Repeated surgical resections for management of high-grade glioma and its impact on quality of life.

PURPOSE: High-grade gliomas (HGG) are aggressive cancers, and their recurrence is inevitable, despite advances in treatment options. While repeated tumor resection has been shown to increase survival rate, its impact on quality of life is not clearly defined. To address this gap, we compared quality of life (QoL) changes in HGG patients who underwent first-time (FTR) versus repeat surgical resections (RSR) for management of recurrence. METHODS: Forty-four adults with HGG who underwent tumor resection were included in this study and classified into either the FTR group (n = 23) or the RSR group (n = 21). All patients completed comprehensive neuropsychological evaluations that included the Functional Assessment of Cancer Therapy-General (FACT-G) and Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) scales, pre-operatively and at two weeks post-operatively. RESULTS: There was no difference between the FTR and RSR groups in any of the QoL indices (all p > .05), except for improved emotional well-being and worsened social well-being, suggesting minimal detrimental effects of repeat surgeries on QoL in comparison to first time surgery. CONCLUSIONS: These results suggest that repeated resection is a viable strategy in certain cases for management of HGG recurrence, with similar impact on QoL as observed in patients undergoing first time surgery. These encouraging outcomes provide useful insight to guide treatment strategies and patient and clinician decision making to optimize surgical and functional outcomes.

SARS-CoV2 entry factors are expressed in primary human glioblastoma and recapitulated in cerebral organoid models.

PURPOSE: Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults with a median overall survival of only 14.6 months despite aggressive treatment. While immunotherapy has been successful in other cancers, its benefit has been proven elusive in GBM, mainly due to a markedly immunosuppressive tumor microenvironment. SARS-CoV-2 has been associated with the development of a pronounced central nervous system (CNS) inflammatory response when infecting different cells including astrocytes, endothelial cells, and microglia. While SARS-CoV2 entry factors have been described in different tissues, their presence and implication on GBM aggressiveness or microenvironment has not been studied on appropriate preclinical models. METHODS: We evaluated the presence of crucial SARS-CoV-2 entry factors: ACE2, TMPRSS2, and NRP1 in matched surgically-derived GBM tissue, cells lines, and organoids; as well as in human brain derived specimens using immunohistochemistry, confocal pixel line intensity quantification, and transcriptome analysis. RESULTS: We show that patient derived-GBM tissue and cell cultures express SARS-CoV2 entry factors, being NRP1 the most crucial facilitator of SARS-CoV-2 infection in GBM. Moreover, we demonstrate that, receptor expression remains present in our GBM organoids, making them an adequate model to study the effect of this virus in GBM for the potential development of viral therapies in the future. CONCLUSION: Our findings suggest that the SARS-CoV-2 virus entry factors are expressed in primary tissues and organoid models and could be potentially utilized to study the susceptibility of GBM to this virus to target or modulate the tumor microenviroment.

Enhanced sensitivity of electrocorticography during awake craniotomy using a novel circular grid electrode.

PURPOSE: Awake craniotomy with intraoperative functional brain mapping (FBM) bedside neurological testing is an important technique used to optimize resective brain surgeries near eloquent cortex. Awake craniotomy performed with electrocorticography (ECoG) and direct electrical stimulation (DES) for FBM can delineate eloquent cortex from lesions and epileptogenic regions. However, current electrode technology demonstrates spatial limitations. Our group has developed a novel circular grid with the goal of improving spatial recording of ECoG to enhance detection of ictal and interictal activity. METHODS: This retrospective study was approved by the institutional review board at Mayo Clinic Florida. We analyzed patients undergoing awake craniotomy with ECoG and DES and compared ECoG data obtained using the 22 contact circular grid to standard 6 contact strip electrode. RESULTS: We included 144 cases of awake craniotomy with ECoG, 73 using circular grid and 71 with strip electrode. No significant differences were seen regarding preoperative clinical and demographic data, duration of ECoG recording (p = 0.676) and use of DES (p = 0.926). Circular grid was more sensitive in detecting periodic focal epileptiform discharges (PFEDs) (p = 0.004), PFEDs plus (p = 0.032), afterdischarges (ADs) per case (p = 0.022) at lower minimum (p = 0.012) and maximum (p < 0.0012) intensity stimulation, and seizures (p = 0.048). PFEDs (p < 0.001), PFEDs plus (p < 0.001), and HFOs (p < 0.001) but not ADs (p = 0.255) predicted electrographic seizures. CONCLUSION: We demonstrate higher sensitivity in detecting ictal and interictal activity on ECoG during awake craniotomy with a novel circular grid compared to strip electrode, likely due to better spatial sampling during ECoG. We also found association between PFEDs and intraoperative seizures.

