Glutamatergic synaptic input to glioma cells drives brain tumour progression.

A network of communicating tumour cells that is connected by tumour microtubes mediates the progression of incurable gliomas. Moreover, neuronal activity can foster malignant behaviour of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here we report a direct communication channel between neurons and glioma cells in different disease models and human tumours: functional bona fide chemical synapses between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses show a typical synaptic ultrastructure, are located on tumour microtubes, and produce postsynaptic currents that are mediated by glutamate receptors of the AMPA subtype. Neuronal activity including epileptic conditions generates synchronised calcium transients in tumour-microtube-connected glioma networks. Glioma-cell-specific genetic perturbation of AMPA receptors reduces calcium-related invasiveness of tumour-microtube-positive tumour cells and glioma growth. Invasion and growth are also reduced by anaesthesia and the AMPA receptor antagonist perampanel, respectively. These findings reveal a biologically relevant direct synaptic communication between neurons and glioma cells with potential clinical implications.

Trans-lateral ventricular approach for surgical treatment of high-located P2-P3 junction posterior cerebral artery aneurysms: from anatomical research to clinical application.

BACKGROUND: Posterior cerebral artery (PCA) aneurysms, though rare, pose treatment challenges. Endovascular therapy is the preferred option, but microsurgery becomes necessary in certain cases. Various microsurgical approaches have been suggested for PCA aneurysms, particularly those at the P2-P3 junction. This study highlights the trans-lateral ventricular approach (TVA) for addressing these complex aneurysms. This study aims to assess the feasibility and safety of the trans-lateral ventricular approach (TVA) for treating high-located complex PCA aneurysms at the P2-P3 junction. The study evaluates both clinical outcomes and anatomical considerations. METHODS: Two cases of PCA aneurysms at the P2-P3 junction were treated using TVA in 2019. Navigation-guided entry via the interparietal sulcus was planned. Ventriculostomy was performed from the cortex to the lateral ventricle's atrium. Medial atrial floor dissection exposed PCA's P2-P3 segments. Neuronavigation and ultrasound-aided guidance was used. Anatomical studies on fixed and contrast-perfused specimens refined the approach. RESULTS: Both cases saw successful aneurysm clipping. The unruptured aneurysm patient was discharged in 6 days. The poor-grade SAH patient required extended ICU care, moving to rehabilitation with mRS = 4. The unruptured complex aneurysm case exhibited no deficits, returning to work in 3 months. Anatomical dissections validated TVA for high-located P2-P3 junction PCA aneurysms. CONCLUSION: While endovascular therapy remains primary, this study demonstrates the viability of navigation-guided TVA for select high-located P2-P3 junction PCA aneurysms. Successes and challenges underscore the importance of patient selection and anatomical awareness.

Clinical Outcome Prediction of Early Brain Injury in Aneurysmal Subarachnoid Hemorrhage: the SHELTER-Score.

BACKGROUND: Despite intensive research on preventing and treating vasospasm and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage (aSAH), mortality and morbidity rates remain high. Early brain injury (EBI) has emerged as possibly the major significant factor in aSAH pathophysiology, emphasizing the need to investigate EBI-associated clinical events for improved patient management and decision-making. This study aimed to identify early clinical and radiological events within 72 h after aSAH to develop a conclusive predictive EBI score for clinical practice. METHODS: This retrospective analysis included 561 consecutive patients with aSAH admitted to our neurovascular center between 01/2014 and 09/2022. Fourteen potential predictors occurring within the initial 72 h after hemorrhage were analyzed. The modified Rankin Scale (mRS) score at 6 months, discretized to three levels (0-2, favorable; 3-5, poor; 6, dead), was used as the outcome variable. Univariate ordinal regression ranked predictors by significance, and forward selection with McFadden's pseudo-R2 determined the optimal set of predictors for multivariate proportional odds logistic regression. Collinear parameters were excluded, and fivefold cross-validation was used to avoid overfitting. RESULTS: The analysis resulted in the Subarachnoid Hemorrhage Associated Early Brain Injury Outcome Prediction score (SHELTER-score), comprising seven clinical and radiological events: age (0-4 points), World Federation of Neurosurgical Societies (0-2.5 points), cardiopulmonary resuscitation (CPR) (2 points), mydriasis (1-2 points), midline shift (0.5-1 points), early deterioration (1 point), and early ischemic lesion (2 points). McFadden's pseudo-R2 = 0.339, area under the curve for death or disability 0.899 and 0.877 for death. A SHELTER-score below 5 indicated a favorable outcome (mRS 0-2), 5-6.5 predicted a poor outcome (mRS 3-5), and ≥ 7 correlated with death (mRS 6) at 6 months. CONCLUSIONS: The novel SHELTER-score, incorporating seven clinical and radiological features of EBI, demonstrated strong predictive performance in determining clinical outcomes. This scoring system serves as a valuable tool for neurointensivists to identify patients with poor outcomes and guide treatment decisions, reflecting the great impact of EBI on the overall outcome of patients with aSAH.

