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The development of novel therapeutics in the field of spinal neurosurgery faces a litany of translational challenges. Achieving precise drug targeting within the confined spaces associated with the spinal cord, canal and vertebra requires the development of next generation delivery systems and devices. These must be capable of overcoming inherent barriers related to drug diffusion, whilst concurrently ensuring optimal drug distribution and retention. In this review, we provide an overview of the most recent advances in the therapeutic management of diseases and disorders affecting the spine, including systems and devices capable of releasing small molecules and biopharmaceuticals that help eliminate pain and restore the mechanical function and stability of the spine. We highlight material-based approaches and minimally invasive techniques that can be employed to provide control over drug release kinetics and improve retention. We also seek to explore how the newest advancements in nanotechnology, biomaterials, additive manufacturing technologies and imaging modalities can be employed in this translational pursuit. Finally, we discuss the landscape of clinical trials and recently approved products aimed at overcoming the complexities associated with drug delivery to the spine., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objectives: Cerebellopontine angle (CPA) meningiomas present challenges given their proximity to neurovascular structures. Postoperative complications and persistent symptoms can debilitate patients, and our ability to predict recovery course remains variable. Here, we examine the presentation, management, and outcomes of patients with CPA meningiomas., Methods: We retrospectively reviewed CPA meningiomas resected at Mass General Brigham, using descriptive statistics and logistic regression to identify predictors of progression or recurrence., Results: In total, 95 patients were identified (median age 59.1 years, 82.1% female) who presented most commonly with hearing loss (49.5%), ataxia (42.1%), and headaches (29.5%). The retrosigmoid (78.9%) or transmastoid retrosigmoid (17.9%) approaches were most frequently used for resection, with gross total resection (GTR) achieved in 62.1% of patients: Simpson grade 1 (32.6%), grade 2 (17.9%), and grade 3 (11.6%). Smaller tumor size (t = 3.17, P = .002) is associated with GTR. For tumors with intracanalicular invasion, drilling the internal auditory canal (IAC) was also associated with GTR (χ2 = 21.8, P < .001). Among cases with invasion, GTR was achieved in 88.5% of cases when the IAC was drilled vs 11.8% of cases when the IAC was not drilled. The cranial nerve VII/VIII complex was frequently inferior (45.6%) or superior (19.1%) to the meningioma. Postoperative hearing loss was stable (38.7%) or improved (54.8%) in most of patients at the final clinical follow-up (median: 39.4 months). 25.3% of patients had progression/recurrence, with some difference between World Health Organization grade 1 (median: 3.0 years, IQR: 2.9 years) and World Health Organization grade 2 (median: 1.6 years, IQR: 2.8 years) tumors. After multivariate adjustment, Simpson grade I (P = .02), Simpson grade II (P = .01), or being of older age (P = .003) were associated with lower odds of progression/recurrence., Conclusion: GTR remains critical to achieve optimal symptom control and reduce progression/recurrence rates for CPA meningiomas. Drilling the IAC is an important predictor of GTR in tumors with intracanalicular invasion., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background: Despite the proven effectiveness of endovascular therapy (EVT) in acute ischemic strokes (AIS) involving anterior circulation large vessel occlusions, isolated posterior cerebral artery (PCA) occlusions (iPCAo) remain underexplored in clinical trials. This study investigates the comparative effectiveness and safety of EVT against medical management (MM) in patients with iPCAo., Methods: This multinational, multicenter propensity score-weighted study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. We included iPCAo patients treated with either EVT or MM. The primary outcome was the modified Rankin Scale (mRS) at 90 days, with secondary outcomes including functional independence, mortality, and safety profiles such as hemorrhagic complications., Results: A total of 177 patients were analyzed (88 MM and 89 EVT). EVT showed a statistically significant improvement in 90-day mRS scores (OR = 0.55, 95% CI = 0.30-1.00, p  = 0.048), functional independence (OR = 2.52, 95% CI = 1.02-6.20, p  = 0.045), and a reduction in 90-day mortality (OR = 0.12, 95% CI = 0.03-0.54, p  = 0.006) compared to MM. Hemorrhagic complications were not significantly different between the groups., Conclusion: EVT for iPCAo is associated with better neurological outcomes and lower mortality compared to MM, without an increased risk of hemorrhagic complications. Nevertheless, these results should be interpreted with caution due to the study's observational design. The findings are hypothesis-generating and highlight the need for future randomized controlled trials to confirm these observations and establish definitive treatment guidelines for this patient population., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Regenhardt serves on a DSMB for a trial sponsored by Rapid Medical, serves as site PI for studies sponsored by Penumbra and Microvention, and receives stroke research grant funding from the National Institutes of Health, Society of Vascular and Interventional Neurology, and Heitman Stroke Foundation. Dr. Guenego reports consultancy for Rapid Medical and Phenox, not directly related to the present work. Dr. Clarençon reports conflicts of interest with Medtronic, Balt Extrusion (consultant), ClinSearch (core lab), Penumbra, Stryker (payment for reading), and Artedrone (Board); all not directly related to the present work. Dr. Henninger received support from W81XWH-19-PRARP-RPA form the CDMRP/DoD, NS131756 and U24NS113844 from the NINDS, and NR020231 from the NINR and received compensation from Myrobalan, Inc. and General Dynamics during the conduct of this study unrelated to this work. Dr. Liebeskind is consultant as Imaging Core Lab to Cerenovus, Genentech, Medtronic, Stryker, Rapid Medical. Dr. Yeo reports Advisory work for AstraZeneca, Substantial support from NMRC Singapore and is a medical advisor for See-mode, Cortiro, and Sunbird Bio, with equity in Ceroflo. All unrelated to the present work. Dr. Griessenauer reports a proctoring agreement with Medtronic and research funding by Penumbra. Dr. Marnat reports conflicts of interest with Microvention Europe, Stryker Neurovascular, Balt (consulting), Medtronic, Johnson & Johnson, and Phenox (paid lectures), all not directly related to the present work. Dr. Puri is a consultant for Medtronic Neurovascular, Stryker NeurovascularBalt, Q’Apel Medical, Cerenovus, Microvention, Imperative Care, Agile, Merit, CereVasc, and Arsenal Medical, he received research grants from NIH, Microvention, Cerenovus, Medtronic Neurovascular, and Stryker Neurovascular, and holds stocks in InNeuroCo, Agile, Perfuze, Galaxy, and NTI. Dr. Tjoumakaris is a consultant for Medtronic and Microvention (funds paid to institution, not personally). Dr. Jabbour is a consultant for Medtronic, Microvention, and Cerus.

Background and Purpose: Progression-free survival (PFS) remains to be validated as an outcome measure for diffuse WHO grade 2 gliomas, and knowledge about the relationships between PFS, post-progression survival (PPS), and overall survival (OS) in this subset of tumors is limited. We sought to assess correlations between PFS and OS, and identify factors associated with PFS, PPS, and OS in patients treated for diffuse supratentorial WHO grade 2 gliomas., Material and Methods: We included 319 patients from three independent observational cohorts. The correlation between PFS and OS was analyzed using independent exponential distributions for PFS and time from progression to death. Cox proportional hazards models were used to determine the effects of covariates on PFS, PPS, and OS., Results: The overall correlation between PFS and OS was rs0.31. The correlation was rs 0.37 for astrocytomas and rs 0.19 for oligodendrogliomas. Longer PFS did not predict longer PPS. Patients with astrocytomas had shorter PFS, PPS, and OS. Larger preoperative tumor volume was a risk factor for shorter PFS, while older age was a risk factor for shorter PPS and OS. Patients who received early radio- and chemotherapy had longer PFS, but shorter PPS and OS., Interpretation: We found a weak correlation between PFS and OS in WHO grade 2 gliomas, with the weakest correlation observed in oligodendrogliomas. Our analyses did not demonstrate any association between PFS and PPS. Critically, predictors of PFS are not necessarily predictors of OS. There is a need for validation of PFS as an endpoint in diffuse WHO grade 2 gliomas.

Objective: Visual acuity (VA) constitutes an important outcome measure in surgery for medial sphenoid wing meningioma (SWM). This study aimed to assess the recovery of tumor-associated impairment of VA and its impact on patient-reported outcome measures (PROMs) as an indication of vision-related quality of life in patients who had undergone surgery for medial SWM., Methods: From 2009 to 2018, 153 consecutive patients with medial SWM underwent surgical treatment at the authors' institutions. Tumor-associated VA was evaluated both on admission and during postoperative follow-up examinations, using Snellen charts. Multivariable analysis was performed to identify independent predictors for postoperative improvement of VA. PROMs were collected based on the National Eye Institute 25-Item Visual Function Questionnaire., Results: Of patients with medial SWM, 53 of 153 (35%) experienced preoperative impairment of VA. The median preoperative duration of visual symptoms was 12 (IQR 3-17) months for the entire study cohort. Multivariable analysis revealed a preoperative duration of visual symptoms ≤ 4 months to be independently associated with postoperative improvement of VA (p = 0.009). Evaluation of PROMs indicated a superior postoperative qualitative extent in the overall health (p = 0.027) and activities of daily living (p = 0.031) categories if preoperative duration of visual impairment was ≤ 4 months., Conclusions: The overall preoperative duration of tumor-related visual impairment significantly correlates to the extent of postoperative visual improvement as well as vision-related PROMs in medial SWM surgery. These results might aid in preoperative patient counseling and help optimize decision-making and preoperative estimation of long-term visual outcome.