Systemic Therapy for Melanoma Brain and Leptomeningeal Metastases.

OPINION STATEMENT: Melanoma has a high propensity to metastasize to the brain which portends a poorer prognosis. With advanced radiation techniques and targeted therapies, outcomes however are improving. Melanoma brain metastases are best managed in a multi-disciplinary approach, including medical oncologists, neuro-oncologists, radiation oncologists, and neurosurgeons. The sequence of therapies is dependent on the number and size of brain metastases, status of systemic disease control, prior therapies, performance status, and neurological symptoms. The goal of treatment is to minimize neurologic morbidity and prolong both progression free and overall survival while maximizing quality of life. Surgery should be considered for solitary metastases, or large and/or symptomatic metastases with edema. Stereotactic radiosurgery offers a benefit over whole-brain radiation attributed to the relative radioresistance of melanoma and reduction in neurotoxicity. Thus far, data supports a more durable response with systemic therapy using combination immunotherapy of ipilimumab and nivolumab, though targeting the presence of BRAF mutations can also be utilized. BRAF inhibitor therapy is often used after immunotherapy failure, unless a more rapid initial response is needed and then can be done prior to initiating immunotherapy. Further trials are needed, particularly for leptomeningeal metastases which currently require the multi-disciplinary approach to determine best treatment plan.

Wireless Stimulation of Motor Cortex Through a Collagen Dura Substitute Using an Ultra-Thin Implant Fabricated on Parylene/PDMS.

We present the design, fabrication, and in vivo testing of an ultra-thin (100 µm) wireless and battery-free implant for stimulation of the brain's cortex. The implant is fabricated on a flexible and transparent parylene/PDMS substrate, and it is miniaturized to dimensions of 15.6 × 6.6 mm 2. The frequency and pulse width of the monophasic voltage pulses are determined through On-Off keying (OOK) modulation of a wireless transmission at 2.45 GHz. Furthermore, the implant triggered a motor response in vivo when tested in 6 rodents. Limb response was observed by wireless stimulation of the brain's motor cortex through an FDA-approved collagen dura substitute that was placed on the dura in the craniotomy site, with no direct contact between the implant's electrodes and the brain's cortical surface. Therefore, the wireless stimulation method reported herein enables the concept of an e-dura substitute, where wireless electronics can be integrated onto a conventional dura substitute to augment its therapeutic function and administer any desired stimulation protocol without the need for post-surgical intervention for battery replacement or reprogramming stimulation parameters.

A Wireless Battery-Free Implant With Optical Telemetry for In Vivo Cortical Stimulation.

We present a 100 µm-thick, wireless, and battery-free implant for brain stimulation through a U.S. Food and Drug Administration-approved collagen dura substitute without contact with the brain's surface, while providing visible-light spectrum telemetry to track the onset of stimulation. The device is fabricated on a 16 × 6.67 mm2 biocompatible parylene/PDMS substrate and is encapsulated with a 2 µm-thick transparent parylene layer that enables the relay of the LED brightness. The in vivo rodent testing confirmed the implant's ability to trigger motor response while generating observable brightness through the skin. The results reveal the prospect of wireless stimulation with enhanced safety by eliminating contact between the implant and the brain, with optical telemetry for facilitated tracking.

Frailty as a Predictor of Postoperative Morbidity and Mortality in Patients Aged 80 Years and Older Undergoing Instrumented Fusion.