2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association.

AIM: The "2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage" replaces the 2012 "Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage." The 2023 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with aneurysmal subarachnoid hemorrhage. METHODS: A comprehensive search for literature published since the 2012 guideline, derived from research principally involving human subjects, published in English, and indexed in MEDLINE, PubMed, Cochrane Library, and other selected databases relevant to this guideline, was conducted between March 2022 and June 2022. In addition, the guideline writing group reviewed documents on related subject matter previously published by the American Heart Association. Newer studies published between July 2022 and November 2022 that affected recommendation content, Class of Recommendation, or Level of Evidence were included if appropriate. Structure: Aneurysmal subarachnoid hemorrhage is a significant global public health threat and a severely morbid and often deadly condition. The 2023 aneurysmal subarachnoid hemorrhage guideline provides recommendations based on current evidence for the treatment of these patients. The recommendations present an evidence-based approach to preventing, diagnosing, and managing patients with aneurysmal subarachnoid hemorrhage, with the intent to improve quality of care and align with patients' and their families' and caregivers' interests. Many recommendations from the previous aneurysmal subarachnoid hemorrhage guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.

Microvascular anastomosis of the human lacrimal gland: a concept study towards transplantation of the human lacrimal gland.

INTRODUCTION: Severe aqueous tear deficiency is caused by primary or secondary main lacrimal gland insufficiency. The transplantation of a human lacrimal gland could become a potential treatment option to provide physiological tears with optimal properties. To this end, we performed an ex vivo study to develop a surgical strategy that would ensure a vascular supply for a lacrimal gland transplant using microvascular techniques. MATERIAL AND METHODS: Five cadaver heads were used to perform a lateral orbitotomy in order to identify the vascular pedicle and the lacrimal gland itself. The principal feasibility and the time of the required surgical steps for an intraorbital microvascular re-anastomosis of the human lacrimal gland were documented. Patency and potential leakage of the anastomosis were tested with hematoxylin intraoperatively. Postoperatively, routine histological, as well as scanning electron microscopy (SEM) of the gland and vascular anastomosis, were performed. RESULTS: The vascular pedicle of all five glands could be isolated over a minimum stretch of at least 1 cm, severed, and successfully reanastmosed microsurgically. Time for arterial anatomization (n = 4) was 23 ± 7 min and 22 ± 3 min for the vein (p = 0.62). The total time for the entire microvascular anastomosis was 46 ± 9 min. All anastomosis were patent upon testing. SEM revealed well-aligned edges of the anastomosis with tight sutures in place. CONCLUSION: Our study demonstrates as proof of principle the feasibility of intraorbital microvascular re-anastomosis of a human lacrimal gland within the presumed window of ischemia of this tissue. This should encourage orbital surgeons to attempt lacrimal gland transplantation in humans in vivo.

Clustering of serum biomarkers involved in post-aneurysmal subarachnoid hemorrhage (aSAH) complications.

