The choroid plexus links innate immunity to CSF dysregulation in hydrocephalus.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.

Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression.

Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM immune microenvironment during tumor evolution and standard of care treatments is limited. Using single-cell transcriptomics and flow cytometry, we unveiled large-scale comprehensive longitudinal changes in immune cell composition throughout tumor progression in an epidermal growth factor receptor-driven genetic mouse GBM model. We identified subsets of proinflammatory microglia in developing GBMs and anti-inflammatory macrophages and protumorigenic myeloid-derived suppressors cells in end-stage tumors, an evolution that parallels breakdown of the blood-brain barrier and extensive growth of epidermal growth factor receptor+ GBM cells. A similar relationship was found between microglia and macrophages in patient biopsies of low-grade glioma and GBM. Temozolomide decreased the accumulation of myeloid-derived suppressor cells, whereas concomitant temozolomide irradiation increased intratumoral GranzymeB+ CD8+T cells but also increased CD4+ regulatory T cells. These results provide a comprehensive and unbiased immune cellular landscape and its evolutionary changes during GBM progression.

An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma.

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.

Co-transplantation of autologous Treg cells in a cell therapy for Parkinson's disease.

The specific loss of midbrain dopamine neurons (mDANs) causes major motor dysfunction in Parkinson's disease, which makes cell replacement a promising therapeutic approach1-4. However, poor survival of grafted mDANs remains an obstacle to successful clinical outcomes5-8. Here we show that the surgical procedure itself (referred to here as 'needle trauma') triggers a profound host response that is characterized by acute neuroinflammation, robust infiltration of peripheral immune cells and brain cell death. When midbrain dopamine (mDA) cells derived from human induced pluripotent stem (iPS) cells were transplanted into the rodent striatum, less than 10% of implanted tyrosine hydroxylase (TH)+ mDANs survived at two weeks after transplantation. By contrast, TH- grafted cells mostly survived. Notably, transplantation of autologous regulatory T (Treg) cells greatly modified the response to needle trauma, suppressing acute neuroinflammation and immune cell infiltration. Furthermore, intra-striatal co-transplantation of Treg cells and human-iPS-cell-derived mDA cells significantly protected grafted mDANs from needle-trauma-associated death and improved therapeutic outcomes in rodent models of Parkinson's disease with 6-hydroxydopamine lesions. Co-transplantation with Treg cells also suppressed the undesirable proliferation of TH- grafted cells, resulting in more compact grafts with a higher proportion and higher absolute numbers of TH+ neurons. Together, these data emphasize the importance of the initial inflammatory response to surgical injury in the differential survival of cellular components of the graft, and suggest that co-transplanting autologous Treg cells effectively reduces the needle-trauma-induced death of mDANs, providing a potential strategy to achieve better clinical outcomes for cell therapy in Parkinson's disease.

Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma.

In this first-in-human, investigator-initiated, open-label study, three participants with recurrent glioblastoma were treated with CARv3-TEAM-E T cells, which are chimeric antigen receptor (CAR) T cells engineered to target the epidermal growth factor receptor (EGFR) variant III tumor-specific antigen, as well as the wild-type EGFR protein, through secretion of a T-cell-engaging antibody molecule (TEAM). Treatment with CARv3-TEAM-E T cells did not result in adverse events greater than grade 3 or dose-limiting toxic effects. Radiographic tumor regression was dramatic and rapid, occurring within days after receipt of a single intraventricular infusion, but the responses were transient in two of the three participants. (Funded by Gateway for Cancer Research and others; INCIPIENT ClinicalTrials.gov number, NCT05660369.).

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease.

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

A rapid genotyping panel for detection of primary central nervous system lymphoma.

Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N = 1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0 to 617 days. Permanent histopathology confirmed PCNSL in 142 of 152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% confidence interval [CI]: 44.1% to 70.4% and 87.2% to 100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2%-74.5% and 83.9%-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

County-level disparities in care for patients with glioblastoma.

