). Previous STA-MCA bypasses were direct (n = 2), indirect (n = 3), or combined/multiple (n = 2). The mean (SD) interval between STA-MCA and OA-MCA procedures was 29.2 (13.1) months. Despite an intact STA-MCA bypass in all 7 cases, all 7 patients had recurrent symptoms and demonstrated residual impaired cerebral perfusion. All 7 patients underwent successful OA-MCA direct revascularization. Follow-up perfusion imaging was obtained for 6 of 7 patients. All 6 of these patients demonstrated improved cerebral blood flow to the revascularized hemispheres. All 7 patients demonstrated clinical improvement. CONCLUSIONS: Patients with ischemic MMD who have continued symptoms and cerebral malperfusion despite previous successful STA-MCA bypass present a challenging clinical scenario. Our series highlights the potential utility of the OA-MCA direct bypass as a salvage therapy for these patients.

Factors associated with preoperative and postoperative seizures in patients undergoing resection of brain metastases.

OBJECTIVE: Epileptic seizures are a common and potentially devastating complication of metastatic brain tumors. Although tumor-related seizures have been described in previous case series, most studies have focused on primary brain tumors and have not differentiated between different types of cerebral metastases. The authors analyzed a large surgical cohort of patients with brain metastases to examine risk factors associated with preoperative and postoperative seizures and to better understand the seizure risk factors of metastatic brain tumors. METHODS: Patients who underwent resection of a brain metastasis at the University of California, San Francisco (UCSF), were retrospectively reviewed. Patients included in the study were ≥ 18 years of age, required resection of a brain metastasis, and were treated at UCSF. Primary cancers included melanoma, non-small cell lung adenocarcinoma, breast adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, renal cell carcinoma, urothelial carcinoma, ovarian carcinoma, cervical squamous cell carcinoma, and endometrial adenocarcinoma. Patients were evaluated for primary cancer type and seizure occurrence, as well as need for use of antiepileptic drugs preoperatively, at time of discharge, and at 6 months postoperatively. Additionally, Engel classification scores were assigned to those patients who initially presented with seizures preoperatively. Univariate and multivariate regression analyses were used to assess the association of tumor type with preoperative seizures. RESULTS: Data were retrospectively analyzed for 348 consecutive patients who underwent surgical treatment of brain metastases between 1998 and 2019. The cohort had a mean age of 60 years at the time of surgery and was 59% female. The mean and median follow-up durations after the date of surgery for the cohort were 22 months and 10.8 months, respectively. In univariate analysis, frontal lobe location (p = 0.05), melanoma (p = 0.02), KRAS mutation in lung carcinoma (p = 0.04), intratumoral hemorrhage (p = 0.04), and prior radiotherapy (p = 0.04) were associated with seizure presentation. Postoperative checkpoint inhibitor use (p = 0.002), prior radiotherapy (p = 0.05), older age (p = 0.002), distant CNS progression (p = 0.004), and parietal lobe tumor location (p = 0.002) were associated with seizures at 6 months postoperatively. The final multivariate model confirmed the independent effects of tumor location in the frontal lobe and presence of intratumoral hemorrhage as predictors of preoperative seizures, and checkpoint inhibitor use and parietal lobe location were identified as significant predictors of seizures at 6 months postoperatively. CONCLUSIONS: Within this surgical cohort of patients with brain metastases, seizures were seen in almost a quarter of patients preoperatively. Frontal lobe metastases and hemorrhagic tumors were associated with higher risk of preoperative seizures, whereas checkpoint inhibitor use and parietal lobe tumors appeared to be associated with seizures at 6 months postoperatively. Future research should focus on the effect of metastatic lesion-targeting therapeutic interventions on seizure control in these patients.

Multiomic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations.

While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multiomics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Among oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine γ-lyase (CTH), which converts cystathionine to the nonessential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.

Impact of the COVID-19 Pandemic on Neurosurgical Transfers: A Single Tertiary Center Study.

OBJECTIVE: Interfacility transfers represent a large proportion of neurosurgical admissions to tertiary care centers each year. In this study, the authors examined the impact of the COVID-19 pandemic on the number of transfers, timing of transfers, demographic profile of transfer patients, and clinical outcomes including rates of surgical intervention. METHODS: A retrospective review of neurosurgical transfer patients at a single tertiary center was performed. Patients transferred from April to November 2020 (the "COVID Era") were compared with an institutional database of transfer patients collected before the COVID-19 pandemic (the "Pre-COVID Era"). During the COVID Era, both emergent and nonemergent neurosurgical services had resumed. A comparison of demographic and clinical factors between the 2 cohorts was performed. RESULTS: A total of 674 patients were included in the study (331 Pre-COVID and 343 COVID-Era patients). Overall, there was no change in the average monthly number of transfers (P = 0.66) or in the catchment area of referral hospitals. However, COVID-Era patients were more likely to be uninsured (1% vs. 4%), had longer transfer times (COVID vs. Pre-COVID Era: 18 vs. 9 hours; P < 0.001), required higher rates of surgical intervention (63% vs. 50%, P = 0.001), had higher rates of spine pathology (17% vs. 10%), and less frequently were admitted to the intensive care unit (34% vs. 52%, P < 0.001). Overall, COVID-Era patients did not experience delays to surgical intervention (3.1 days vs. 3.6 days, P = 0.2). When analyzing the subgroup of COVID-Era patients, COVID infection status did not impact the time of transfer or rates of operation, although COVID-infected patients experienced a longer time to surgery after admission (14 vs. 2.9 days, P < 0.001). CONCLUSION: The COVID-19 pandemic did not reduce the number of monthly transfers, operation rates, or catchment area for transfer patients. Transfer rates of uninsured patients increased during the COVID Era, potentially reflecting changes in access to community neurosurgery care. Shorter time to surgery seen in COVID-Era patients possibly reflects institutional policies that improved operating room efficiency to compensate for surgical backlogs. COVID status affeted time to surgery, reflecting the preoperative care that these patients require before intervention.