Post-aSAH sequela is characterized by the onset of life-threatening complications along with the upregulated underlying inflammation. Cerebral vasospasm (CVS) is one of the most frequent complication after aSAH, which contributes majorly to delayed cerebral ischemia and poor clinical outcome. The objective of this study was to identify the clusters of serum biomarkers that are associated with cerebral vasospasm (CVS) after suffering from aneurysmal subarachnoid hemorrhage (aSAH). In this single-center study, serum concentrations of 10 potential biomarkers, together with clinical and demographic parameters, for 66 aSAH patients were recorded within 24 h after aSAH. The dataset was split into a training set (43 patients) and a validation set. Correlation heatmaps for both datasets were computed. Variables with inconsistent correlations on the two subsets were excluded. Clusters of relevant biomarkers were identified on the complete set, separately for patients who developed post-aSAH CVS and those who did not. Two clusters were found to be specific for patients who suffered from CVS: mitochondrial gene fragments (cytochrome B (Cyt-B), cytochrome C oxidase subunit-1 (Cox-1), displacement loop (D-loop), and IL-23, and the other one, containing IL-6, IL-10, age, and Hunt and Hess score. Clusters of serum biomarkers, analyzed within 24 h of the onset of aSAH, days before the CVS development, are expressed differently in patients suffering from post-aSAH CVS, compared to patients without CVS. This suggests that these biomarkers may be involved in the pathophysiological processes leading to CVS and may be used as its early predictors. These interesting findings are potentially highly relevant for the management of CVS and call for validation on a larger sample of patients.

Defining activities in neurovascular microsurgery training: entrustable professional activities for vascular neurosurgery.

BACKGROUND: Entrustable professional activities (EPAs) represent an assessment framework with an increased focus on competency-based assessment. Originally developed and adopted for undergraduate medical education, concerns over resident ability to practice effectively after graduation have led to its implementation in residency training but yet not in vascular neurosurgery. Subjective assessment of resident or fellow performance can be problematic, and thus, we aim to define core EPAs for neurosurgical vascular training. METHODS: We used a nominal group technique in a multistep interaction between a team of experienced neurovascular specialists and a medical educator to identify relevant EPAs. Panel members provided feedback on the EPAs until they reached consent. RESULTS: The process produced seven core procedural EPAs for vascular residency and fellowship training, non-complex aneurysm surgery, complex aneurysm surgery, bypass surgery, arteriovenous malformation resection, spinal dural fistula surgery, perioperative management, and clinical decision-making. CONCLUSION: These seven EPAs for vascular neurosurgical training may support and guide the neurosurgical society in the development and implementation of EPAs as an evaluation tool and incorporate entrustment decisions in their training programs.

Blood Pressure Affects the Early CT Perfusion Imaging in Patients with aSAH Reflecting Early Disturbed Autoregulation.

BACKGROUND: Early computed tomography perfusion (CTP) is frequently used to predict delayed cerebral ischemia following aneurysmatic subarachnoid hemorrhage (aSAH). However, the influence of blood pressure on CTP is currently controversial (HIMALAIA trial), which differs from our clinical observations. Therefore, we aimed to investigate the influence of blood pressure on early CTP imaging in patients with aSAH. METHODS: We retrospectively analyzed the mean transit time (MTT) of early CTP imaging within 24 h after bleeding prior to aneurysm occlusion with respect to blood pressure shortly before or after the examination in 134 patients. We correlated the cerebral blood flow with the cerebral perfusion pressure in the case of patients with intracranial pressure measurement. We performed a subgroup analysis of good-grade (World Federation of Neurosurgical Societies [WFNS] I-III), poor-grade (WFNS IV-V), and solely WFNS grade V aSAH patients. RESULTS: Mean arterial pressure (MAP) significantly correlated inversely with the mean MTT in early CTP imaging (R = - 0.18, 95% confidence interval [CI] - 0.34 to - 0.01, p = 0.042). Lower mean blood pressure was significantly associated with a higher mean MTT. Subgroup analysis revealed an increasing inverse correlation when comparing WFNS I-III (R = - 0.08, 95% CI - 0.31 to 0.16, p = 0.53) patients with WFNS IV-V (R = - 0.2, 95% CI - 0.42 to 0.05, p = 0.12) patients, without reaching statistical significance. However, if only patients with WFNS V are considered, a significant and even stronger correlation between MAP and MTT (R = - 0.4, 95% CI - 0.65 to 0.07, p = 0.02) is observed. In patients with intracranial pressure monitoring, a stronger dependency of cerebral blood flow on cerebral perfusion pressure is observed for poor-grade patients compared with good-grade patients. CONCLUSIONS: The inverse correlation between MAP and MTT in early CTP imaging, increasing with the severity of aSAH, suggests an increasing disturbance of cerebral autoregulation with the severity of early brain injury. Our results emphasize the importance of maintaining physiological blood pressure values in the early phase of aSAH and preventing hypotension, especially in patients with poor-grade aSAH.

