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Background Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. Methods Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. Results In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. Conclusions Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura.

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq ( n  = 6) and exome sequencing ( n  = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted. Vestibular schwannomas are benign tumours which can lead to neurological symptoms and morbidity. Here, the authors use single cell RNA-seq and ATAC-seq to identify Schwann cell subtypes in the tumour microenvironment which mimic a nerve injury phenotype.

Perioperative steroid protocols for patients undergoing transsphenoidal surgery (TSS) for pituitary pathology vary by institution. To assess the safety of withholding glucocorticoids in patients undergoing TSS. Patients with an intact hypothalamic-pituitary-adrenal (HPA) axis undergoing TSS for a pituitary tumor at the same academic institution between 2012 and 2015 were randomized to either receive 100 mg of intravenous hydrocortisone followed by 0.5 mg of intravenous dexamethasone every 6 h for 4 doses (STER, n = 23) or to undergo surgery without steroids (NOSTER, n = 20). Postoperative cortisol levels were then used to determine the need for glucocorticoids after surgery. Data regarding postoperative cortisol levels, hospital stay length, and complications were collected. Mean postoperative 8 am cortisol levels were higher in the NOSTER group compared to the STER group (745 ± 359 nmol/L and 386 ± 193 nmol/L, respectively, P = .001) and more patients were discharged on glucocorticoids in the STER group (42% vs 12%, P = .07). There was no difference in the incidence of postoperative complications, including hyperglycemia, diabetes insipidus, or permanent adrenal insufficiency. Permanent adrenal insufficiency occurred in 8% of patients. Perioperative steroids can be safely withheld in patients with an intact HPA axis undergoing TSS. Although administration of perioperative glucocorticoids does not appear to increase the risk of complications, it may interfere with assessment of the HPA axis after surgery.

Background The use of intraoperative MRI (iMRI) during treatment of gliomas may increase extent of resection (EOR), decrease need for early reoperation, and increase progression-free and overall survival, but has not been fully validated, particularly in the pediatric population. Objective To assess the accuracy of iMRI to identify residual tumor in pediatric patients with glioma and determine the effect of iMRI on decisions for resection, complication rates, and other outcomes. Methods We retrospectively analyzed a multicenter database of pediatric patients (age ≤ 18 years) who underwent resection of pathologically confirmed gliomas. Results We identified 314 patients (mean age 9.7 ± 4.6 years) with mean follow-up of 48.3 ± 33.6 months (range 0.03–182.07 months) who underwent surgery with iMRI. There were 201 (64.0%) WHO grade I tumors, 57 (18.2%) grade II, 24 (7.6%) grade III, 9 (2.9%) grade IV, and 23 (7.3%) not classified. Among 280 patients who underwent resection using iMRI, 131 (46.8%) had some residual tumor and underwent additional resection after the first iMRI. Of the 33 tissue specimens sent for pathological analysis after iMRI, 29 (87.9%) showed positive tumor pathology. Gross total resection was identified in 156 patients (55.7%), but this was limited by 69 (24.6%) patients with unknown EOR. Conclusions Analysis of the largest multicenter database of pediatric gliomas resected using iMRI demonstrated additional tumor resection in a substantial portion of cases. However, determining the impact of iMRI on EOR and outcomes remains challenging because iMRI use varies among providers nationally. Continued refinement of iMRI techniques for use in pediatric patients with glioma may improve outcomes.

In a trial of minimally invasive cerebral hematoma removal within 24 hours after onset of hemorrhage, functional outcomes were better with surgery than with medical treatment, particularly among patients with lobar hemorrhages.

Purpose The clinical benefit of combined intraoperative magnetic resonance imaging (iMRI) and endoscopy for transsphenoidal pituitary adenoma resection has not been completely characterized. This study assessed the impact of microscopy, endoscopy, and/or iMRI on progression-free survival, extent of resection status (gross-, near-, and sub-total resection), and operative complications. Methods Retrospective analyses were performed on 446 transsphenoidal pituitary adenoma surgeries at a single institution between 1998 and 2012. Multivariate analyses were used to control for baseline characteristics, differences during extent of resection status, and progression-free survival analysis. Results Additional surgery was performed after iMRI in 56/156 cases (35.9 %), which led to increased extent of resection status in 15/156 cases (9.6 %). Multivariate ordinal logistic regression revealed no increase in extent of resection status following iMRI or endoscopy alone; however, combining these modalities increased extent of resection status (odds ratio 2.05, 95 % CI 1.21–3.46) compared to conventional transsphenoidal microsurgery. Multivariate Cox regression revealed that reduced extent of resection status shortened progression-free survival for near- versus gross-total resection [hazard ratio (HR) 2.87, 95 % CI 1.24–6.65] and sub- versus near-total resection (HR 2.10; 95 % CI 1.00–4.40). Complication comparisons between microscopy, endoscopy, and iMRI revealed increased perioperative deaths for endoscopy versus microscopy (4/209 and 0/237, respectively), but this difference was non-significant considering multiple post hoc comparisons (Fisher exact, p  = 0.24). Conclusions Combined use of endoscopy and iMRI increased pituitary adenoma extent of resection status compared to conventional transsphenoidal microsurgery, and increased extent of resection status was associated with longer progression-free survival. Treatment modality combination did not significantly impact complication rate.