BACKGROUND AND OBJECTIVES: Degenerative spine disease is a leading cause of disability, with increasing prevalence in the older patients. While age has been identified as an independent predictor of outcomes, its predictive value is limited for similar older patients. Here, we aimed to determine the most predictive frailty score of adverse events in patients aged 80 and older undergoing instrumented lumbar fusion. METHODS: We proceeded with a multisite (3 tertiary academic centers) retrospective review including patients undergoing instrumented fusion aged 80 and older from January 2010 to present. A composite end point encompassing 30-day return to operating room, readmission, and mortality was created. We estimated the area under the receiver operating characteristic curve for frailty scores (Modified Frailty Index-5 [MFI-5], Modified Frailty Index-11 [MFI-11], and Charlson Comorbidity Index [CCI]) in relation to that composite score. In addition, we estimated the association between each score and the composite end point by means of logistic regression. RESULTS: A total of 153 patients with an average age of 85 years at the time of surgery were included. We observed a 30-day readmission rate of 11.1%, reoperation of 3.9%, and mortality of 0.6%. The overall rate of the composite end point at 30 days was 25 (15.1%). The AUC for MFI-5 was 0.597 (0.501-0.693), for MFI-11 was 0.620 (0.518-0.723), and for CCI was 0.564 (0.453-0.675). The association between the scores and composite end point did not reach statistical significance for MFI-5 (odds ratio [OR] = 1.45 [0.98-2.15], P = .061) and CCI (OR = 1.13 [0.97-1.31], P = .113) but was statistically significant for MFI-11 (OR = 1.46 [1.07-2.00], P = .018). CONCLUSION: This is the largest study comparing frailty index scores in octogenarians undergoing instrumented lumbar fusion. Our findings suggest that while MFI-11 score correlated with adverse events, the predictive ability of existing scores remains limited, highlighting the need for better approaches to identify select patients at age extremes.

Intracranial aneurysms in patients with acute ischemic stroke prevalence and influence on mechanical thrombectomy over 14 years in a tertiary-care center.

INTRODUCTION: The prevalence of intracranial aneurysms (IA) in patients with acute ischemic stroke (AIS) requiring mechanical thrombectomy (MT) is unclear. OBJECTIVE: To describe the prevalence of IA in patients with AIS and their influence on MT. MATERIALS & METHODS: This is a retrospective cohort study on all patients admitted with a diagnosis of AIS from January 2008 to March 2022 at a tertiary academic center. The records were reviewed for demographic, clinical, imaging, and outcomes data. Only patients who had CTA at admission were included in this analysis. RESULTS: Among 2265 patients admitted with AIS, this diagnosis was confirmed in 2113 patients (93.3 %). We included 1111 patients (52.6 %) who had head CTA and 321 (28.9 %) who underwent MT. The observed prevalence of aneurysms on CTA was 4.5 % (50/1111 patients), and 8 (16 %) had multiple aneurysms. MT was performed in 7 patients harboring IAs: 6 ipsilateral (5 proximal and 1 distal to the occlusion)and 1 contralateral aneurysm.. The patient with a contralateral aneurysm had a TICI 2B score In patients with ipsilateral aneurysms, TICI 2B or 3 was achieved in 3 cases (50 %), which is significantly lower than historical control of MT (91.6 %) without IA (p = 0.01). No aneurysms ruptured during MT. The aneurysm noted distal to the occlusion was mycotic. CONCLUSION: In this analysis, the observed prevalence of IA in patients with AIS was 4.5%. Ipsilateral aneurysms (proximal or distal to the occlusion site) deserve particular attention, given the potential risk of rupture during MT. Aneurysms located distal to the occlusion were mycotic and the rate of recanization in patients with ipsilateral aneurysms was low compared to historical controls. Further studies are needed to improve the outcomes in patients with IA requiring MT.

Awake Craniotomy Program Implementation.