The impact of preoperative MRI-based apparent diffusion coefficients on local recurrence and outcome in patients with cerebral metastases.

BACKGROUND: Surgery of single cerebral metastases is standard but frequently fails to achieve local tumour control. Reliable predictors for local tumour progression and overall survival are unknown. MRI-based apparent diffusion coefficients (ADC) correlate with tumour cellularity and invasion. The present study analysed a potential relation between the MRI based apparent diffusion coefficients local recurrence and outcome in patients with brain metastases. METHODS: A retrospective analysis was performed for patients with cerebral metastases and complete surgical resection evaluated by an early postoperative MRI < 72h. Minimal ADC and mean ADC were assessed in preoperative 1,5T-MRI scans by placing regions of interests in the tumour and the peritumoural tissue. RESULTS: Analysis of the relation between ADC values, local progression and outcome was performed in 86 patients with a mean age of 59 years (range 33-83 years). Primary site was NSCLC in 37.2% of all cases. Despite complete resection 33.7% of all patients suffered from local in-brain-progression. There were no significant differences in ADC values in groups based on histology. In the present cohort, the mean ADCmin and the mean ADCmean within the metastasis did not differ significantly between patients with and without a later local in-brain progression (634 × 10-6 vs. 661 × 10-6 mm2/s and 1324 × 10-6 vs. 1361 × 10-6 mm2/s; 1100 × 10-6 vs. 1054 × 10-6 mm2/s; each p > 0.05). Mean ADC values did not correlate significantly with PFS and OAS. CONCLUSION: In the present study analysed ADC values had no significant impact on local in brain progression and survival parameters.

Would they do it again? Final treatment decisions in malignant brain tumour patients-a caregiver's perspective.

PURPOSE: Overall survival of malignant brain tumour patients has significantly been increased over the last years. However, therapy remains palliative, and side effects should be balanced. Once terminal phase is entered, both patients and caregivers may find it hard to accept, and further therapies are demanded. But little is known about this highly sensitive period. Therefore, we analysed the last therapy decisions from the family caregiver's perspective. Would they support their beloved ones in the same way or would they now recommend a different therapy decision? METHODS: Caregivers of deceased malignant brain tumour patients, treated at our neurooncological centre between 2011 and 2017, were included. We designed a questionnaire to analyse the impact of the last therapy decision (resection, chemotherapy, radiotherapy), focusing on probable repeat of the choice taken and general therapy satisfaction. Independent variables, for example "satisfaction with therapy", were analysed using linear regression analysis, the coefficient of determination R2 and the standardized regression coefficient ß. The binary logistic regression analyses were taken to illustrate relationships with the dichotomously scaled outcome parameter "re-choice of therapy". Odds ratio analyses were used to determine the strength of a relationship between two characteristics. RESULTS: Data from 102 caregivers (life partners (70.6%)) were analysed retrospectively. Each 40% of patients died in a hospice or at home (20% in a hospital). In 67.6% the last therapy was chemotherapy followed by radiotherapy (16.7%) and surgery (15.7%). A positive evaluation of the last therapy was significantly correlated to re-choosing of respective therapy (chemo-/radiotherapy: p = 0.000) and satisfaction with informed consent (p = 0.000). Satisfaction regarding interpersonal contact was significantly correlated to satisfaction with resection (p = 0.000) and chemotherapy (p = 0.000 27 caregivers (28.7%) felt overburdened with this situation). CONCLUSION: This analysis demonstrates a significant correlation between a positive relation of patient/caregiver/physician and the subjective perception of the latest therapy. It underlines the central role of caregivers, who should be involved in therapy discussions. Neurooncologists should be specially trained in communication and psycho-oncology.