Background: Medium vessel occlusion (MeVO) strokes, particularly affecting the M2 segment of the middle cerebral artery, represent a critical proportion of acute ischemic strokes, posing significant challenges in management and outcome prediction. The efficacy of mechanical thrombectomy (MT) in MeVO stroke may warrant reliable predictors of functional outcomes. This study aimed to investigate the prognostic value of follow-up infarct volume (FIV) for predicting 90-day functional outcomes in MeVO stroke patients undergoing MT., Methods: This multicenter, retrospective cohort study analyzed data from the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry, covering patients with acute ischemic stroke due to M2 segment occlusion treated with MT. We examined the relationship between 90-day functional outcomes, measured by the modified Rankin Scale (mRS), and follow-up infarct volume (FIV), assessed through CT or MRI within 12-36 h post-MT., Results: Among 130 participants, specific FIV thresholds were identified with high specificity and sensitivity for predicting outcomes. A FIV ⩽5 ml was highly specific for predicting favorable and excellent outcomes. The optimal cut-off for both prognostications was identified at ⩽15 ml by the Youden Index, with significant reductions in the likelihood of favorable outcomes observed above a 40 ml threshold. Receiver Operator Curve (ROC) analyses confirmed FIV as a superior predictor of functional outcomes compared to traditional recanalization scores, such as final modified thrombolysis in cerebral infarction score (mTICI). Multivariable analysis further highlighted the inverse relationship between FIV and positive functional outcomes., Conclusions: FIV within 36 h post-MT serves as a potent predictor of 90-day functional outcomes in patients with M2 segment MeVO strokes. Establishing FIV thresholds may aid in the prognostication of stroke outcomes, suggesting a role for FIV in guiding post intervention treatment decisions and informing clinical practice. Future research should focus on validating these findings across diverse patient populations and exploring the integration of FIV measurements with other clinical and imaging markers to enhance outcome prediction accuracy., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Regenhardt serves on a DSMB for a trial sponsored by Rapid Medical, serves as site PI for studies sponsored by Penumbra and Microvention, and receives stroke research grant funding from the National Institutes of Health, Society of Vascular and Interventional Neurology, and Heitman Stroke Foundation.Dr. Guenego reports consultancy for Rapid Medical and Phenox, not directly related to the present work.Dr. Clarençon reports conflicts of interest with Medtronic, Balt Extrusion (consultant), ClinSearch (core lab), Penumbra, Stryker (payment for reading) and Artedrone (Board); all not directly related to the present work.Dr. Henninger received support from W81XWH-19-PRARP-RPA form the CDMRP/DoD, NS131756 and U24NS113844 from the NINDS, and NR020231 from the NINR and received compensation from Myrobalan, Inc. and General Dynamics during the conduct of this study unrelated to this work.Dr. Liebeskind is consultant as Imaging Core Lab to Cerenovus, Genentech, Medtronic, Stryker, Rapid Medical.Dr. Yeo reports Advisory work for AstraZeneca, Substantial support from NMRC Singapore and is a medical advisor for See-mode, Cortiro and Sunbird Bio, with equity in Ceroflo. All unrelated to the present work.Dr. Griessenauer reports a proctoring agreement with Medtronic and research funding by Penumbra.Dr. Marnat reports conflicts of interest with Microvention Europe, Stryker Neurovascular, Balt (consulting), Medtronic, Johnson & Johnson and Phenox (paid lectures), all not directly related to the present work.Dr. Puri is a consultant for Medtronic Neurovascular, Stryker NeurovascularBalt, Q’Apel Medical, Cerenovus, Microvention, Imperative Care, Agile, Merit, CereVasc and Arsenal Medical, he received research grants from NIH, Microvention, Cerenovus, Medtronic Neurovascular and Stryker Neurovascular, and holds stocks in InNeuroCo, Agile, Perfuze, Galaxy and NTI.Dr. Tjoumakaris is a consultant for Medtronic and Microvention (funds paid to institution, not personally).Dr. Jabbour is a consultant for Medtronic, Microvention and Cerus.

Dynamic tracking of spinal instrumentation could facilitate real-time evaluation of hardware integrity and in so doing alert patients/clinicians of potential failure(s). Critically, no method yet exists to continually monitor the integrity of spinal hardware and by proxy the process of spinal arthrodesis; as such hardware failures are often not appreciated until clinical symptoms manifest. Accordingly, herein, we report on the development and engineering of a bio-adhesive metal detector array (BioMDA), a potential wearable solution for real-time, non-invasive positional analyses of osseous implants within the spine. The electromagnetic coupling mechanism and intimate interfacial adhesion enable the precise sensing of the metallic implants position without the use of radiation. The customized decoupling models developed facilitate the precise determination of the horizontal and vertical positions of the implants with incredible levels of accuracy (e.g., <0.5 mm). These data support the potential use of BioMDA in real-time/dynamic postoperative monitoring of spinal implants., (© 2024. The Author(s).)

Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSV) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T-cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell-mediated immunity may lead to more durable tumor regression. To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine codelivering peptide antigens and Toll-like receptor 7 and 8 agonists (referred to as SNAPvax),which induces robust tumor-specific T-cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T-cell responses, viral replication, and preclinical efficacy. The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumor volume and increases in virus replication and tumor antigen-specific CD8+ T cells. These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors., (©2024 American Association for Cancer Research.)

Background and Purpose: The management of acute ischemic stroke (AIS) due to distal medium vessel occlusion (DMVO) remains uncertain, particularly in comparing the effectiveness of intravenous thrombolysis (IVT) plus mechanical thrombectomy (MT) versus IVT alone. This study aimed to evaluate the safety and efficacy in DMVO patients treated with either MT-IVT or IVT alone., Methods: This multinational study analyzed data from 37 centers across North America, Asia, and Europe. Patients with AIS due to DMVO were included, with data collected from September 2017 to July 2023. The primary outcome was functional independence, with secondary outcomes including mortality and safety measures such as types of intracerebral hemorrhage., Results: The study involved 1,057 patients before matching, and 640 patients post-matching. Functional outcomes at 90 days showed no significant difference between groups in achieving good functional recovery (modified Rankin Scale 0-1 and 0-2), with adjusted odds ratios (OR) of 1.21 (95% confidence interval [CI] 0.81 to 1.79; P=0.35) and 1.00 (95% CI 0.66 to 1.51; P>0.99), respectively. Mortality rates at 90 days were similar between the two groups (OR 0.75, 95% CI 0.44 to 1.29; P=0.30). The incidence of symptomatic intracerebral hemorrhage was comparable, but any type of intracranial hemorrhage was significantly higher in the MT-IVT group (OR 0.43, 95% CI 0.29 to 0.63; P<0.001)., Conclusion: The results of this study indicate that while MT-IVT and IVT alone show similar functional and mortality outcomes in DMVO patients, MT-IVT presents a higher risk of hemorrhagic complications, thus MT-IVT may not routinely offer additional benefits over IVT alone for all DMVO stroke patients. Further prospective randomized trials are needed to identify patient subgroups most likely to benefit from MT-IVT treatment in DMVO.

Interim results from two phase 1 trials demonstrate progress in the use of chimeric antigen receptor (CAR) T cell therapy for recurrent glioblastoma (GBM).

Background: Acute ischemic stroke (AIS) from primary medium vessel occlusions (MeVO) is a prevalent condition associated with substantial morbidity and mortality. Despite the common use of mechanical thrombectomy (MT) in AIS, predictors of poor outcomes in MeVO remain poorly characterized., Methods: In this prospectively collected, retrospectively reviewed, multicenter, multinational study, data from the MAD-MT (Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy) registry were analyzed. The study included 1568 patients from 37 academic centers across North America, Asia, and Europe, treated with MT, with or without intravenous tissue plasminogen activator (IVtPA), between September 2017 and July 2021., Results: Among the 1568 patients, 347 (22.2%) experienced very poor outcomes (modified Rankin score (mRS), 5-6). Key predictors of poor outcomes were advanced age (odds ratio (OR): 1.03; 95% confidence interval (CI): 1.02 to 1.04; p < 0.001), higher baseline National Institutes of Health Stroke Scale (NIHSS) scores (OR: 1.07; 95% CI: 1.05 to 1.10; p < 0.001), pre-operative glucose levels (OR: 1.01; 95% CI: 1.00 to 1.02; p < 0.001), and a baseline mRS of 4 (OR: 2.69; 95% CI: 1.25 to 5.82; p = 0.011). The multivariable model demonstrated good predictive accuracy with an area under the receiver-operating characteristic (ROC) curve of 0.76., Conclusions: This study demonstrates that advanced age, higher NIHSS scores, elevated pre-stroke mRS, and pre-operative glucose levels significantly predict very poor outcomes in AIS-MeVO patients who received MT. These findings highlight the importance of a comprehensive risk assessment in primary MeVO patients for personalized treatment strategies. However, they also suggest a need for cautious patient selection for endovascular thrombectomy. Further prospective studies are needed to confirm these findings and explore targeted therapeutic interventions., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Regenhardt serves on a DSMB for a trial sponsored by Rapid Medical, serves as site PI for studies sponsored by Penumbra and Microvention, and receives stroke research grant funding from the National Institutes of Health, Society of Vascular and Interventional Neurology, and Heitman Stroke Foundation. Dr Guenego reports consultancy for Rapid Medical and Phenox, not directly related to the present work. Dr Clarençon reports conflicts of interest with Medtronic, Balt Extrusion (consultant), ClinSearch (core lab), Penumbra, Stryker (payment for reading), and Artedrone (Board); all not directly related to the present work. Dr Henninger received support from CDMRP/DoD W81XWH-19-PRARP-RPA and NINDS NS131756, during the conduct of the study. Dr Liebeskind is consultant as Imaging Core Lab to Cerenovus, Genentech, Medtronic, Stryker, and Rapid Medical. Dr Yeo reports Advisory work for AstraZeneca, substantial support from NMRC Singapore, and is a medical advisor for See-mode, Cortiro, and Sunbird Bio, with equity in Ceroflo. All unrelated to the present work. Dr Griessenauer reports a proctoring agreement with Medtronic and research funding by Penumbra. Dr Marnat reports conflicts of interest with Microvention Europe, Stryker Neurovascular, Balt (consulting), Medtronic, Johnson & Johnson, and Phenox (paid lectures), all not directly related to the present work. Dr Puri is a consultant for Medtronic Neurovascular, Stryker NeurovascularBalt, Q’Apel Medical, Cerenovus, Microvention, Imperative Care, Agile, Merit, CereVasc, and Arsenal Medical; he received research grants from NIH, Microvention, Cerenovus, Medtronic Neurovascular, and Stryker Neurovascular; and he holds stocks in InNeuroCo, Agile, Perfuze, Galaxy, and NTI. Dr Tjoumakaris is a consultant for Medtronic and Microvention (funds paid to institution, not personally). Dr Jabbour is a consultant for Medtronic, Microvention, and Cerus.