Sphenoparietal Sinus Dural Arteriovenous Fistulas: A Series of 10 Patients.

BACKGROUND: Dural arteriovenous fistulas (DAVFs) of the sphenoparietal sinus or sphenoid wing region are uncommon lesions with unique and interesting angioarchitecture. Understanding appropriate anatomy and recognizing patterns provide important treatment implications. OBJECTIVE: To describe a single surgeon's experience with open surgical treatment of sphenoparietal sinus DAVFs, the surgical indications for this uncommon lesion, and the microsurgical techniques related to its treatment and to review the literature on its surgical treatment. METHODS: Consecutive cases of sphenoparietal sinus DAVF treatment conducted by a single surgeon over 24 years (1997-2020) were retrospectively reviewed. Published reports of similar cases were reviewed. RESULTS: Of 202 surgically treated DAVFs, 10 lesions in 10 patients were sphenoparietal sinus DAVFs. Four patients presented with intracranial hemorrhage, 3 with headache, and 2 with pulsatile tinnitus; 1 patient was incidentally identified as having a DAVF during treatment for a ruptured aneurysm. Most patients (7 of 10) had undergone endovascular embolization previously. Nine patients had Borden type III DAVFs and one had a Borden type II fistula. Surgery in all 10 patients resulted in angiographically confirmed fistula obliteration. Clinical outcomes at the last follow-up, measured by a modified Rankin Scale (mRS) score, were excellent in 6 patients (mRS ≤ 2) and poor in 1 patient (mRS ≥ 3); late outcomes were not available for 3 patients. CONCLUSION: Sphenoparietal sinus DAVFs are an uncommon anatomic subtype. Careful attention to angiographic detail leads to identification of the site of venous interruption and results in a high rate of surgical cure with excellent clinical outcomes.

Validation of the Ruptured Arteriovenous Malformation Grading Scale in a pediatric cohort.

OBJECTIVE: Pediatric brain arteriovenous malformations (AVMs) are the leading cause of spontaneous intracranial hemorrhage (SICH) in children. Although the incidence of SICH is low in pediatric populations, such events cause substantial morbidity. The recently created Ruptured Arteriovenous Malformation Grading Scale (RAGS) is proposed as a reliable and novel grading system to specifically serve as a predictor of clinical outcomes in patients following AVM rupture, similar to the Hunt and Hess (HH) grade for ruptured aneurysms. While these data are promising, pediatric patients were notably absent from the original study validating the RAGS. Therefore, correlation of the RAGS score with clinical outcomes following AVM rupture in individuals younger than 18 years of age using the RAGS score is needed. The objective of this study was to validate the RAGS in a cohort of pediatric patients with AVMs who presented with hemorrhage, thereby demonstrating the score's generalizability, and expanding its external validity. METHODS: A cohort of children with ruptured AVMs were retrospectively reviewed. Using disability, measured by the modified Rankin Scale (mRS), as the response variable, the area under the receiver operating characteristic curve (AUROC) was calculated for patients based on their RAGS scores for three time periods. The AUROC values were then compared with those generated by two commonly used clinical grading systems, the HH classification and Glasgow Coma Scale. RESULTS: A total of 81 children who presented with ruptured AVMs were included in the study, with a mean follow-up duration of 4 years. The RAGS score outperformed other clinical grading scales in predicting mRS scores, with AUROC values of 0.81, 0.82, and 0.81 at three distinct follow-up periods. CONCLUSIONS: The RAGS score correlated well with the clinical outcome after AVM rupture in pediatric patients. Additional validation studies across multiple treatment centers are needed to further demonstrate the generalizability of the scoring system.

CD97 is associated with mitogenic pathway activation, metabolic reprogramming, and immune microenvironment changes in glioblastoma.

Glioblastoma (GBM) is the most common primary brain tumor with a median survival under two years. Using in silico and in vitro techniques, we demonstrate heterogeneous expression of CD97, a leukocyte adhesion marker, in human GBM. Beyond its previous demonstrated role in tumor invasion, we show that CD97 is also associated with upregulation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/Erk) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathways in GBM. While CD97 knockout decreased Akt activation, CD97 targeting did not alter MAPK/Erk activation, did not slow GBM cell proliferation in culture, and increased levels of glycolytic and oxidative phosphorylation metabolites. Treatment with a soluble CD97 inhibitor did not alter activation of the MAPK/Erk and PI3K/Akt pathways. Tumors with high CD97 expression were associated with immune microenvironment changes including increased naïve macrophages, regulatory T cells, and resting natural killer (NK) cells. These data suggest that, while CD97 expression is associated with conflicting effects on tumor cell proliferative and metabolic pathways that overall do not affect tumor cell proliferation, CD97 exerts pro-tumoral effects on the tumor immune microenvironment, which along with the pro-invasive effects of CD97 we previously demonstrated, provides impetus to continue exploring CD97 as a therapeutic target in GBM.