Structural damage burden and hypertrophic olivary degeneration in pediatric postoperative cerebellar mutism syndrome.

Cerebellar mutism syndrome (CMS) occurs in one out of four children after posterior fossa tumor surgery, with open questions regarding risk factors, pathophysiology, and prevention strategies. Because of similarities between several cerebellar syndromes, a common pathophysiology with damage to the dentato-thalamo-cortical and dentato-rubro-olivary pathways has been proposed. Hypertrophic olivary degeneration (HOD) is an imaging correlate of cerebellar injury observed for instance in stroke patients. Aim of this study was to investigate whether the occurrence and severity of CMS correlates with the extent of damage to the relevant anatomical structures and whether HOD is a time-dependent postoperative neuroimaging correlate of CMS. We performed a retrospective single center study of CMS patients compared with matched non-CMS controls. CMS occurred in 10 children (13% of the overall cohort) with a median age of 8 years. Dentate nucleus (DN) injury significantly correlated with CMS, and superior cerebellar peduncle (SCP) injury was associated by tendency. HOD was observed as a dynamic neuroimaging phenomenon in the postoperative course and its presence significantly correlated with CMS and DN injury. Children who later developed HOD had an earlier onset and tended to have longer persistence of CMS. These findings can guide surgical measures to protect the DN and SCP during posterior fossa tumor resections and to avoid a high damage burden (i.e., bilateral damage). Development of intraoperative neuromonitoring of the cerebellar efferent pathways as well as improved preoperative risk stratification could help to establish a patient-specific strategy with optimal balance between degree of resection and functional integrity.

Time trends in the risk of delayed cerebral ischemia after subarachnoid hemorrhage: a meta-analysis of randomized controlled trials.

OBJECTIVE: Delayed cerebral ischemia (DCI) contributes to morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). Continuous improvement in the management of these patients, such as neurocritical care and aneurysm repair, may decrease the prevalence of DCI. In this study, the authors aimed to investigate potential time trends in the prevalence of DCI in clinical studies of DCI within the last 20 years. METHODS: PubMed, Embase, and the Cochrane library were searched from 2000 to 2020. Randomized controlled trials that reported clinical (and radiological) DCI in patients with aSAH who were randomized to a control group receiving standard care were included. DCI prevalence was estimated by means of random-effects meta-analysis, and subgroup analyses were performed for the DCI sum score, Fisher grade, clinical grade on admission, and aneurysm treatment method. Time trends were evaluated by meta-regression. RESULTS: The search strategy yielded 5931 records, of which 58 randomized controlled trials were included. A total of 4424 patients in the control arm were included. The overall prevalence of DCI was 0.29 (95% CI 0.26-0.32). The event rate for prevalence of DCI among the high-quality studies was 0.30 (95% CI 0.25-0.34) and did not decrease over time (0.25% decline per year; 95% CI -2.49% to 1.99%, p = 0.819). DCI prevalence was higher in studies that included only higher clinical or Fisher grades, and in studies that included only clipping as the treatment modality. CONCLUSIONS: Overall DCI prevalence in patients with aSAH was 0.29 (95% CI 0.26-0.32) and did not decrease over time in the control groups of the included randomized controlled trials.