Background: Acute ischemic stroke (AIS) caused by distal medium vessel occlusions (DMVOs) represents a significant proportion of overall stroke cases. While intravenous thrombolysis (IVT) has been a primary treatment, advancements in endovascular procedures have led to increased use of mechanical thrombectomy (MT) in DMVO stroke patients. However, symptomatic intracerebral hemorrhage (sICH) remains a critical complication of AIS, particularly after undergoing intervention. This study aims to identify factors associated with sICH in DMVO stroke patients undergoing MT., Methods: This retrospective analysis utilized data from the Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy (MAD-MT) registry, involving 37 centers across North America, Asia, and Europe. Middle cerebral artery (MCA) DMVO stroke patients were included. The primary outcome measured was sICH, as defined per the Heidelberg Bleeding Classification. Univariable and multivariable logistic regression were used to identify factors independently associated with sICH., Results: Among 1708 DMVO stroke patients, 148 (8.7%) developed sICH. Factors associated with sICH in DMVO patients treated with MT included older age (adjusted odds ratio (aOR) 1.01, 95% confidence interval (95% CI) 1.00 to 1.03, P=0.048), distal occlusion site (M3, M4) compared with medium occlusions (M2) (aOR 1.71, 95% CI 1.07 to 2.74, P=0.026), prior use of antiplatelet drugs (aOR 2.06, 95% CI 1.41 to 2.99, P<0.001), lower Alberta Stroke Program Early CT Scores (ASPECTS) (aOR 0.75, 95% CI 0.66 to 0.84, P<0.001), higher preoperative blood glucose level (aOR 1.00, 95% CI 1.00 to 1.01, P=0.012), number of passes (aOR 1.27, 95% CI 1.15 to 1.39, P<0.001), and successful recanalization (Thrombolysis In Cerebral Infarction (TICI) 2b-3) (aOR 0.43, 95% CI 0.28 to 0.66, P<0.001)., Conclusion: This study provides novel insight into factors associated with sICH in patients undergoing MT for DMVO, emphasizing the importance of age, distal occlusion site, prior use of antiplatelet drugs, lower ASPECTS, higher preoperative blood glucose level, and procedural factors such as the number of passes and successful recanalization. Pending confirmation, consideration of these factors may improve personalized treatment strategies., Competing Interests: Competing interests: Dr Regenhardt serves on a DSMB for a trial sponsored by Rapid Medical, serves as site PI for studies sponsored by Penumbra and Microvention, and receives stroke research grant funding from the National Institutes of Health, Society of Vascular and Interventional Neurology, and Heitman Stroke Foundation. Dr Guenego reports consultancy for Rapid Medical and Phenox, not directly related to the present work. Dr Clarençon reports conflicts of interest with Medtronic, Balt Extrusion (consultant), ClinSearch (core lab), Penumbra, Stryker (payment for reading) and Artedrone (Board); all not directly related to the present work. Dr Henninger received support from W81XWH-19-PRARP-RPA from the CDMRP/DoD, NS131756 and U24NS113844 from the NINDS, and NR020231 from the NINR and received compensation from Myrobalan, Inc and General Dynamics during the conduct of this study unrelated to this work. Dr Liebeskind is consultant as Imaging Core Lab to Cerenovus, Genentech, Medtronic, Stryker, Rapid Medical. Dr Yeo reports Advisory work for AstraZeneca, substantial support from NMRC Singapore and is a medical advisor for See-mode, Cortiro and Sunbird Bio, with equity in Ceroflo; all unrelated to the present work. Dr Griessenauer reports a proctoring agreement with Medtronic and research funding by Penumbra. Dr Marnat reports conflicts of interest with Microvention Europe, Stryker Neurovascular, Balt (consulting), Medtronic, Johnson & Johnson and Phenox (paid lectures), all not directly related to the present work. Dr Puri is a consultant for Medtronic Neurovascular, Stryker Neurovascular, Balt, Q’Apel Medical, Cerenovus, Microvention, Imperative Care, Agile, Merit, CereVasc and Arsenal Medical, he received research grants from NIH, Microvention, Cerenovus, Medtronic Neurovascular and Stryker Neurovascular, and holds stocks in InNeuroCo, Agile, Perfuze, Galaxy and NTI. Dr Tjoumakaris is a consultant for Medtronic and Microvention (funds paid to institution, not personally). Dr Jabbour is a consultant for Medtronic, Microvention and Cerus. HS and VY are guarantors of the study., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The efficacy of endovascular treatment (EVT) in acute ischaemic stroke due to distal medium vessel occlusion (DMVO) remains uncertain. Our study aimed to evaluate the safety and efficacy of EVT compared with the best medical management (BMM) in DMVO., Methods: In this prospectively collected, retrospectively reviewed, multicentre cohort study, we analysed data from the Multicentre Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy registry. Patients with acute ischaemic stroke due to DMVO in the M2, M3 and M4 segments who underwent EVT or received BMM were included. Primary outcome measures comprised 10 co-primary endpoints, including functional independence (mRS 0-2), excellent outcome (mRS 0-1), mortality (mRS 6) and haemorrhagic complications. Propensity score matching was employed to balance the cohorts., Results: Among 2125 patients included in the primary analysis, 1713 received EVT and 412 received BMM. After propensity score matching, each group comprised 391 patients. At 90 days, no significant difference was observed in achieving mRS 0-2 between EVT and BMM (adjusted OR 1.00, 95% CI 0.67 to 1.50, p>0.99). However, EVT was associated with higher rates of symptomatic intracerebral haemorrhage (8.4% vs 3.0%, adjusted OR 3.56, 95% CI 1.69 to 7.48, p<0.001) and any intracranial haemorrhage (37% vs 19%, adjusted OR 2.61, 95% CI 1.81 to 3.78, p<0.001). Mortality rates were similar between groups (13% in both, adjusted OR 1.48, 95% CI 0.87 to 2.51, p=0.15)., Conclusion: Our findings suggest that while EVT does not significantly improve functional outcomes compared with BMM in DMVO, it is associated with higher risks of haemorrhagic complications. These results support a cautious approach to the use of EVT in DMVO and highlight the need for further prospective randomised trials to refine treatment strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Dual antiplatelet therapy (DAPT) is necessary to minimize the risk of periprocedural thromboembolic complications associated with aneurysm embolization using pipeline embolization device (PED). We aimed to assess the impact of platelet function testing (PFT) on reducing periprocedural thromboembolic complications associated with PED flow diversion in patients receiving aspirin and clopidogrel., Methods: Patients with unruptured intracranial aneurysms requiring PED flow diversion were identified from 13 centers for retrospective evaluation. Clinical variables including the results of PFT before treatment, periprocedural DAPT regimen, and intracranial complications occurring within 72 h of embolization were identified. Complication rates were compared between PFT and non-PFT groups. Differences between groups were tested for statistical significance using the Wilcoxon rank sum, Fisher exact, or χ 2 tests. A P -value <.05 was statistically significant., Results: 580 patients underwent PED embolization with 262 patients dichotomized to the PFT group and 318 patients to the non-PFT group. 13.7% of PFT group patients were clopidogrel nonresponders requiring changes in their pre-embolization DAPT regimen. Five percentage of PFT group [2.8%, 8.5%] patients experienced thromboembolic complications vs 1.6% of patients in the non-PFT group [0.6%, 3.8%] ( P = .019). Two (15.4%) PFT group patients with thromboembolic complications experienced permanent neurological disability vs 4 (80%) non-PFT group patients. 3.7% of PFT group patients [1.5%, 8.2%] and 3.5% [1.8%, 6.3%] of non-PFT group patients experienced hemorrhagic intracranial complications ( P > .9)., Conclusion: Preprocedural PFT before PED treatment of intracranial aneurysms in patients premedicated with an aspirin and clopidogrel DAPT regimen may not be necessary to significantly reduce the risk of procedure-related intracranial complications., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Objective: Recent work on ischemic cerebellar stroke has suggested that the resection of infarcted tissue may lead to improved functional outcomes compared with decompressive surgery alone. Nonetheless, no studies have assessed the extent to which necrotic tissue should be resected or if there are any volumetric thresholds capable of predicting functional outcomes in this patient population. In this study, the authors aimed to determine potential thresholds for volume reduction in ischemic cerebellar stroke in an effort to optimize the management of ischemic cerebellar stroke and, in so doing, improve functional outcomes., Methods: This study is a multicentric retrospective study of patients who underwent surgery for the management of ischemic cerebellar stroke. Volumetric analyses of infarcted tissue present on CT scans were performed before and after surgical intervention(s). The final infarct volume (FIV) was computed as a percentage of the initial infarct volume (postoperative infarct volume/preoperative infarct volume × 100). The primary endpoint was functional outcome at 3 months, as determined by the modified Rankin Scale (mRS) score; mRS scores 0-2 were considered as favorable and mRS scores 3-6 as unfavorable. Receiver operating characteristic curves were used to explore the relationship between postoperative infarct volumes and FIV versus mRS score, and Youden's index was used to estimate potential volumetric thresholds., Results: A total of 91 patients were included in the study. The mean pre- and postoperative infarct volumes were 45.25 (SD 18.32) cm3 and 29.56 (SD 26.61) cm3, respectively. Patients undergoing necrosectomy, regardless of whether via craniotomy or craniectomy, were more likely to have a favorable outcome at discharge (OR 16.62, 95% CI 2.12-130.33; p = 0.008) and at 3 months (OR 24.12, 95% CI 3.03-192.18; p = 0.003) postoperatively. Postoperative infarct volumes ≤ 17 cm3 yielded a sensitivity of 77% and a specificity of 68% with regard to the prediction of favorable outcome at 3 months. The resection ≥ 50% of infarcted tissue was also predictive of favorable outcomes at 3 months (OR 7.7, 95% CI 2.7-21.8; p < 0.001)., Conclusions: The reduction of necrotic tissue volumes by at least 50% and/or the reduction of the infarct volume by ≤ 17 cm3 appear to be associated with favorable outcomes in patients with surgically managed ischemic cerebellar strokes.