OBJECTIVE: Racial and socioeconomic disparities in neuro-oncological care for patients with brain tumors remain underexplored. This study aimed to analyze county-level disparities in glioblastoma (GBM) care in the United States, focusing on access to surgery and the use of adjuvant temozolomide chemotherapy and radiation therapy. METHODS: Using repeated cross-sectional data from the Surveillance, Epidemiology, and End Results 17 database; the Area Health Resources File; and the American Community Survey, from 2010 to 2019, the authors performed multivariate regression analyses to understand the associations between county-level racial and socioeconomic characteristics, as well as the rates of surgery performed, delays in surgery, and use of adjuvant chemotherapy and radiation therapy for newly diagnosed GBM. RESULTS: In total, 29,609 GBM patients from 602 different US counties over a decade were included in this study. Counties with lower rates of surgery for GBM were associated with a higher percentage of Black residents (coefficient [CE] -0.001, 95% CI -0.002 to 0; p < 0.05) and being located in the Midwest (CE -0.132, 95% CI -0.195 to -0.069; p < 0.001) or West (CE -0.127, 95% CI -0.189 to -0.065; p < 0.001) relative to the Northeast. Counties with delayed surgical treatment were more likely to lack neurosurgeons (adjusted OR [aOR] 2.52, 95% CI 1.77-3.60; p < 0.001), have a higher percentage of Black residents (aOR 1.011, 95% CI 1.00-1.02; p < 0.05), and be located in the Midwest (aOR 3.042, 95% CI 1.12-8.24; p < 0.05) or West (aOR 3.175, 95% CI 1.12-8.97 p < 0.05). Counties with high rates of adjuvant radiation therapy were less likely to have higher percentages of Black residents (aOR 0.987, 95% CI 0.980-0.995; p < 0.01) and uninsured individuals (aOR 0.962, 95% CI 0.937-0.987; p < 0.01). CONCLUSIONS: Counties without neurosurgeons and those with a higher percentage of Black patients have delays in surgical care and demonstrate lower overall rates of surgery and adjuvant therapy for GBM. This study underscores the need for targeted interventions and policies that address structural barriers in healthcare access, improve equitable distribution of the neurosurgery workforce, and ensure timely and comprehensive GBM care to all populations.

Clinical outcomes as a function of the number of samples taken during stereotactic needle biopsies: a meta-analysis.

BACKGROUND: Stereotactic needle biopsy remains the cornerstone for tissue diagnosis for tumors located in regions of the brain that are difficult to access through open surgery. OBJECTIVE: We perform a meta-analysis of the literature to examine the relation between number of samples taken during biopsy and diagnostic yield, morbidity and mortality. METHODS: We identified 2416 patients from 28 cohorts in studies published in PubMed database that studied stereotactic needle biopsies for tumor indications. Meta-analysis by proportions and meta-regression analyses were performed. RESULTS: On meta-analysis, the morbidity profile of the published needle biopsy studies clustered into three groups: studies that performed < 3 samples (n = 8), 3-6 samples (n = 13), and > 6 samples during biopsy (n = 7). Pooled estimates for biopsy related morbidity were 4.3%, 16.3%, and 17% for studies reporting < 3, 3-6, and > 6 biopsy samples, respectively. While these morbidity estimates significantly differed (p < 0.001), the diagnostic yields reported for studies performing < 3 biopsies, 3-6 samples, and > 6 samples were comparable. Pooled estimates of diagnostic yield for these three groups were 90.4%, 93.8%, and 88.1%, respectively. Mortality did not significantly differ between studies reporting differing number of samples taken during biopsy. CONCLUSIONS: Our meta-analysis suggests that morbidity risk in needle biopsy is non-linearly associated with the number of samples taken. There was no association between the number of biopsies taken, and diagnostic yield or mortality.

From laboratory to clinic: Translation of extracellular vesicle based cancer biomarkers.