Synthetic vascular grafts as a new treatment option for space-occupying tumor bed cysts.

INTRODUCTION: Several authors have reported the formation of slit valves as the underlying pathomechanism of space-occupying tumor bed cysts. Iatrogenic slit valves following the resection of high-grade gliomas have been linked to certain risk factors such as intraoperative opening of the ventricles and attempts to seal these. The best therapeutic management of such cystic lesions remains elusive. Several treatment options such as cyst fenestration or cystoperitoneal shunting have been employed but remain associated with high rates of recurrence. With the given complications of the above-described treatment options, the objective was to devise a new therapy option that is safe and effective and treats the slit valve itself rather than its symptoms. METHODS: Between the years of 2010 and 2020, we successfully treated four patients with high-pressure tumor bed cysts following glioma resection by implantation of synthetic ringed vascular grafts into the slit valve. RESULTS: Postoperatively, the tumor bed cysts were regressive in all patients. Moreover, none of the treatment patients developed any complications associated with the implanted vascular grafts. Revision-free survival was 10, 12, 53, and 126 months, respectively. CONCLUSION: The use of synthetic vascular grafts as a means of stenting slit valves is a safe and effective novel treatment option for high-pressure tumor bed cysts.

Psychooncological distress in low-grade glioma patients-a monocentric study.

BACKGROUND: Patients diagnosed with low-grade glioma (LGG) must live with constant knowledge of an upcoming malignant tumor transformation which may lead to increased anxiety and reduced quality of life. Here, we (1) analyzed the prevalence and risk factors for distress in LGG patients using (2) different screening tools to subsequently (3) evaluate their need for psychological support. METHOD: Patients with LGG-suspicious findings in MRI studies as well as patients with histopathological confirmed LGG were screened using three established self-assessment instruments (Hospital Anxiety and Depression Scale, Distress Thermometer, EORTC-QLQ-C30-BN20). Screening results were correlated with sociodemographic factors. RESULTS: One hundred forty-nine patients (74 men and 75 women) were prospectively included. Patients were further divided into different subgroups regarding the time of screening and diagnosis. An increased level of distress was observed in 20.8% (mean score 1.21, 95% CI 1.15-1.28) of all patients screened by HADS. Significant associated factors were pre-existing psychiatric disorders (p = 0.003) and psychotropic medication (p = 0.029). HRQoL (p = 0.022) and global health item (p = 0.015), as well as future uncertainty (p = 0.047), assessed by the EORTC-QLQ-C30-BN20 were significantly higher in those patients without histopathological diagnosis. Increased distress was significantly correlated with results in chosen sub-items of the HRQoL questionnaire (p < 0.001). CONCLUSIONS: Our results demonstrate the need for frequent distress screening. If specific tools are not available, HRQoL questionnaires can also be used. Patients with pre-existing psychological stress should be offered additional psychooncological support, irrespectively of the time of screening or tumor diagnosis. CLINICAL TRIAL REGISTRATION NUMBER: 4087.

Non-adjustable gravitational valves or adjustable valves in the treatment of hydrocephalus after aneurysmal subarachnoid hemorrhage patients?