Importance: Implementing multidisciplinary teams for treatment of complex brain tumors needing awake craniotomies is associated with significant costs. To date, there is a paucity of analysis on the cost utility of introducing advanced multidisciplinary standardized teams to enable awake craniotomies. Objective: To assess the cost utility of introducing a standardized program of awake craniotomies. Design, Setting, and Participants: A retrospective economic evaluation was conducted at Mayo Clinic Florida. All patients with single, unilateral lesions who underwent elective awake craniotomies between January 2016 and December 2021 were considered eligible for inclusion. The economic perspective of the health care institution and a time horizon of 1 year were considered. Data were analyzed from October 2022 to May 2023. Exposure: Treatment with an awake craniotomy before standardization (2016-2018) compared with treatment with awake craniotomy after standardization (2018-2021). Main Outcomes and Measures: Patient demographics, perioperative, and postoperative outcomes, including length of stay, intensive care (ICU) admission, extent of resection, readmission rates, and 1-year mortality were compared between patients undergoing surgery before and after standardization. Direct medical costs were estimated from Medicare reimbursement rates for all billed procedures. A cost-utility analysis was performed considering differences in direct medical costs and in 1-year mortality within the periods before and after standardization of procedures. Uncertainty was explored in probability sensitivity analysis. Results: A total of 164 patients (mean [SD] age, 49.9 [15.7] years; 98 [60%] male patients) were included in the study. Of those, 56 underwent surgery before and 108 after implementation of procedure standardization. Procedure standardization was associated with reductions in length of stay from a mean (SD) of 3.34 (1.79) to 2.46 (1.61) days (difference, 0.88 days; 95% CI, 0.33-1.42 days; P = .002), length of stay in ICU from a mean (SD) of 1.32 (0.69) to 0.99 (0.90) nights (difference, 0.33 nights; 95% CI, 0.06-0.60 nights; P = .02), 30-day readmission rate from 14% (8 patients) in the prestandardization cohort to 5% (5 patients) (difference, 9%; 95% CI, 19.6%-0.3%; P = .03), while extent of resection and intraoperative complication rates were similar between both cohorts. The standardized protocol was associated with mean (SD) savings of $7088.80 ($12 389.50) and decreases in 1-year mortality (dominant intervention). This protocol was found to be cost saving in 75.5% of all simulations in probability sensitivity analysis. Conclusions and Relevance: In this economic evaluation of standardization of awake craniotomy, there was a generalized reduction in length of stay, ICU admission time, and direct medical costs with implementation of an optimized protocol. This was achieved without compromising patient outcomes and with similar extent of resection, complication rates, and reduced readmission rates.

From the Operating Room to the Laboratory: Role of the Neuroscience Tissue Biorepository in the Clinical, Translational, and Basic Science Research Pipeline.

OBJECTIVE: To establish a neurologic disorder-driven biospecimen repository to bridge the operating room with the basic science laboratory and to generate a feedback cycle of increased institutional and national collaborations, federal funding, and human clinical trials. METHODS: Patients were prospectively enrolled from April 2017 to July 2022. Tissue, blood, cerebrospinal fluid, bone marrow aspirate, and adipose tissue were collected whenever surgically safe. Detailed clinical, imaging, and surgical information was collected. Neoplastic and nonneoplastic samples were categorized and diagnosed in accordance with current World Health Organization classifications and current standard practices for surgical pathology at the time of surgery. RESULTS: A total of 11,700 different specimens from 813 unique patients have been collected, with 14.2% and 8.5% of patients representing ethnic and racial minorities, respectively. These include samples from a total of 463 unique patients with a primary central nervous system tumor, 88 with metastasis to the central nervous system, and 262 with nonneoplastic diagnoses. Cerebrospinal fluid and adipose tissue dedicated banks with samples from 130 and 16 unique patients, respectively, have also been established. Translational efforts have led to 42 new active basic research projects; 4 completed and 6 active National Institutes of Health-funded projects; and 2 investigational new drug and 5 potential Food and Drug Administration-approved phase 0/1 human clinical trials, including 2 investigator initiated and 3 industry sponsored. CONCLUSION: We established a comprehensive biobank with detailed notation with broad potential that has helped us to transform our practice of research and patient care and allowed us to grow in research and clinical trials in addition to providing a source of tissue for new discoveries.

What Factors Predict the Development of Neurologic Deficits Following Resection of Intramedullary Spinal Cord Tumors: A Multi-Center Study.

