A profile on the WISE cortical strip for intraoperative neurophysiological monitoring

INTRODUCTION: During intraoperative neurophysiological monitoring in neurosurgery, brain electrodes are placed to record electrocorticography or to inject current for direct cortical stimulation. A low impedance electrode may improve signal quality. AREAS COVERED: We review here a brain electrode (WISE Cortical Strip, WCS®), where a thin polymer strip embeds platinum nanoparticles to create conductive electrode contacts. The low impedance contacts enable a high signal-to-noise ratio, allowing for better detection of small signals such as high-frequency oscillations (HFO). The softness of the WCS may hinder sliding the electrode under the dura or advancing it to deeper structures as the hippocampus but assures conformability with the cortex even in the resection cavity. We provide an extensive review on WCS including a market overview, an introduction to the device (mechanistics, cost aspects, performance standards, safety and contraindications) and an overview of the available pre- and post-approval data. EXPERT OPINION: The WCS improves signal detection by lower impedance and better conformability to the cortex. The higher signal-to-noise ratio improves the detection of challenging signals. The softness of the electrode may be a disadvantage in some applications and an advantage in others

Low impedance electrodes improve detection of high frequency oscillations in the intracranial EEG

OBJECTIVE Epileptic fast ripple oscillations (FR, 250-500 Hz) indicate epileptogenic tissue with high specificity. However, their low amplitude makes detection demanding against noise. Since thermal noise is reduced by low impedance electrodes (LoZ), we investigate here whether this noise reduction is relevant in the FR frequency range. METHODS We analyzed intracranial electrocorticography during neurosurgery of 10 patients where a low impedance electrode was compared to a standard electrode (HiZ) with equal surface area during stimulation of the somatosensory evoked potential, which evokes a robust response in the FR frequency range. To estimate the noise level, we computed the difference between sweep 2n and sweep 2n + 1 for all sweeps. RESULTS The power spectral density of the noise spectrum improved for the LoZ over all frequencies. In the FR range, the median noise level improved from HiZ (0.153 µV) to LoZ (0.089 µV). For evoked FR, the detection rate improved (91% for HiZ vs. 100% for LoZ). CONCLUSIONS Low impedance electrodes for intracranial EEG reduce noise in the FR frequency range and may thereby improve FR detection. SIGNIFICANCE Improving the measurement chain may enhance the diagnostic value of FR as biomarkers for epileptogenic tissue

Collagen-bound fibrin sealant (TachoSil®) for dural closure in cranial surgery: single-centre comparative cohort study and systematic review of the literature

Cerebrospinal fluid (CSF) leakage is a well-known complication of craniotomies and there are several dural closure techniques. One commonly used commercial product as adjunct for dural closure is the collagen-bound fibrin sealant TachoSil®. We analysed whether the addition of TachoSil has beneficial effects on postoperative complications and outcomes. Our prospective, institutional database was retrospectively queried, and 662 patients undergoing craniotomy were included. Three hundred fifty-two were treated with dural suture alone, and in 310, TachoSil was added after primary suture. Our primary endpoint was the rate of postoperative complications associated with CSF leakage. Secondary endpoints included functional, disability and neurological outcome. Systematic review according to PRISMA guidelines was performed to identify studies comparing primary dural closure with and without additional sealants. Postoperative complications associated with CSF leakage occurred in 24 (7.74%) and 28 (7.95%) procedures with or without TachoSil, respectively (p = 0.960). Multivariate analysis confirmed no significant differences in complication rate between the two groups (aOR 0.97, 95% CI 0.53-1.80, p = 0.930). There were no significant disparities in postoperative functional, disability or neurological scores. The systematic review identified 661 and included 8 studies in the qualitative synthesis. None showed a significant superiority of additional sealants over standard technique regarding complications, rates of revision surgery or outcome. According to our findings, we summarize that routinary use of TachoSil and similar products as adjuncts to primary dural sutures after intracranial surgical procedures is safe but without clear advantage in complication avoidance or outcome. Future studies should investigate whether their use is beneficial in high-risk settings

Management of brainstem haemorrhages

Among spontaneous intracranial haemorrhages, primary non-traumatic brainstem haemorrhages are associated with the highest mortality rate. Patients classically present with rapid neurological deterioration. Previous studies have found that the severity of initial neurological symptoms and hydrocephalus are predictors of poor outcomes. In addition, radiological parameters aim to classify brainstem haematomas according to volume, extension and impact on prognosis. However, previous studies have failed to agree on a differentiated radiological classification for outcome and functional recovery. Electrophysiology, including motor, auditory and somatosensory evoked potentials, is used to estimate the extent of the initial injury and predict functional recovery. The current management of brainstem haematomas remains conservative, focusing on initial close neurocritical care monitoring. Surgical treatment concepts exist, but similarly to general intracranial haemorrhage management, they continue to be controversial and have not been sufficiently investigated. This is especially the case for haematomas in the posterior fossa, as these are excluded from most current clinical trials. Existing studies were mostly carried out before the present millennium began, and limitations are evident in the adaptation of those results and recommendations to current management, with today’s technological and diagnostic possibilities. We therefore recommend the re-evaluation of brainstem haemorrhages in the modern neurosurgical and intensive care environment

The association of patient age with postoperative morbidity and mortality following resection of intracranial tumors