Background: Brain computed tomography (CT) is an accessible and commonly utilized technique for assessing brain structure. In cases of idiopathic normal pressure hydrocephalus (iNPH), the presence of ventriculomegaly is often neuroradiologically evaluated by visual rating and manually measuring each image. Previously, we have developed and tested a deep-learning-model that utilizes transfer learning from magnetic resonance imaging (MRI) for CT-based intracranial tissue segmentation. Accordingly, herein we aimed to enhance the segmentation of ventricular cerebrospinal fluid (VCSF) in brain CT scans and assess the performance of automated brain CT volumetrics in iNPH patient diagnostics., Methods: The development of the model used a two-stage approach. Initially, a 2D U-Net model was trained to predict VCSF segmentations from CT scans, using paired MR-VCSF labels from healthy controls. This model was subsequently refined by incorporating manually segmented lateral CT-VCSF labels from iNPH patients, building on the features learned from the initial U-Net model. The training dataset included 734 CT datasets from healthy controls paired with T1-weighted MRI scans from the Gothenburg H70 Birth Cohort Studies and 62 CT scans from iNPH patients at Uppsala University Hospital. To validate the model's performance across diverse patient populations, external clinical images including scans of 11 iNPH patients from the Universitatsmedizin Rostock, Germany, and 30 iNPH patients from the University of Alabama at Birmingham, United States were used. Further, we obtained three CT-based volumetric measures (CTVMs) related to iNPH., Results: Our analyses demonstrated strong volumetric correlations (ϱ=0.91, p<0.001) between automatically and manually derived CT-VCSF measurements in iNPH patients. The CTVMs exhibited high accuracy in differentiating iNPH patients from controls in external clinical datasets with an AUC of 0.97 and in the Uppsala University Hospital datasets with an AUC of 0.99., Discussion: CTVMs derived through deep learning, show potential for assessing and quantifying morphological features in hydrocephalus. Critically, these measures performed comparably to gold-standard neuroradiology assessments in distinguishing iNPH from healthy controls, even in the presence of intraventricular shunt catheters. Accordingly, such an approach may serve to improve the radiological evaluation of iNPH diagnosis/monitoring (i.e., treatment responses). Since CT is much more widely available than MRI, our results have considerable clinical impact., Competing Interests: J.D.B. has an equity position in Treovir, Centile Bioscience, and UpFront Diagnostics. JDB is also on the QV Bioelectronics and NeuroX1 boards of scientific advisors. M.Sr., J.S., and M.Sc. have equity positions in Centile Bioscience. M.Sc. has served on advisory boards for Roche and Novo Nordisk, received speaker honoraria from Bioarctic, Eisai, Genentech, Novo Nordisk and Roche and receives research support (to the institution) from Alzpath, Bioarctic, Novo Nordisk and Roche (outside scope of submitted work). He is a co-founder of Centile Bioscience and serves as associate editor with Alzheimer’s Research & Therapy.

The emerging field of cancer neuroscience reshapes our understanding of the intricate relationship between the nervous system and cancer biology; this new paradigm is likely to fundamentally change and advance neuro-oncological care. The profound interplay between cancers and the nervous system is reciprocal: Cancer growth can be induced and regulated by the nervous system; conversely, tumors can themselves alter the nervous system. Such crosstalk between cancer cells and the nervous system is evident in both the peripheral and central nervous systems. Recent advances have uncovered numerous direct neuron-cancer interactions at glioma-neuronal synapses, paracrine mechanisms within the tumor microenvironment, and indirect neuroimmune interactions. Neurosurgeons have historically played a central role in neuro-oncological care, and as the field of cancer neuroscience is becoming increasingly established, the role of neurosurgical intervention is becoming clearer. Examples include peripheral denervation procedures, delineation of neuron-glioma networks, development of neuroprostheses, neuromodulatory procedures, and advanced local delivery systems. The present review seeks to highlight key cancer neuroscience mechanisms with neurosurgical implications and outline the future role of neurosurgical intervention in cancer neuroscience., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Glioblastoma is the most common and lethal central nervous system malignancy with a median survival after progression of only 6-9 months. Major biochemical mechanisms implicated in glioblastoma recurrence include aberrant molecular pathways, a recurrence-inducing tumor microenvironment, and epigenetic modifications. Contemporary standard-of-care (surgery, radiation, chemotherapy, and tumor treating fields) helps to control the primary tumor but rarely prevents relapse. Cytoreductive treatment such as surgery has shown benefits in recurrent glioblastoma; however, its use remains controversial. Several innovative treatments are emerging for recurrent glioblastoma, including checkpoint inhibitors, chimeric antigen receptor T cell therapy, oncolytic virotherapy, nanoparticle delivery, laser interstitial thermal therapy, and photodynamic therapy. This review seeks to provide readers with an overview of (1) recent discoveries in the molecular basis of recurrence; (2) the role of surgery in treating recurrence; and (3) novel treatment paradigms emerging for recurrent glioblastoma.

Background: Mechanical thrombectomy (MT) has revolutionized the treatment of acute ischemic stroke (AIS) due to large vessel occlusion (LVO), but its efficacy and safety in medium vessel occlusion (MeVO) remain less explored. This multicenter, retrospective study aims to investigate the incidence and clinical outcomes of vessel perforations (confirmed by extravasation during an angiographic series) during MT for AIS caused by MeVO., Methods: Data were collected from 37 academic centers across North America, Asia, and Europe between September 2017 and July 2021. A total of 1373 AIS patients with MeVO underwent MT. Baseline characteristics, procedural details, and clinical outcomes were analyzed., Results: The incidence of vessel perforation was 4.8% (66/1373). Notably, our analysis indicates variations in perforation rates across different arterial segments: 8.9% in M3 segments, 4.3% in M2 segments, and 8.3% in A2 segments ( p  = 0.612). Patients with perforation had significantly worse outcomes, with lower rates of favorable angiographic outcomes (TICI 2c-3: 23% vs 58.9%, p  < 0.001; TICI 2b-3: 56.5% vs 88.3%, p  < 0.001). Functional outcomes were also worse in the perforation group (mRS 0-1 at 3 months: 22.7% vs 36.6%, p  = 0.031; mRS 0-2 at 3 months: 28.8% vs 53.9%, p  < 0.001). Mortality was higher in the perforation group (30.3% vs 16.8%, p  = 0.008)., Conclusion: This study reveals that while the occurrence of vessel perforation in MT for AIS due to MeVO is relatively rare, it is associated with poor functional outcomes and higher mortality. The findings highlight the need for increased caution and specialized training in performing MT for MeVO. Further prospective research is required for risk mitigation strategies., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Regenhardt serves on a DSMB for a trial sponsored by Rapid Medical, serves as site PI for studies sponsored by Penumbra and Microvention, and receives stroke research grant funding from the National Institutes of Health, Society of Vascular and Interventional Neurology, and Heitman Stroke Foundation. Dr. Guenego reports consultancy for Rapid Medical and Phenox, not directly related to the present work. Prof. Clarençon reports conflicts of interest with Medtronic, Balt Extrusion (consultant), ClinSearch (core lab), Penumbra, Stryker (payment for reading), and Artedrone (Board); all not directly related to the present work. Dr. Henninger received support from NINDS NS131756, during the conduct of the study. Dr. Liebeskind is consultant as Imaging Core Lab to Cerenovus, Genentech, Medtronic, Stryker, Rapid Medical. Dr. Nguyen reports advisory board with Idorsia. Dr. Yeo reports Advisory work for AstraZeneca, Substantial support from NMRC Singapore and is a medical advisor for See-mode, Cortiro, and Sunbird Bio, with equity in Ceroflo. All unrelated to the present work. Dr. Griessenauer reports a proctoring agreement with Medtronic and research funding by Penumbra. Dr. Marnat reports conflicts of interest with Microvention Europe, Stryker Neurovascular, Balt (consulting), Medtronic, Johnson & Johnson, and Phenox (paid lectures), all not directly related to the present work. Pr Sibon reports conflict of interest with Medtronic, Sanofi, Bayer, Boehringer-Ingelheim, Novartis, Novo-Nordisk, BMS-Pfizer (board and paid lectures), all not directly related to the present work. Dr. Yedavalli is a consultant for RAPID (Ischemaview, Menlo Park, CA). Dr. Vagal is a consultant for Viz AI. She is also PI of Imaging core lab for ENDOLOW study funded by Cerenovus (monies go to the institution). Dr. Gopinathan reports conflicts of interest with Microvention, Stryker Neurovascular, Medtronic, BD, Penumbra (paid lectures, workshops, and proctoring), all not directly related to the present work. Dr. Bernstock has an equity position in Treovir Inc., an oHSV clinical stage company and UpFront Diagnostics. JDB is also on the Centile Bioscience and NeuroX1 boards of scientific advisors.

Intrinsic, expansile pontine tumors typically occur in the pediatric population. These tumors characteristically present as diffuse intrinsic pontine glioma (DIPG), which is now considered as diffuse midline glioma (DMG), H3K27-mutated of the pons. DIPG has limited treatment options and a poor prognosis, and the value of tissue diagnosis from an invasive biopsy remains controversial. This study presents the case of a 19-year-old female with clinical and imaging hallmarks of DIPG, who underwent a biopsy of a tumor in the region of the right middle cerebellar peduncle. Her lesional cells were negative for H3K27M alterations and had low-grade histologic features. Next-generation sequencing revealed a frameshift mutation in the NF1 gene as the likely driver mutation. These features suggest a diagnosis of a low-grade glioma associated with NF1 loss of function, with far-reaching consequences regarding both treatment strategy and prognosis. This case provides support for the utility of diagnostic tissue biopsy in cases of suspected DIPG., Competing Interests: JB has an equity position in Treovir Inc. and UpFront Diagnostics. JB is also on the Centile Bioscience, QV Bioelectronics, and NeuroX1 boards of scientific advisors. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Bernstock, Karandikar, Chen, Seidlitz, Friedman, Meredith, Liu, Haas-Kogan, Reardon and Peruzzi.)