BACKGROUND: Intramedullary spinal cord tumors are challenging to resect, and their postoperative neurological outcomes are often difficult to predict, with few studies assessing this outcome. METHODS: We reviewed the medical records of all patients surgically treated for Intramedullary spinal cord tumors at our multisite tertiary care institution (Mayo Clinic Arizona, Mayo Clinic Florida, Mayo Clinic Rochester) between June 2002 and May 2020. Variables that were significant in the univariate analyses were included in a multivariate logistic regression. "MissForest" operating on the Random Forest algorithm, was used for data imputation, and K-prototype was used for data clustering. Heatmaps were added to show correlations between postoperative neurological deficit and all other included variables. Shapley Additive exPlanations were implemented to understand each feature's importance. RESULTS: Our query resulted in 315 patients, with 160 meeting the inclusion criteria. There were 53 patients with astrocytoma, 66 with ependymoma, and 41 with hemangioblastoma. The mean age (standard deviation) was 42.3 (17.5), and 48.1% of patients were women (n = 77/160). Multivariate analysis revealed that pathologic grade >3 (OR = 1.55; CI = [0.67, 3.58], P = 0.046 predicted a new neurological deficit. Random Forest algorithm (supervised machine learning) found age, use of neuromonitoring, histology of the tumor, performing a midline myelotomy, and tumor location to be the most important predictors of new postoperative neurological deficits. CONCLUSIONS: Tumor grade/histology, age, use of neuromonitoring, and myelotomy type appeared to be most predictive of postoperative neurological deficits. These results can be used to better inform patients of perioperative risk.

Two- versus multi-rod constructs for adult spinal deformity: A systematic review and Random-effects and Bayesian meta-analysis.

BACKGROUND: Surgical approaches in adult spinal deformity are associated with high rates of adverse events including hardware failure and rod fracture. Recently, some reports have emerged comparing multiple-rod constructs with 2-rod constructs suggesting potential benefits with the former. However, these have been limited by variability in observed outcomes, which have limited the change of paradigm in adult spinal deformity surgery. OBJECTIVE: To compare the rate of rod fracture, pseudoarthrosis, proximal junctional kyphosis and re-operation between 2-RC and M-RC. METHODS: MEDLINE/Pubmed, Web of Science and Embase were searched without language restrictions for relevant articles from inception until October 2021. All observational cohort studies assessing patients with ADS undergoing 3-column osteotomy and comparing 2-RC with M-RC procedures on pseudarthrosis, rod fracture, kyphosis or reoperation were included. Data were independently extracted by 2 authors. Random-effects and Bayesian meta-analysis were used. RESULTS: Six primary studies met inclusion criteria, yielding a total of 448 participants, with 223 receiving 2-RC and 225 M-RC. The random-effects meta-analysis pointed to a significantly lower risk of rod fracture associated with M-RC (RR = 0.43, 95 %CI = 0.28-0.66), with moderate heterogeneity being observed (I2 = 20 %, p = 0.28). The random-effects meta-analysis pointed to a lower risk of pseudoarthrosis with M-RC than with 2-RC (RR = 0.49, CI = 0.28-0.84, to a lower rate of re-operation with M-RC than with 2-RC (RR = 0.52, CI = 0.28-0.97) and to a similar rate of proximal junctional kyphosis between 2-RC and M-RC patients (RR = 0.91, CI = 0.60-1.39). Low heterogeneity was observed for studies comparing pseudoarthrosis (I2 = 9 %, p = 0.35), re-operation (I2 = 0 %, p = 0.41) and proximal junctional kyphosis (I2 = 0 %, p = 0.85). DISCUSSION: These findings suggest that multiple rod-fracture constructs are associated with lower rates of rod fracture, re-operation rates, pseudoarthrosis but not proximal junctional kyphosis. Future studies should address the impact of other modulators of heterogeneity such as body mass index, metal alloys and length of the constructs.

Endoscopic Endonasal Approach for Resection of a Recurrent Craniopharyngioma: Techniques to Maximize Surgical Exposure and Extent of Resection.