INTRODUCTION The postoperative functional status of patients with intracranial tumors is influenced by patient-specific factors, including age. RESEARCH QUESTION This study aimed to elucidate the association between age and postoperative morbidity or mortality following the resection of brain tumors. MATERIAL AND METHODS A multicenter database was retrospectively reviewed. Functional status was assessed before and 3-6 months after tumor resection by the Karnofsky Performance Scale (KPS). Uni- and multivariable linear regression were used to estimate the association of age with postoperative change in KPS. Logistic regression models for a ≥10-point decline in KPS or mortality were built for patients ≥75 years. RESULTS The total sample of 4864 patients had a mean age of 56.4 ​± ​14.4 years. The mean change in pre-to postoperative KPS was -1.43. For each 1-year increase in patient age, the adjusted change in postoperative KPS was -0.11 (95% CI -0.14 - - 0.07). In multivariable analysis, patients ≥75 years had an odds ratio of 1.51 to experience postoperative functional decline (95%CI 1.21-1.88) and an odds ratio of 2.04 to die (95%CI 1.33-3.13), compared to younger patients. DISCUSSION Patients with intracranial tumors treated surgically showed a minor decline in their postoperative functional status. Age was associated with this decline in function, but only to a small extent. CONCLUSION Patients ≥75 years were more likely to experience a clinically meaningful decline in function and about two times as likely to die within the first 6 months after surgery, compared to younger patients

Maximal surgical tumour load reduction in immune-checkpoint inhibitor naïve patients with melanoma brain metastases correlates with prolonged survival

Background: Recent therapeutic advances in metastatic melanoma have led to improved overall survival (OS) rates, with consequently an increased incidence of brain metastases (BM). The role of BM resection in the era of targeted and immunotherapy should be reassessed. In the current study we analysed the role of residual intracranial tumour load in a cohort of melanoma BM patients. Methods: Retrospective single-centre analysis of a prospective registry of resected melanoma BM from 2013 to 2021. Correlations of residual tumour volume and outcome were determined with respect to patient, tumour and treatment regimens characteristics. Results: 121 individual patients (66% male, mean age 59.9 years) were identified and included in the study. Pre- and postoperative systemic treatments included BRAF/MEK inhibitors, as well as combination or monotherapy of immune-checkpoint inhibitors (ICIs). Median OS of the entire cohort was 20 months. Cox proportional-hazard analysis revealed postoperative anti-CTLA4+anti-PD-1 therapy (HR 0.07, p = .01) and postoperative residual intracranial tumour burden (HR 1.4, p = .027) as significant predictors for OS. Further analysis revealed that ICI-naïve patients with residual tumour volume ≤3.5 cm3 and postoperative ICI showed significantly prolonged OS compared to patients with residual volume >3.5 cm3 (p < .0001). Subgroup analysis of ICI-naïve patients showed steroid intake postoperatively to be negatively associated with OS, however residual tumour volume ≤3.5 cm3 remained independently correlated with superior OS (HR 0.14, p < .001). Conclusion: Besides known predictive factors like postoperative ICI, a maximal intracranial tumour burden reduction seems to be beneficial, especially in ICI-naïve patients. This highlights the importance of local CNS control and the need to further investigating the role of initial surgical tumour load reduction in randomised clinical trials. Keywords: Brain metastases; Extent of resection; Immunotherapy; Melanoma; Tumour residua

Vaccination with designed neopeptides induces intratumoral, cross-reactive CD4+ T cell responses in glioblastoma

Purpose: The low mutational load of some cancers is considered one reason for the difficulties to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutation to enhance their immunogenicity. Experimental Design: Exome- and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides. Subsequently, in silico HLA-anchor placements were used to deduce putative T cell receptor contacts of peptides. Single amino acids of TCR contacting residues were then mutated by amino acid replacements. Overall, 175 peptides were synthesized and sets of 25 each containing both peptides designed to bind to HLA class I and II molecules applied in the vaccination. Upon development of a tumor recurrence, the tumor-infiltrating lymphocytes (TILs) were characterized in detail both at the bulk and clonal level. Results: The immune response of peripheral blood T cells to vaccine peptides, including natural peptides and designed neopeptides, gradually increased with repetitive vaccination, but remained low. In contrast, at the time of tumor recurrence, CD8+ TILs and CD4+ TILs responded to 45% and 100% respectively of the vaccine peptides. Further, TIL-derived CD4+ T cell clones showed strong responses and tumor cell lysis not only against the designed neopeptide but also against the unmutated natural peptides of the tumor. Conclusions: Turning tumor self-peptides into foreign antigens by introduction of designed mutations is a promising strategy to induce strong intratumoral CD4+ T cell responses in a cold tumor like glioblastoma

High-throughput identification of repurposable neuroactive drugs with potent anti-glioblastoma activity

Glioblastoma, the most aggressive primary brain cancer, has a dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we systematically screened repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling more than 2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug-target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of more than 1 million compounds with high patient validation accuracy. Deep multimodal profiling confirmed Ca$^{2+}$-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the anti-depressant vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology

A T-cell antigen atlas for meningioma: novel options for immunotherapy

Meningiomas are the most common primary intracranial tumors. Although most symptomatic cases can be managed by surgery and/or radiotherapy, a relevant number of patients experience an unfavorable clinical course and additional treatment options are needed. As meningiomas are often perfused by dural branches of the external carotid artery, which is located outside the blood-brain barrier, they might be an accessible target for immunotherapy. However, the landscape of naturally presented tumor antigens in meningioma is unknown. We here provide a T-cell antigen atlas for meningioma by in-depth profiling of the naturally presented immunopeptidome using LC-MS/MS. Candidate target antigens were selected based on a comparative approach using an extensive immunopeptidome data set of normal tissues. Meningioma-exclusive antigens for HLA class I and II are described here for the first time. Top-ranking targets were further functionally characterized by showing their immunogenicity through in vitro T-cell priming assays. Thus, we provide an atlas of meningioma T-cell antigens which will be publicly available for further research. In addition, we have identified novel actionable targets that warrant further investigation as an immunotherapy option for meningioma