Background: Stroke remains a major health concern globally, with oral anticoagulants widely prescribed for stroke prevention. The efficacy and safety of mechanical thrombectomy (MT) in anticoagulated patients with distal medium vessel occlusions (DMVO) are not well understood., Methods: This retrospective analysis involved 1282 acute ischemic stroke (AIS) patients who underwent MT in 37 centers across North America, Asia, and Europe from September 2017 to July 2023. Data on demographics, clinical presentation, treatment specifics, and outcomes were collected. The primary outcomes were functional outcomes at 90 days post-MT, measured by modified Rankin Scale (mRS) scores. Secondary outcomes included reperfusion rates, mortality, and hemorrhagic complications., Results: Of the patients, 223 (34%) were on anticoagulation therapy. Anticoagulated patients were older (median age 78 vs 74 years; p  < 0.001) and had a higher prevalence of atrial fibrillation (77% vs 26%; p  < 0.001). Their baseline National Institutes of Health Stroke Scale (NIHSS) scores were also higher (median 12 vs 9; p  = 0.002). Before propensity score matching (PSM), anticoagulated patients had similar rates of favorable 90-day outcomes (mRS 0-1: 30% vs 37%, p  = 0.1; mRS 0-2: 47% vs 50%, p  = 0.41) but higher mortality (26% vs 17%, p  = 0.008). After PSM, there were no significant differences in outcomes between the two groups., Conclusion: Anticoagulated patients undergoing MT for AIS due to DMVO did not show significant differences in 90-day mRS outcomes, reperfusion, or hemorrhage compared to non-anticoagulated patients after adjustment for covariates., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Regenhardt serves on a DSMB for a trial sponsored by Rapid Medical, serves as site PI for studies sponsored by Penumbra and Microvention, and receives stroke research grant funding from the National Institutes of Health, Society of Vascular and Interventional Neurology, and Heitman Stroke Foundation.Dr. Guenego reports consultancy for Rapid Medical and Phenox, not directly related to the present work.Dr. Clarençon reports conflicts of interest with Medtronic, Balt Extrusion (consultant), ClinSearch (core lab), Penumbra, Stryker (payment for reading) and Artedrone (Board); all not directly related to the present work.Dr. Henninger received support from W81XWH-19-PRARP-RPA form the CDMRP/DoD, NS131756 and U24NS113844 from the NINDS, and NR020231 from the NINR and received compensation from Myrobalan, Inc. and General Dynamics during the conduct of this study unrelated to this work.Dr. Liebeskind is consultant as Imaging Core Lab to Cerenovus, Genentech, Medtronic, Stryker, Rapid Medical.Dr. Yeo reports Advisory work for AstraZeneca, Substantial support from NMRC Singapore and is a medical advisor for See-mode, Cortiro and Sunbird Bio, with equity in Ceroflo. All unrelated to the present work.Dr. Griessenauer reports a proctoring agreement with Medtronic and research funding by Penumbra.Dr. Marnat reports conflicts of interest with Microvention Europe, Stryker Neurovascular, Balt (consulting), Medtronic, Johnson & Johnson and Phenox (paid lectures), all not directly related to the present work.Dr. Puri is a consultant for Medtronic Neurovascular, Stryker NeurovascularBalt, Q’Apel Medical, Cerenovus, Microvention, Imperative Care, Agile, Merit, CereVasc and Arsenal Medical, he received research grants from NIH, Microvention, Cerenovus, Medtronic Neurovascular and Stryker Neurovascular, and holds stocks in InNeuroCo, Agile, Perfuze, Galaxy and NTI.Dr. Tjoumakaris is a consultant for Medtronic and Microvention (funds paid to institution, not personally).Dr. Jabbour is a consultant for Medtronic, Microvention and Cerus.

Objective: This study was conducted to investigate the impact of antiplatelet administration in the periprocedural period on the occurrence of thromboembolic complications (TECs) in patients undergoing treatment using the Woven EndoBridge (WEB) device for intracranial wide-necked bifurcation aneurysms. The primary objective was to assess whether the use of antiplatelets in the pre- and postprocedural phases reduces the likelihood of developing TECs, considering various covariates., Methods: A retrospective multicenter observational study was conducted within the WorldWideWEB Consortium and comprised 38 academic centers with endovascular treatment capabilities. Univariable and multivariable logistic regression analyses were performed to determine the association between antiplatelet use and TECs, adjusting for covariates. Missing predictor data were addressed using multiple imputation., Results: The study comprised two cohorts: one addressing general thromboembolic events and consisting of 1412 patients, among whom 103 experienced TECs, and another focusing on symptomatic thromboembolic events and comprising 1395 patients, of whom 50 experienced symptomatic TECs. Preprocedural antiplatelet use was associated with a reduced likelihood of overall TECs (OR 0.32, 95% CI 0.19-0.53, p < 0.001) and symptomatic TECs (OR 0.49, 95% CI 0.25-0.95, p = 0.036), whereas postprocedural antiplatelet use showed no significant association with TECs. The study also revealed additional predictors of TECs, including stent use (overall: OR 4.96, 95% CI 2.38-10.3, p < 0.001; symptomatic: OR 3.24, 95% CI 1.26-8.36, p = 0.015), WEB single-layer sphere (SLS) type (overall: OR 0.18, 95% CI 0.04-0.74, p = 0.017), and posterior circulation aneurysm location (symptomatic: OR 18.43, 95% CI 1.48-230, p = 0.024)., Conclusions: The findings of this study suggest that the preprocedural administration of antiplatelets is associated with a reduced likelihood of TECs in patients undergoing treatment with the WEB device for wide-necked bifurcation aneurysms. However, postprocedural antiplatelet use did not show a significant impact on TEC occurrence.

Background: Optimal anesthetic strategy for the endovascular treatment of stroke is still under debate. Despite scarce data concerning anesthetic management for medium and distal vessel occlusions (MeVOs) some centers empirically support a general anesthesia (GA) strategy in these patients., Methods: We conducted an international retrospective study of MeVO cases. A propensity score matching algorithm was used to mitigate potential differences across patients undergoing GA and conscious sedation (CS). Comparisons in clinical and safety outcomes were performed between the two study groups GA and CS. The favourable outcome was defined as a modified Rankin Scale (mRS) 0-2 at 90 days. Safety outcomes were 90-days mortality and symptomatic intracranial hemorrhage (sICH). Predictors of a favourable outcome and sICH were evaluated with backward logistic regression., Results: After propensity score matching 668 patients were included in the CS and 264 patients in the GA group. In the matched cohort, either strategy CS or GA resulted in similar rates of good functional outcomes (50.1% vs. 48.4%), and successful recanalization (89.4% vs. 90.2%). The GA group had higher rates of 90-day mortality (22.6% vs. 16.5%, p < 0.041) and sICH (4.2% vs. 0.9%, p = 0.001) compared to the CS group. Backward logistic regression did not identify GA vs CS as a predictor of good functional outcome (OR for GA vs CS = 0.95 (0.67-1.35)), but GA remained a significant predictor of sICH (OR = 5.32, 95% CI 1.92-14.72)., Conclusion: Anaesthetic strategy in MeVOs does not influence favorable outcomes or final successful recanalization rates, however, GA may be associated with an increased risk of sICH and mortality., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood-brain barrier (BBB) penetration, hemodynamic complexities, and drug-tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care.