Craniopharyngiomas are challenging tumors of the central nervous system that originate from epithelial remnants of the Rathke pouch.1-3 Despite maximum safe resection, these tumors present a high tendency to recur (∼20%-40%), even after apparent gross total resection.1,2 The management of recurrent craniopharyngiomas is more challenging, associated with a higher risk of permanent morbidity and complications.1,3 The endoscopic endonasal approach is an option for recurrent tumors, especially in the presence of a previous transcranial approach.1,3-7 In Video 1, we present a case of a 63-year-old man with a recurrent craniopharyngioma with a 2-month history of visual decline, confusion, impaired memory, and episodes of urinary incontinence. On physical examination, he presented slow speech, word-finding difficulties, and left homonymous hemianopsia. Magnetic resonance imaging evidenced a large suprasellar, retrochiasmatic mass with solid (calcified) and cystic components with interval progression compared with previous scans. Treatment options were discussed, and the patient consented to undergo maximum safe resection through an extended endoscopic endonasal approach. Surgical techniques are presented side by side with anatomic dissections to illustrate key steps of the procedure. The patient tolerated the procedure well, with gross total resection of the tumor and without complications or postoperative cerebrospinal fluid leaks. He was subsequently discharged home on postoperative day 5 with continued hormonal replacement therapy. On follow-up, the patient presented marked improvement in his cognitive function. The patient gave informed consent for the use of their images.

Risk factors for preoperative and postoperative seizures in patients with glioblastoma according to the 2021 World Health Organization classification.

OBJECTIVE: To identify risk factors for developing glioblastoma (GBM) related preoperative (PRS) and postoperative seizures (POS). Also, we aimed to analyze the impact of PRS and POS on survival in a GBM cohort according to the revised 2021 WHO glioma classification. METHODS: We performed a single-center retrospective cohort study of patients with GBM (according to the 2021 World Health Organization Classification) treated at Mayo Clinic Florida between January 2018 and July 2022. Seizures were stratified into preoperative seizures (PRS) and postoperative seizures (POS, >7 days after surgery). Associations between patients' characteristics and overall survival with PRS and POS were assessed. RESULTS: One hundred nineteen adults (mean =60.9 years), 49 (41.2 %) females, were identified. The rates of PRS and POS in the cohort were 35.3 % (n = 42) and 37.8 % (n = 45), respectively. Patients with PRS were younger (p = 0.035) and were likely to undergo intraoperative electrocorticography. The incidence of PRS (p = 0.049) and POS (p<0.001) was lower among patients with tumors located in the occipital location. PRS increased the risk of POS after adjusting for age and sex (RR: 2.59, CI = 1.44-4.65, p = 0.001). There was no association between PRS or POS and other patient-related factors, including several tumor molecular markers (TMMs) examined. PRS (p = 0.036), POS (p<0.001), and O6-Methylguanine-DNA Methyltransferase (MGMT) promotor methylation status (p = 0.032) were associated with longer survival time. CONCLUSIONS: PRS and POS are associated with non-occipital tumor location and longer survival time in patients with GBM. While younger ages predicted PRS, PRS predicted POS. Well-designed prospective studies with larger sample sizes are needed to clarify the influence of TMMs in the genesis of epileptic seizures in patients with GBM.

Dual-Device Neuromodulation in Epilepsy.

OBJECTIVE: Current methods of neuromodulation have been shown to reduce seizures in patients with drug-resistant epilepsy, and in a small percentage of patients it has rendered them seizure-free when surgical resection is not feasible. While polytherapy with antiseizure medication is not uncommon, dual neurostimulation has received limited attention. We set out to identify trends and changes in the use of dual neurostimulation to understand choosing device combinations. METHODS: We reviewed the Mayo Clinic database in Florida of patients who underwent vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS) from October 1998 through September 2021. The prevalence of active VNS with DBS or RNS was considered dual therapy. RESULTS: In total, 131 patients (71 female) underwent 164 VNS-associated procedures, 28 received RNS, and 8 received DBS (6 anterior thalamic DBS; 2 thalamic centromedian nucleus DBS). Active dual stimulation occurred in 3 of 28 patients who received RNS and 8 of 8 patients who received DBS (P = 0.006), mean duration of 28 and 16.3 months, respectively. Patients who received VNS-DBS were more likely to have a previous response to VNS (P = 0.025) and were unresponsive to more antiseizure medications (P = 0.020). The VNS-RNS group had focal seizures more likely to have electroclinical localization (P = 0.005) and more frequently underwent invasive electroencephalographic monitoring (P = 0.026). CONCLUSIONS: The ability to localize was the primary decision-maker in prompting RNS versus DBS. RNS surgery was more likely to be preceded by invasive electroencephalographic monitoring. Previous VNS responsiveness was more prominent in patients with DBS. Dual therapy was safe. Prospective multicenter studies of dual-device neuromodulation are needed.