PURPOSE: Hydrocephalus requiring permanent CSF shunting after aneurysmal subarachnoid hemorrhage (aSAH) is frequent. It is unknown which type of valve is optimal. This study evaluates if the revision rate of gravitational differential pressure valves (G-DPVs, GAV® system (B Braun)) (G-DPV) is comparable to adjustable pressure valves (Codman Medos Hakim) (APV) in the treatment of post-aSAH hydrocephalus. METHODS: The use of a gravitational differential pressure valve is placed in direct comparison with an adjustable pressure valve system. A retrospective chart review is performed to compare the revision rates for the two valve systems. RESULTS: Within the registry from Radboud University Medical Center, 641 patients with a SAH could be identified from 1 January 2013 until 1 January 2019, whereas at the Heinrich Heine University, 617 patients were identified, totaling 1258 patients who suffered from aSAH. At Radboud University Medical Center, a gravitational differential pressure valve is used, whereas at the Heinrich Heine University, an adjustable pressure valve system is used. One hundred sixty-six (13%) patients required permanent ventricular peritoneal or atrial shunting. Shunt dysfunction occurred in 36 patients: 13 patients of the 53 (25%) of the gravitational shunt cohort, and in 23 of the 113 (20%) patients with an adjustable shunt (p = 0.54). Revision was performed at a mean time of 3.2 months after implantation with the gravitational system and 8.2 months with the adjustable shunt system. Combined rates of over- and underdrainage leading to revision were 7.5% (4/53) for the gravitational and 3.5% (4/113) for the adjustable valve system (p = 0 .27). CONCLUSION: The current study does not show a benefit of a gravitational pressure valve (GAV® system) over an adjustable pressure valve (CODMAN ® HAKIM®) in the treatment of post-aSAH hydrocephalus. The overall need for revision is high and warrants further improvements in care.

Janus Faced HMGB1 and Post-Aneurysmal Subarachnoid Hemorrhage (aSAH) Inflammation.

Aneurysmal subarachnoid hemorrhage (aSAH), resulting majorly from the rupture of intracranial aneurysms, is a potentially devastating disease with high morbidity and mortality. The bleeding aneurysms can be successfully secured; however, the toxic and mechanical impact of the blood extravasation into the subarachnoid space damages the brain cells leading to the release of different damage-associated molecular pattern molecules (DAMPs). DAMPs upregulate the inflammation after binding their cognate receptors on the immune cells and underlies the early and delayed brain injury after aSAH. Moreover, these molecules are also associated with different post-aSAH complications, which lead to poor clinical outcomes. Among these DAMPs, HMGB1 represents a prototypical protein DAMP that has been well characterized for its proinflammatory role after aSAH and during different post-aSAH complications. However, recent investigations have uncovered yet another face of HMGB1, which is involved in the promotion of brain tissue remodeling, neurovascular repair, and anti-inflammatory effects after SAH. These different faces rely on different redox states of HMGB1 over the course of time after SAH. Elucidation of the dynamics of these redox states of HMGB1 has high biomarker as well as therapeutic potential. This review mainly highlights these recent findings along with the conventionally described normal role of HMGB1 as a nuclear protein and as a proinflammatory molecule during disease (aSAH).

Crosstalk between ß-Catenin and CCL2 Drives Migration of Monocytes towards Glioblastoma Cells.

Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) is a fast growing and highly heterogeneous tumor, often characterized by the presence of glioblastoma stem cells (GSCs). The plasticity of GSCs results in therapy resistance and impairs anti-tumor immune response by influencing immune cells in the tumor microenvironment (TME). Previously, ß-catenin was associated with stemness in GBM as well as with immune escape mechanisms. Here, we investigated the effect of ß-catenin on attracting monocytes towards GBM cells. In addition, we evaluated whether CCL2 is involved in ß-catenin crosstalk between monocytes and tumor cells. Our analysis revealed that shRNA targeting ß-catenin in GBMs reduces monocytes attraction and impacts CCL2 secretion. The addition of recombinant CCL2 restores peripheral blood mononuclear cells (PBMC) migration towards medium (TCM) conditioned by shß-catenin GBM cells. CCL2 knockdown in GBM cells shows similar effects and reduces monocyte migration to a similar extent as ß-catenin knockdown. When investigating the effect of CCL2 on ß-catenin activity, we found that CCL2 modulates components of the Wnt/ß-catenin pathway and alters the clonogenicity of GBM cells. In addition, the pharmacological ß-catenin inhibitor MSAB reduces active ß-catenin, downregulates the expression of associated genes and alters CCL2 secretion. Taken together, we showed that ß-catenin plays an important role in attracting monocytes towards GBM cells in vitro. We hypothesize that the interactions between ß-catenin and CCL2 contribute to maintenance of GSCs via modulating immune cell interaction and promoting GBM growth and recurrence.