Purpose: Pituitary adenomas are the most common tumor of the pituitary gland and comprise nearly 15% of all intracranial masses. These tumors are stratified into functional or silent categories based on their pattern of hormone expression and secretion. Preliminary evidence supports differential clinical outcomes between some functional pituitary adenoma (FPA) subtypes and silent pituitary adenoma (SPA) subtypes., Methods: We collected and analyzed the medical records of all patients undergoing resection of SPAs or FPAs from a single high-volume neurosurgeon between 2007 and 2018 at Brigham and Women's Hospital. Descriptive statistics and the Mantel-Cox log-rank test were used to identify differences in outcomes between these cohorts, and multivariate logistic regression was used to identify predictors of radiographic recurrence for SPAs., Results: Our cohort included 88 SPAs and 200 FPAs. The majority of patients in both cohorts were female (48.9% of SPAs and 63.5% of FPAs). SPAs were larger in median diameter than FPAs (2.1 cm vs. 1.2 cm, p < 0.001). The most frequent subtypes of SPA were gonadotrophs (55.7%) and corticotrophs (30.7%). Gross total resection (GTR) was achieved in 70.1% of SPA resections and 86.0% of FPA resections (p < 0.001). SPAs had a higher likelihood of recurring (hazard ratio [HR] 3.2, 95% confidence interval [95%CI] 1.6-7.2) and a higher likelihood of requiring retreatment for recurrence (HR 2.5; 95%CI 1.0-6.1). Subset analyses revealed that recurrence and retreatment were more both likely for subtotally resected SPAs than subtotally resected FPAs, but this pattern was not observed in SPAs and FPAs after GTR. Among SPAs, recurrence was associated with STR (odds ratio [OR] 9.3; 95%CI 1.4-64.0) and younger age (OR 0.92 per year; 95%CI 0.88-0.98) in multivariable analysis. Of SPAs that recurred, 12 of 19 (63.2%) were retreated with repeat surgery (n = 11) or radiosurgery (n = 1), while the remainder were observed (n = 7).There were similar rates of recurrence across different SPA subtypes., Conclusion: Patients undergoing resection of SPAs should be closely monitored for disease recurrence through more frequent clinical follow-up and diagnostic imaging than other adenomas, particularly among patients with STR and younger patients. Several patients can be observed after radiographic recurrence, and the decision to retreat should be individualized. Longitudinal clinical follow-up of SPAs, including an assessment of symptoms, endocrine function, and imaging remains critical., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Space-occupying cerebellar stroke (SOCS) when coupled with neurological deterioration represents a neurosurgical emergency. Although current evidence supports surgical intervention in such patients with SOCS and rapid neurological deterioration, the optimal surgical methods/techniques to be applied remain a matter of debate., Methods: We conducted a retrospective, multicenter study of patients undergoing surgery for SOCS. Patients were stratified according to the type of surgery as (1) suboccipital decompressive craniectomy (SDC) or (2) suboccipital craniotomy with concurrent necrosectomy. The primary end point examined was functional outcome using the modified Rankin Scale (mRS) at discharge and at 3 months (mRS 0-3 defined as favorable and mRS 4-6 as unfavorable outcome). Secondary end points included the analysis of in-house postoperative complications, mortality, and length of hospitalization., Results: Ninety-two patients were included in the final analysis: 49 underwent necrosectomy and 43 underwent SDC. Those with necrosectomy displayed significantly higher rate of favorable outcome at discharge as compared with those who underwent SDC alone: 65.3% vs 27.9%, respectively ( P < .001, odds ratios 4.9, 95% CI 2.0-11.8). This difference was also observed at 3 months: 65.3% vs 41.7% ( P = .030, odds ratios 2.7, 95% CI 1.1-6.7). No significant differences were observed in mortality and/or postoperative complications, such as hemorrhagic transformation, infection, and/or the development of cerebrospinal fluid leaks/fistulas., Conclusion: In the setting of SOCS, patients treated with necrosectomy displayed better functional outcomes than those patients who underwent SDC alone. Ultimately, prospective, randomized studies will be needed to confirm this finding., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Importance: According to the current American Heart Association/American Stroke Association guidelines, decompressive surgery is indicated in patients with cerebellar infarcts that demonstrate severe cerebellar swelling. However, there is no universal definition of swelling and/or infarct volume(s) available to support a decision for surgery., Objective: To evaluate functional outcomes in surgically compared with conservatively managed patients with cerebellar infarcts., Design, Setting, and Participants: In this retrospective multicenter cohort study, patients with cerebellar infarcts treated at 5 tertiary referral hospitals or stroke centers within Germany between 2008 and 2021 were included. Data were analyzed from November 2020 to November 2023., Exposures: Surgical treatment (ie, posterior fossa decompression plus standard of care) vs conservative management (ie, medical standard of care)., Main Outcomes and Measures: The primary outcome examined was functional status evaluated by the modified Rankin Scale (mRS) at discharge and 1-year follow-up. Secondary outcomes included the predicted probabilities for favorable outcome (mRS score of 0 to 3) stratified by infarct volumes or Glasgow Coma Scale score at admission and treatment modality. Analyses included propensity score matching, with adjustments for age, sex, Glasgow Coma Scale score at admission, brainstem involvement, and infarct volume., Results: Of 531 included patients with cerebellar infarcts, 301 (57%) were male, and the mean (SD) age was 68 (14.4) years. After propensity score matching, a total of 71 patients received surgical treatment and 71 patients conservative treatment. There was no significant difference in favorable outcomes (ie, mRS score of 0 to 3) at discharge for those treated surgically vs conservatively (47 [66%] vs 45 [65%]; odds ratio, 1.1; 95% CI, 0.5-2.2; P > .99) or at follow-up (35 [73%] vs 33 [61%]; odds ratio, 1.8; 95% CI, 0.7-4.2; P > .99). In patients with cerebellar infarct volumes of 35 mL or greater, surgical treatment was associated with a significant improvement in favorable outcomes at 1-year follow-up (38 [61%] vs 3 [25%]; odds ratio, 4.8; 95% CI, 1.2-19.3; P = .03), while conservative treatment was associated with favorable outcomes at 1-year follow-up in patients with infarct volumes of less than 25 mL (2 [34%] vs 218 [74%]; odds ratio, 0.2; 95% CI, 0-1.0; P = .047)., Conclusions and Relevance: Overall, surgery was not associated with improved outcomes compared with conservative management in patients with cerebellar infarcts. However, when stratifying based on infarct volume, surgical treatment appeared to be beneficial in patients with larger infarct volumes, while conservative management appeared favorable in patients with smaller infarct volumes.

Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here, we present an ExM variant, decrowding expansion pathology (dExPath), that can expand proteins away from each other in human brain pathology specimens, including formalin-fixed paraffin-embedded (FFPE) clinical specimens. Immunostaining of dExPath-expanded specimens reveals, with nanoscale precision, previously unobserved cellular structures, as well as more continuous patterns of staining. This enhanced molecular staining results in observation of previously invisible disease marker-positive cell populations in human glioma specimens, with potential implications for tumor aggressiveness. dExPath results in improved fluorescence signals even as it eliminates lipofuscin-associated autofluorescence. Thus, this form of expansion-mediated protein decrowding may, through improved epitope access for antibodies, render immunohistochemistry more powerful in clinical science and, perhaps, diagnosis.

The review begins with an overview of the fundamental principles/physics underlying light, fluorescence, and other light-matter interactions in biological tissues. It then focuses on 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence spectroscopy methods used in neurosurgery (e.g., intensity, time-resolved) and in so doing, describe their specific features (e.g., hardware requirements, main processing methods) as well as their strengths and limitations. Finally, we review current clinical applications and future directions of 5-ALA-induced protoporphyrin IX (PpIX) fluorescence spectroscopy in neurosurgery., Competing Interests: PV is a consultant for an unrelated imaging study for NX Development Corp and has multiple patents or provisional patents on fluorescence imaging technologies for fluorescence-guided neurosurgery. PV and JB have equity in Lumiere Optix. JB has an equity position in Treovir Inc. and UpFront Diagnostics. JB is also on the Centile Bioscience, QV Bioelectronics, and NeuroX1 boards of scientific advisors. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gautheron, Bernstock, Picart, Guyotat, Valdés and Montcel.)

Purpose: Chat generative pre-trained transformer (GPT) is a novel large pre-trained natural language processing software that can enable scientific writing amongst a litany of other features. Given this, there is a growing interest in exploring the use of ChatGPT models as a modality to facilitate/assist in the provision of clinical care., Methods: We investigated the time taken for the composition of neurosurgical discharge summaries and operative reports at a major University hospital. In so doing, we compared currently employed speech recognition software (i.e., SpeaKING) vs novel ChatGPT for three distinct neurosurgical diseases: chronic subdural hematoma, spinal decompression, and craniotomy. Furthermore, factual correctness was analyzed for the abovementioned diseases., Results: The composition of neurosurgical discharge summaries and operative reports with the assistance of ChatGPT leads to a statistically significant time reduction across all three diseases/report types: p < 0.001 for chronic subdural hematoma, p < 0.001 for decompression of spinal stenosis, and p < 0.001 for craniotomy and tumor resection. However, despite a high degree of factual correctness, the preparation of a surgical report for craniotomy proved to be significantly lower (p = 0.002)., Conclusion: ChatGPT assisted in the writing of discharge summaries and operative reports as evidenced by an impressive reduction in time spent as compared to standard speech recognition software. While promising, the optimal use cases and ethics of AI-generated medical writing remain to be fully elucidated and must be further explored in future studies., (© 2024. The Author(s).)

Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, likely due to methylation of the STING promoter. Nonetheless, several preclinical studies suggest that inducing cGAS/STING signaling in the glioma immune microenvironment could be therapeutically beneficial, and cGAS/STING signaling has been shown to mediate inflammatory and antitumor effects of other modalities either in use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, and oncolytic virotherapy. In this Review, we discuss cGAS/STING signaling in gliomas, its implications for glioma immunobiology, compartment-specific roles for STING signaling in influencing immune surveillance, and efforts to target STING signaling - either directly or indirectly - for antiglioma therapy.

Objective: Relatively little is known about the safety and accuracy of catheter placement for oncolytic viral therapy in children with malignant brain tumors. Accordingly, this study combines data from two phase I clinical trials that employed viral immunotherapy across two institutions to describe the adverse event profile, safety, and accuracy associated with the stereotactic placement and subsequent removal of intratumoral catheters., Methods: Children with progressive/recurrent supratentorial malignant tumors were enrolled in two clinical trials (NCT03043391 and NCT02457845) and treated with either the recombinant polio:rhinovirus (lerapolturev) or the genetically modified oncolytic herpesvirus (G207). Age, sex, race, tumor diagnosis, and tumor location were analyzed. Events related to the catheter placement or removal were categorized. A catheter that was either pulled back or could not be used was defined as "misplaced." Neuronavigation software was used to analyze the accuracy of catheter placement for NCT03043391. Descriptive statistics were performed., Results: Nineteen patients were treated across the two completed trials with a total of 49 catheters. The mean ± SD (range) age was 14.1 ± 3.6 (7-19) years. All tumors were grade 3 or 4 gliomas. Nonlobar catheter tip placement included the corpus callosum, thalamus, insula, and cingulate gyrus. Six of 19 patients (31.6%) had minor hemorrhage noted on CT; however, no patients were symptomatic and/or required intervention related to these findings. One of 19 patients had a delayed CSF leak after catheter removal that required oversewing of the surgical site. No patients developed infection or a neurological deficit. In 7 patients with accuracy data, the mean ± SD distance of the planned trajectory (PT) to the catheter tip was 1.57 ± 1.6 mm, the mean angle of the PT to the catheter was 2.43° ± 2.1°, and the greatest distance of PT to the catheter in the parallel plane was 1.54 ± 1.5 mm. Three of 49 (6.1%) catheters were considered misplaced., Conclusions: Although instances of minor hemorrhage were encountered, they were clinically asymptomatic. One of 49 catheters required intervention for a CSF leak. Congruent with previous studies in the literature, the stereotactic placement of catheters in these pediatric tumor patients was accurate with approximately 95% of catheters having been adequately placed.