The past decade has witnessed a rapid growth in the field of extracellular vesicle (EV) based biomarkers for the diagnosis and monitoring of cancer. Several studies have reported novel EV based biomarkers, but the technical and clinical validation phase has been hampered by general challenges common to biomedical research field as well as specific challenges inherent to the nanoparticle field. This has led to more common failures than success stories in the biomarker discovery pipeline. As a result, more attention must be focused on the process of biomarker discovery, verification, and validation to allow for translation and application of novel EV based research to patient care. Herein, we briefly discuss the hurdles and potential solutions in EV biomarker discovery and verification and validation, and clinical translation.

Glioblastomas located in proximity to the subventricular zone (SVZ) exhibited enrichment of gene expression profiles associated with the cancer stem cell state.

INTRODUCTION: Conflicting results have been reported in the association between glioblastoma proximity to the subventricular zone (SVZ) and enrichment of cancer stem cell properties. Here, we examined this hypothesis using magnetic resonance (MR) images derived from 217 The Cancer Imaging Archive (TCIA) glioblastoma subjects. METHODS: Pre-operative MR images were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Distances were calculated from the centroid of CE tumor volumes to the SVZ and correlated with gene expression profiles of the corresponding glioblastomas. Correlative analyses were performed between SVZ distance, gene expression patterns, and clinical survival. RESULTS: Glioblastoma located in proximity to the SVZ showed increased mRNA expression patterns associated with the cancer stem-cell state, including CD133 (P = 0.006). Consistent with the previous observations suggesting that glioblastoma stem cells exhibit increased DNA repair capacity, glioblastomas in proximity to the SVZ also showed increased expression of DNA repair genes, including MGMT (P = 0.018). Reflecting this enhanced DNA repair capacity, the genomes of glioblastomas in SVZ proximity harbored fewer single nucleotide polymorphisms relative to those located distant to the SVZ (P = 0.003). Concordant with the notion that glioblastoma stem cells are more aggressive and refractory to therapy, patients with glioblastoma in proximity to SVZ exhibited poorer progression free and overall survival (P < 0.01). CONCLUSION: An unbiased analysis of TCIA suggests that glioblastomas located in proximity to the SVZ exhibited mRNA expression profiles associated with stem cell properties, increased DNA repair capacity, and is associated with poor clinical survival.

Correlation Structure in Micro-ECoG Recordings is Described by Spatially Coherent Components.

Electrocorticography (ECoG) is becoming more prevalent due to improvements in fabrication and recording technology as well as its ease of implantation compared to intracortical electrophysiology, larger cortical coverage, and potential advantages for use in long term chronic implantation. Given the flexibility in the design of ECoG grids, which is only increasing, it remains an open question what geometry of the electrodes is optimal for an application. Conductive polymer, PEDOT:PSS, coated microelectrodes have an advantage that they can be made very small without losing low impedance. This makes them suitable for evaluating the required granularity of ECoG recording in humans and experimental animals. We used two-dimensional (2D) micro-ECoG grids to record intra-operatively in humans and during acute implantations in mouse with separation distance between neighboring electrodes (i.e., pitch) of 0.4 mm and 0.2/0.25 mm respectively. To assess the spatial properties of the signals, we used the average correlation between electrodes as a function of the pitch. In agreement with prior studies, we find a strong frequency dependence in the spatial scale of correlation. By applying independent component analysis (ICA), we find that the spatial pattern of correlation is largely due to contributions from multiple spatially extended, time-locked sources present at any given time. Our analysis indicates the presence of spatially structured activity down to the sub-millimeter spatial scale in ECoG despite the effects of volume conduction, justifying the use of dense micro-ECoG grids.

Correction to: Is the new ASNM intraoperative neuromonitoring supervision "guideline" a trustworthy guideline? A commentary.