Abstract BACKGROUND Neurofibromatosis type 2 (NF2) often results in profound hearing loss and cochlear implantation is an emerging hearing rehabilitation option. However, cochlear implant (CI) outcomes in this population vary, and intraoperative monitoring to predict cochlear nerve viability and subsequent outcomes is not well-established. OBJECTIVE To review the use of intraoperative electrically evoked cochlear nerve monitoring in patients with NF2 simultaneous translabyrinthine (TL) vestibular schwannoma (VS) resection and cochlear implantation. METHODS A retrospective review was performed of 3 patients with NF2 that underwent simultaneous TL VS resection and cochlear implantation with electrical auditory brainstem response (eABR) measured throughout tumor resection. Patient demographics, preoperative assessments, surgical procedures, and outcomes were reviewed. RESULTS Patients 1 and 3 had a reliable eABR throughout tumor removal. Patient 2 had eABR pretumor removal, but post-tumor removal eABR presence could not be reliably determined because of electrical artifact interference. All patients achieved auditory percepts upon CI activation. Patients 1 and 2 experienced a decline in CI performance after 1 yr and after 3 mo, respectively. Patient 3 continues to perform well at 9 mo. Patients 2 and 3 are daily users of their CI. CONCLUSION Cochlear implantation is attainable in cases of NF2-associated VS resection. Intraoperative eABR may facilitate cochlear nerve preservation during tumor removal, though more data and long-term outcomes are needed to refine eABR methodology and predictive value for this population.

Toll-like receptor 4 (Tlr-4) mediates many biological effects of lipopolysaccharide (LPS), which has antitumoral effects on glioblastoma both in vivo and in vitro. However, the precise role of Tlr-4 in these antitumoral effects remains unknown. The role of Tlr-4 in the antitumoral effect of LPS on glioblastomas was assessed in wild-type BALB/c mice and in Tlr-4 knockout (KO) BALB/c mice. Mice were implanted with DBT glioblastoma cells intracranially or subcutaneously, were treated with intratumoral LPS, and were assessed by histopathological examination for degrees of tumor progression and inflammation. Flow cytometry and Western blotting with antibodies to the Tlr-4 receptor and flow cytometry to the related CD14 moiety were performed to quantitate the expression levels of these two receptors by glioblastoma cells. For subcutaneous tumors, LPS caused near complete tumor elimination in wild-type mice, but only a 50% reduction in Tlr-4 KO mice. For mice implanted with intracranial glioblastomas, LPS increased survival times modestly in wild-type mice, but showed no benefit in the Tlr-4 KO mice. There were no histological differences among wild-type and Tlr-4 KO mice, except for tumor size. In both models, an early neutrophilic and later macrophage-rich inflammatory infiltrate were seen after LPS administration. Quantitative flow cytometry and Western blotting showed no Tlr-4 receptor or CD14 expression in murine and human glioblastoma cells in vitro, and Western blotting suggested that Tlr-4 effects are mediated by nontumoral elements such as microglia and inflammatory cells. LPS-induced antitumoral effects on glioblastoma multiforme are mediated, in part, by the Tlr-4 receptor. Further understanding of this process may lead to novel treatment strategies for this uniformly fatal disease.

Background While most meningiomas are benign, aggressive meningiomas are associated with high levels of recurrence and mortality. A single institution’s Gamma Knife radiosurgical experience with atypical and malignant meningiomas is presented, stratified by the most recent WHO classification. Methods Thirty-one patients with atypical and 4 patients with malignant meningiomas treated with Gamma Knife radiosurgery between July 2000 and July 2011 were retrospectively reviewed. All patients underwent prior surgical resection. Overall survival was the primary endpoint and rate of disease recurrence in the brain was a secondary endpoint. Patients who had previous radiotherapy or prior surgical resection were included. Kaplan-Meier and Cox proportional hazards models were used to estimate survival and identify factors predictive of recurrence and survival. Results Post-Gamma Knife recurrence was identified in 11 patients (31.4%) with a median overall survival of 36 months and progression-free survival of 25.8 months. Nine patients (25.7%) had died. Three-year overall survival (OS) and progression-free survival (PFS) rates were 78.0% and 65.0%, respectively. WHO grade II 3-year OS and PFS were 83.4% and 70.1%, while WHO grade III 3-year OS and PFS were 33.3% and 0%. Recurrence rate was significantly higher in patients with a prior history of benign meningioma, nuclear atypia, high mitotic rate, spontaneous necrosis, and WHO grade III diagnosis on univariate analysis; only WHO grade III diagnosis was significant on multivariate analysis. Overall survival was adversely affected in patients with WHO grade III diagnosis, prior history of benign meningioma, prior fractionated radiotherapy, larger tumor volume, and higher isocenter number on univariate analysis; WHO grade III diagnosis and larger treated tumor volume were significant on multivariate analysis. Conclusion Atypical and anaplastic meningiomas remain difficult tumors to treat. WHO grade III diagnosis and treated tumor volume were significantly predictive of recurrence and survival on multivariate analysis in aggressive meningioma patients treated with radiosurgery. Larger tumor size predicts poor survival, while nuclear atypia, necrosis, and increased mitotic rate are risk factors for recurrence. Clinical and pathologic predictors may help identify patients that are at higher risk for recurrence.