Objective: Giant aneurysms in pediatric patients are vascular lesions that can cause significant neurological morbidity and mortality. Their rarity has precluded large cohort studies to inform their management. The objective of this study was to understand the clinical course and outcomes of giant aneurysms in pediatric patients., Methods: The authors performed a multi-institutional cohort study of cases from Boston Children's Hospital and Barrow Neurological Institute, as well as a systematic review and pooled cohort analysis of previously reported cases using descriptive statistics and multivariate regression modeling., Results: Fifteen patients were included in the multi-institutional cohort, and an additional 88 patients were included from 14 series, yielding 103 patients within the pooled cohort. Among the pooled cohort, the most common aneurysm locations were in the middle cerebral artery (36%), internal carotid artery (27%), vertebral artery (11%), and vertebrobasilar junction (8%). Within 69 cases containing radiographic data in the analysis, 38% of aneurysms were saccular. Twenty-eight cases presented with aneurysm rupture (28%), including 0% of cavernous carotid aneurysms, 26% of other anterior circulation aneurysms, and 44% of posterior circulation aneurysms (p = 0.003). In multivariate analysis, posterior circulation location (OR 2.66, 95% CI 1.03-6.86) and younger age (OR 0.90 per year, 95% CI 0.81-1.00) were associated with aneurysm rupture presentation. Most cases were treated (97%) rather than observed (3%). The mortality rate was 3% for unruptured aneurysms and 18% for ruptured aneurysms. A favorable neurological outcome occurred in 80% of unruptured aneurysm cases and 54% of ruptured cases. In multivariate analysis, unruptured aneurysm presentation (OR 3.74, 95% CI 1.24-11.29) and endovascular treatment modality (OR 5.05, 95% CI 1.56-16.29) were associated with a favorable outcome., Conclusions: Giant aneurysms are rare entities in pediatric patients that are unlikely to be discovered incidentally and usually merit treatment. Most patients survive with good neurological outcome, even in ruptured aneurysm cases. These data reveal that posterior circulation location and younger age are risk factors that correlate with an increased risk of aneurysm rupture.

The neuroimmunology of traumatic brain injury (TBI) has recently gained recognition as a crucial element in the secondary pathophysiological consequences that occur following neurotrauma. Both immune cells residing within the central nervous system (CNS) and those migrating from the periphery play significant roles in the development of secondary brain injury. However, the precise mechanisms governing communication between innate and adaptive immune cells remain incompletely understood, partly due to a limited utilization of relevant experimental models and techniques. Therefore, in this discussion, we outline current methodologies that can aid in the exploration of TBI neuroimmunology, with a particular emphasis on the interactions between resident neuroglial cells and recruited lymphocytes. These techniques encompass adoptive cell transfer, intra-CNS injection(s), selective cellular depletion, genetic manipulation, molecular neuroimaging, as well as in vitro co-culture systems and the utilization of organoid models. By incorporating key elements of both innate and adaptive immunity, these methods facilitate the examination of clinically relevant interactions. In addition to these preclinical approaches, we also detail an emerging avenue of research that seeks to leverage human biofluids. This approach enables the investigation of how resident and infiltrating immune cells modulate neuroglial responses after TBI. Considering the growing significance of neuroinflammation in TBI, the introduction and application of advanced methodologies will be pivotal in advancing translational research in this field., Competing Interests: JB had an equity position in Treovir Inc. and UpFront Diagnostics. JB was also a co-founder of Centile Bioscience and on the NeuroX1 scientific advisory board. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Abou-El-Hassan, Bernstock, Chalif, Yahya, Rezende, Weiner and Izzy.)

Background: Temporal muscle thickness (TMT) on cranial CT scans has recently been identified as a prognostic imaging parameter for assessing a patient's baseline frailty. Here, we analyzed whether TMT correlates with Traumatic brain injury (TBI) severity and whether it can be used to predict outcome(s) after TBI., Methods: We analyzed the radiological and clinical data sets of 193 patients with TBI who were admitted to our institution and correlated the radiological data with clinical outcomes after stratification for TMT., Results: Our analyses showed a significant association between high TMT and increased risk for intracranial hemorrhage ( p = 0.0135) but improved mRS at 6 months ( p = 0.001) as compared to patients with low TMT. Congruent with such findings, a lower TMT was associated with falls and reduced outcomes at 6 months ( p < 0.0001 and p < 0.0001)., Conclusion: High TMT was robustly associated with head trauma sequelae but was also associated with good clinical outcomes in TBI patients. These findings consolidate the significance of TMT as an objective marker of frailty in TBI patients; such measurements may ultimately be leveraged as prognostic indicators.

mRNA vaccines have played a critical role in controlling the SARS-CoV-2 pandemic, and are being actively studied for use in other diseases. There is a growing interest in applying mRNA vaccines at mucosal surfaces as it enables access to a unique immune reservoir in a less-invasive manner. However, mucosal surfaces present several barriers to mRNA uptake, including degrading enzymes, mucus, and clearance mechanisms. In this mini-review, we discuss our understanding of the immune response to mucosal mRNA vaccines as it compares to systemic mRNA vaccines. We also highlight physical and chemical methods for enhancing mRNA uptake across mucosal tissues. Mucosal mRNA vaccination is a nascent field of research, which will greatly benefit from fundamental investigations into the mechanisms of immune activation and the development of technologies for improved delivery., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Exact Sciences, Horizon, Pavoda, Entreza Inc. CBSET, Avaxia, Lyndra, Novo Nordisk, SNS Nano, Hoffman La Roche, Janssen, Egalet, BMS, Synlogic, Freenome, Suono Bio, Merck, Verily, Eagle Pharmaceuticals Inc., Vivtex, Celero Systems, Bilayer Therapeutics Inc., Teal Bio Inc., Oracle, Wired Consulting, Avadel Pharmaceuticals, Moderna, Syntis Bio, Vitakey, CSL Vifor., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Abnormalities in notochordal development can cause a range of developmental malformations, including the split notochord syndrome and split cord malformations. We describe two cases that appear related to unusual notochordal malformations, in a female and a male infant diagnosed in the early postnatal and prenatal periods, which were treated at our institution. These cases were unusual from prior cases given a shared constellation of an anterior cervicothoracic meningocele with a prominent "neural stalk," which coursed ventrally from the spinal cord into the thorax in proximity to a foregut duplication cyst., Methods: Two patients with this unusual spinal cord anomaly were assessed clinically, and with neuroimaging and genetics studies., Results: We describe common anatomical features (anterior neural stalk arising from the spinal cord, vertebral abnormality, enteric duplication cyst, and diaphragmatic hernia) that support a common etiopathogenesis and distinguish these cases. In both cases, we opted for conservative neurosurgical management in regards to the spinal cord anomaly. We proposed a preliminary theory of the embryogenesis that explains these findings related to a persistence of the ventral portion of the neurenteric canal., Conclusion: These cases may represent a form of spinal cord malformation due to a persistent neurenteric canal and affecting notochord development that has rarely been described. Over more than 1 year of follow-up while managed conservatively, there was no evidence of neurologic dysfunction, so far supporting a treatment strategy of observation., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Human brain size changes dynamically through early development, peaks in adolescence, and varies up to 2-fold among adults. However, the molecular genetic underpinnings of interindividual variation in brain size remain unknown. Here, we leveraged postmortem brain RNA sequencing and measurements of brain weight (BW) in 2,531 individuals across three independent datasets to identify 928 genome-wide significant associations with BW. Genes associated with higher or lower BW showed distinct neurodevelopmental trajectories and spatial patterns that mapped onto functional and cellular axes of brain organization. Expression of BW genes was predictive of interspecies differences in brain size, and bioinformatic annotation revealed enrichment for neurogenesis and cell-cell communication. Genome-wide, transcriptome-wide, and phenome-wide association analyses linked BW gene sets to neuroimaging measurements of brain size and brain-related clinical traits. Cumulatively, these results represent a major step toward delineating the molecular pathways underlying human brain size variation in health and disease., Competing Interests: Declaration of interests J.S., R.A.I.B., J.D.B., and A.F.A.-B. are directors and hold equity in Centile Bioscience. J.D.B. holds positions/equity in UpFront Diagnostics, Treovir, and NeuroX1. A.F.A.-B. receives consulting income from Octave Bioscience., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Under what circumstances, is it ethical to perform tumor surgery on a brain-dead individual? The neurosurgeons at Brigham and Women's Hospital were recently faced with such a question when asked to operate on a 28-year-old man who was pronounced brain-dead secondary to a severe brain-stem injury. His advanced directives clearly documented a desire for organ donation. During his transplant work-up, cranial imaging suggested a possible cerebellar mass of unknown etiology that was concerning for metastatic disease. Despite negative full body imaging, the neurosurgical team was asked to perform an open biopsy of the intracranial lesion to rule out occult systemic cancer. This case invites many nuanced questions related to the decisions surgeons and the broader medical community must make in the face of pursuing viable organs for the many in need. What is the moral standing and personhood eligibility of brain-dead individuals? What is the scope of medical interventions and procedures that surgeons are ethically bound to carry out? How ought the desire for increased medical intervention to try to save organs be balanced with practical limitations given limited medical resources?, Competing Interests: JDB has an equity position in Treovir Inc. and is a member of the board of scientific advisors for Upfront Diagnostics, Centile Biosciences, and NeuroX1. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Bernstock, Chalif, Jha, Brown, Essayed, Caplan and Peruzzi.)

Discogenic back pain, a subset of chronic back pain, is caused by intervertebral disc (IVD) degeneration, and imparts a notable socioeconomic health burden on the population. However, degeneration by itself does not necessarily imply discogenic pain. In this review, we highlight the existing literature on the pathophysiology of discogenic back pain, focusing on the biomechanical and biochemical steps that lead to pain in the setting of IVD degeneration. Though the pathophysiology is incompletely characterized, the current evidence favors a framework where degeneration leads to IVD inflammation, and subsequent immune milieu recruitment. Chronic inflammation serves as a basis of penetrating neovascularization and neoinnervation into the IVD. Hence, nociceptive sensitization emerges, which manifests as discogenic back pain. Recent studies also highlight the complimentary roles of low virulence infections and central nervous system (CNS) metabolic state alteration. Targeted therapies that seek to disrupt inflammation, angiogenesis, and neurogenic pathways are being investigated. Regenerative therapy in the form of gene therapy and cell-based therapy are also being explored.

Immunotherapy failures can result from the highly suppressive tumour microenvironment that characterizes aggressive forms of cancer such as recurrent glioblastoma (rGBM) 1,2 . Here we report the results of a first-in-human phase I trial in 41 patients with rGBM who were injected with CAN-3110-an oncolytic herpes virus (oHSV) 3 . In contrast to other clinical oHSVs, CAN-3110 retains the viral neurovirulence ICP34.5 gene transcribed by a nestin promoter; nestin is overexpressed in GBM and other invasive tumours, but not in the adult brain or healthy differentiated tissue 4 . These modifications confer CAN-3110 with preferential tumour replication. No dose-limiting toxicities were encountered. Positive HSV1 serology was significantly associated with both improved survival and clearance of CAN-3110 from injected tumours. Survival after treatment, particularly in individuals seropositive for HSV1, was significantly associated with (1) changes in tumour/PBMC T cell counts and clonal diversity, (2) peripheral expansion/contraction of specific T cell clonotypes; and (3) tumour transcriptomic signatures of immune activation. These results provide human validation that intralesional oHSV treatment enhances anticancer immune responses even in immunosuppressive tumour microenvironments, particularly in individuals with cognate serology to the injected virus. This provides a biological rationale for use of this oncolytic modality in cancers that are otherwise unresponsive to immunotherapy (ClinicalTrials.gov: NCT03152318 )., (© 2023. The Author(s).)