Proposed definition of competencies for surgical neuro-oncology training.

OBJECTIVE: The aim of this work is to define competencies and entrustable professional activities (EPAs) to be imparted within the framework of surgical neuro-oncological residency and fellowship training as well as the education of medical students. Improved and specific training in surgical neuro-oncology promotes neuro-oncological expertise, quality of surgical neuro-oncological treatment and may also contribute to further development of neuro-oncological techniques and treatment protocols. Specific curricula for a surgical neuro-oncologic education have not yet been established. METHODS: We used a consensus-building approach to propose skills, competencies and EPAs to be imparted within the framework of surgical neuro-oncological training. We developed competencies and EPAs suitable for training in surgical neuro-oncology. RESULT: In total, 70 competencies and 8 EPAs for training in surgical neuro-oncology were proposed. EPAs were defined for the management of the deteriorating patient, the management of patients with the diagnosis of a brain tumour, tumour-based resections, function-based surgical resections of brain tumours, the postoperative management of patients, the collaboration as a member of an interdisciplinary and/or -professional team and finally for the care of palliative and dying patients and their families. CONCLUSIONS AND RELEVANCE: The present work should subsequently initiate a discussion about the proposed competencies and EPAs and, together with the following discussion, contribute to the creation of new training concepts in surgical neuro-oncology.

Vagus nerve stimulation in patients with Lennox-Gastaut syndrome: A meta-analysis.

OBJECTIVES: Lennox-Gastaut syndrome (LGS) is among the most severe epileptic and developmental encephalopathies. A meta-analysis was performed to evaluate the effectiveness of adjunctive vagus nerve stimulation (VNS Therapy) in patients with LGS. MATERIALS & METHODS: PubMed database was queried (January 1997 to September 2018) to identify publications reporting on the efficacy of VNS Therapy in patients with LGS, with or without safety findings. Primary endpoint of the meta-analysis was the proportion of responders (≥50% reduction in seizure frequency). Random-effects analysis was used to calculate weighted mean estimates and confidence intervals. Heterogeneity was evaluated by statistical tests including I2 . RESULTS: Of 2752 citations reviewed, 17 articles (480 patients) were eligible including 10 retrospective studies and seven prospective studies. A random-effects model produced a pooled proportion of 54% (95% confidence intervals [CI]: 45%, 64%) of patients with LGS who responded to adjunctive VNS Therapy (p for heterogeneity <0.001, I2 =72.9%). Per an exploratory analysis, the calculated incidence of serious adverse events associated with VNS Therapy was 9% (95% CI: 5%, 14%); the rate was higher than in long-term efficacy studies of heterogeneous cohorts with drug-resistant epilepsy and likely attributed to variable definitions of serious adverse events across studies. CONCLUSIONS: The meta-analysis of 480 patients with LGS suggests that 54% of patients responded to adjunctive VNS Therapy and that the treatment option was safe and well-tolerated. The response in patients with LGS was comparable to heterogeneous drug-resistant epilepsy populations. A clinical and surgical overview has been included to facilitate the use of VNS in LGS.

Application of clinical prediction modeling in pediatric neurosurgery: a case study.

There has been an increasing interest in articles reporting on clinical prediction models in pediatric neurosurgery. Clinical prediction models are mathematical equations that combine patient-related risk factors for the estimation of an individual's risk of an outcome. If used sensibly, these evidence-based tools may help pediatric neurosurgeons in medical decision-making processes. Furthermore, they may help to communicate anticipated future events of diseases to children and their parents and facilitate shared decision-making accordingly. A basic understanding of this methodology is incumbent when developing or applying a prediction model. This paper addresses this methodology tailored to pediatric neurosurgery. For illustration, we use original pediatric data from our institution to illustrate this methodology with a case study. The developed model is however not externally validated, and clinical impact has not been assessed; therefore, the model cannot be recommended for clinical use in its current form.