Oncolytic viral (OV) therapies are promising novel treatment modalities for cancers refractory to conventional treatment, such as glioblastoma, within the central nervous system (CNS). Although OVs have received regulatory approval for use in the CNS, efficacy is hampered by obstacles related to delivery, under-/over-active immune responses, and the "immune-cold" nature of most CNS malignancies. SUMO, the Small Ubiquitin-like Modifier, is a family of proteins that serve as a high-level regulator of a large variety of key physiologic processes including the host immune response. The SUMO pathway has also been implicated in the pathogenesis of both wild-type viruses and CNS malignancies. As such, the intersection of OV biology with the SUMO pathway makes SUMOtherapeutics particularly interesting as adjuvant therapies for the enhancement of OV efficacy alone and in concert with other immunotherapeutic agents. Accordingly, the authors herein provide: 1) an overview of the SUMO pathway and its role in CNS malignancies; 2) describe the current state of CNS-targeted OVs; and 3) describe the interplay between the SUMO pathway and the viral lifecycle and host immune response., Competing Interests: JB has an equity position in Treovir Inc., a clinical stage oHSV company and is a member of the board of scientific advisors for Upfront Diagnostics, Centile Biosciences, and NeuroX1. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Karandikar, Suh, Gerstl, Blitz, Qu, Won, Gessler, Arnaout, Smith, Peruzzi, Yang, Friedman and Bernstock.)

Background: Several individual predictors for outcomes in patients with cerebellar stroke (CS) have been previously identified. There is, however, no established clinical score for CS. Therefore, the aim of this study was to develop simple and accurate grading scales for patients with CS in an effort to better estimate mortality and outcomes., Methods: This multicentric retrospective study included 531 patients with ischemic CS presenting to 5 different academic neurosurgical and neurological departments throughout Germany between 2008 and 2021. Logistic regression analysis was performed to determine independent predictors related to 30-day mortality and unfavorable outcome (modified Rankin Scale score of 4-6). By weighing each parameter via calculation of regression coefficients, an ischemic CS-score and CS-grading scale (CS-GS) were developed and internally validated., Results: Independent predictors for 30-day mortality were aged ≥70 years (odds ratio, 5.2), Glasgow Coma Scale score 3 to 4 at admission (odds ratio, 2.6), stroke volume ≥25 cm 3 (odds ratio, 2.7), and involvement of the brain stem (odds ratio, 3.9). When integrating each parameter into the CS-score, age≥70 years and brain stem stroke were assigned 2 points, Glasgow Coma Scale score 3 to 4, and stroke volume≥25 cm 3 1 point resulting in a score ranging from 0 to 6. CS-score of 0, 1, 2, 3, 4, 5, and 6 points resulted in 30-day mortality of 1%, 6%, 6%, 17%, 21%, 55%, and 67%, respectively. Independent predictors for 30-day unfavorable outcomes consisted of all components of the CS-score with an additional variable focused on comorbidities (CS-GS). Except for Glasgow Coma Scale score 3 to 4 at admission, which was assigned 3 points, all other parameters were assigned 1 point resulting in an overall score ranging from 0 to 7. CS-GS of 0, 1, 2, 3, 4, 5, 6, and 7 points resulted in 30-day unfavorable outcome of 1%, 17%, 33%, 40%, 50%, 80%, 77%, and 100%, respectively. Both 30-day mortality and unfavorable outcomes increased with increasing CS-score and CS-GS ( P <0.001)., Conclusions: The CS-score and CS-GS are simple and accurate grading scales for the prediction of 30-day mortality and unfavorable outcome in patients with CS. While the score systems proposed here may not directly impact treatment decisions, it may help discuss mortality and outcome with patients and caregivers., Competing Interests: Disclosures Dr Bernstock reports stock holdings in Treovir, LLC; compensation from POCKiT Diagnostics for consultant services; compensation from Avidea Technologies for consultant services; and compensation from Centile Bio for consultant services. Dr Günther reports compensation from Daiichi Sankyo Company for other services; compensation from Boehringer Ingelheim for other services; compensation from Ipsen Pharma SAS for other services; compensation from PFIZER PHARMA GMBH for other services; compensation from Occlutech GmbH for other services; and grants from Merz Pharmaceuticals GmbH. Dr Konczalla reports compensation from Aesculap AG for other services and compensation from Carl Zeiss Meditec AG for other services. Dr Schaefer reports travel support from Bayer. Dr Senft reports compensation from brainlab for consultant services; compensation from Bayer for expert witness services; and compensation from Stryker for other services. Dr Walter reports grants from Amgen; grants from PFIZER PHARMA GMBH; grants from Bayer Healthcare; grants from Boehringer Ingelheim; grants from Bristol-Myers Squibb; grants from Amarin Pharma Inc; grants from Daiichi Sankyo Europe GmbH; grants from Merz Pharmaceuticals GmbH; and grants from Merz Pharmaceuticals GmbH.

Cerebral proliferative angiopathy (CPA) is an entity distinct from that of classical arteriovenous malformations. As such, few reports have considered the long-term follow-up of patients with hemorrhage in CPA. Accordingly, herein the authors present a case of recurrent hemorrhage in CPA with 32 years of follow-up and in so doing summarize the literature of hemorrhagic cases in CPA. A 19-year-old presented with focal awareness seizures and diagnostic work-up revealed a left hemispheric vascular lesion. The patient presented again with intracranial hemorrhage at ages 28, 43 and 51. Angioarchitectural workup revealed intermingled brain parenchyma between vascular spaces, absence of dominant feeders and a clear nidus consistent with CPA. The size and diffuse nature of the lesion deemed it inoperable. Given our case and review of the literature it is apparent that CPA has a high risk of re-hemorrhage in the rare event that hemorrhage does occur., Competing Interests: J.D.B. has an equity position in Treovir LLC and is a member of the POCKiT Diagnostics, NeuroX1 and Centile Bio Boards of Scientific Advisors. J.V.E.G., A. D. K., E.F.T. and R.D. report no conflicts., (© The Author(s) 2023.)

Purpose: Pituitary carcinomas are a rare entity that respond poorly to multimodal therapy. Patients follow a variable disease course that remains ill-defined., Methods: We present an institutional case series of patients treated for pituitary carcinomas over a 30-year period from 1992 to 2022. A systematic review was conducted to identify prior case series of patients with pituitary carcinomas., Results: Fourteen patients with a mean age at pituitary carcinoma diagnosis of 52.5 years (standard deviation [SD] 19.4) met inclusion criteria. All 14 patients had tumor subtypes confirmed by immunohistochemistry and hormone testing, with the most common being ACTH-producing pituitary adenomas (n = 12). Patients had a median progression-free survival (PFS) of 1.4 years (range 0.7-10.0) and a median overall survival (OS) of 8.4 years (range 2.3-24.0) from pituitary adenoma diagnosis. Median PFS and OS were 0.6 years (range 0.0-2.2) and 1.5 years (range 0.1-9.6) respectively upon development of metastases. Most patients (n = 12) had locally invasive disease to the cavernous sinus, dorsum sellae dura, or sphenoid sinus prior to metastasis. Common sites of metastasis included the central nervous system, liver, lung, and bone. In a pooled analysis including additional cases from the literature, treatment of metastases with chemotherapy or a combination of radiation therapy and chemotherapy significantly prolonged PFS (p = 0.02), while failing to significantly improve OS (p = 0.14)., Conclusion: Pituitary carcinomas are highly recurrent, heterogenous tumors with variable responses to treatment. Multidisciplinary management with an experienced neuro-endocrine and neuro-oncology team is needed given the unrelenting nature of this disease., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Cavernous venous malformations (CavVMs) account for a spectrum of lesions with a shared pathogenesis. Their anatomical location dictates their clinical features and surgical treatment. Extradural and dura-based CavVMs were discussed in Part 1 of this review. In this part, intradural CavVMs are discussed, encompassing malformations growing within the intradural space without direct dural involvement. In addition to classic intra-axial CavVMs, cranial nerve CavVMs, intraventricular CavVMs, and intradural extramedullary spinal CavVMs are discussed in this group, given the similar natural history and specific management challenges. Herein the authors focus on critical clinical aspects of and surgical management of these malformations based on their location and discuss optimal surgical approaches at each of these anatomical locations with illustrative cases. The commonalities of the natural history and surgical management that are dictated by anatomical considerations lend to a new location-based taxonomy for classification of CavVMs.

Cavernous-type malformations are venous lesions that occur in multiple locations throughout the body, and when present in the CNS, they have canonically been referred to as cavernomas, cavernous angiomas, and cerebral cavernous malformations. Herein all these lesions are referred to as "cavernous venous malformations" (CavVMs), which is congruent with the current International Society for the Study of Vascular Anomalies classification system. Even though histologically similar, depending on their location relative to the dura mater, these malformations can have different features. In Part 1 of this review, the authors discuss and review pertinent clinical knowledge with regard to CavVMs as influenced by anatomical location, starting with the dural and extradural malformations. They particularly emphasize dural CavVMs (including those in the cavernous sinus), orbital CavVMs, and spinal CavVMs. The genetic and histopathological features of CavVMs in these locations are reviewed, and commonalities in their presumed mechanisms of pathogenesis support the authors' conceptualization of a spectrum of a single disease entity. Illustrative cases for each subtype are presented, and the pathophysiological and genetic features linking dural and extradural to intradural CavVMs are examined. A new classification is proposed to segregate CavVMs based on the location from which they arise, which guides their natural history and treatment.