The article Is the new ASNM intraoperative neuromonitoring supervision "guideline" a trustworthy guideline? A commentary, written by Stanley A. Skinner, Elif Ilgaz Aydinlar, Lawrence F. Borges, Bob S. Carter, Bradford L. Currier, Vedran Deletis, Charles Dong, John Paul Dormans, Gea Drost, Isabel Fernandez­Conejero, E. Matthew Hoffman, Robert N. Holdefer, Paulo Andre Teixeira Kimaid, Antoun Koht, Karl F. Kothbauer, David B. MacDonald, John J. McAuliffe III, David E. Morledge, Susan H. Morris, Jonathan Norton, Klaus Novak, Kyung Seok Park, Joseph H. Perra, Julian Prell, David M. Rippe, Francesco Sala, Daniel M. Schwartz, Martín J. Segura, Kathleen Seidel, Christoph Seubert, Mirela V. Simon, Francisco Soto, Jeffrey A. Strommen, Andrea Szelenyi, Armando Tello, Sedat Ulkatan, Javier Urriza and Marshall Wilkinson, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 05 January 2019 without open access. With the author(s)' decision to opt for Open Choice the copyright of the article changed on 30 January 2019 to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made. The original article has been corrected.

Navigating the Landscape of Tumor Extracellular Vesicle Heterogeneity.

The last decade has seen a rapid expansion of interest in extracellular vesicles (EVs) released by cells and proposed to mediate intercellular communication in physiological and pathological conditions. Considering that the genetic content of EVs reflects that of their respective parent cell, many researchers have proposed EVs as a source of biomarkers in various diseases. So far, the question of heterogeneity in given EV samples is rarely addressed at the experimental level. Because of their relatively small size, EVs are difficult to reliably isolate and detect within a given sample. Consequently, standardized protocols that have been optimized for accurate characterization of EVs are lacking despite recent advancements in the field. Continuous improvements in pre-analytical parameters permit more efficient assessment of EVs, however, methods to more objectively distinguish EVs from background, and to interpret multiple single-EV parameters are lacking. Here, we review EV heterogeneity according to their origin, mode of release, membrane composition, organelle and biochemical content, and other factors. In doing so, we also provide an overview of currently available and potentially applicable methods for single EV analysis. Finally, we examine the latest findings from experiments that have analyzed the issue at the single EV level and discuss potential implications.

Sub-millimeter ECoG pitch in human enables higher fidelity cognitive neural state estimation.

Electrocorticography (ECoG), electrophysiological recording from the pial surface of the brain, is a critical measurement technique for clinical neurophysiology, basic neurophysiology studies, and demonstrates great promise for the development of neural prosthetic devices for assistive applications and the treatment of neurological disorders. Recent advances in device engineering are poised to enable orders of magnitude increase in the resolution of ECoG without comprised measurement quality. This enhancement in cortical sensing enables the observation of neural dynamics from the cortical surface at the micrometer scale. While these technical capabilities may be enabling, the extent to which finer spatial scale recording enhances functionally relevant neural state inference is unclear. We examine this question by employing a high-density and low impedance 400 µm pitch microECoG (µECoG) grid to record neural activity from the human cortical surface during cognitive tasks. By applying machine learning techniques to classify task conditions from the envelope of high-frequency band (70-170Hz) neural activity collected from two study participants, we demonstrate that higher density grids can lead to more accurate binary task condition classification. When controlling for grid area and selecting task informative sub-regions of the complete grid, we observed a consistent increase in mean classification accuracy with higher grid density; in particular, 400 µm pitch grids outperforming spatially sub-sampled lower density grids up to 23%. We also introduce a modeling framework to provide intuition for how spatial properties of measurements affect the performance gap between high and low density grids. To our knowledge, this work is the first quantitative demonstration of human sub-millimeter pitch cortical surface recording yielding higher-fidelity state estimation relative to devices at the millimeter-scale, motivating the development and testing of µECoG for basic and clinical neurophysiology as well as towards the realization of high-performance neural prostheses.

Chimeric antigen receptor T-cell immunotherapy for glioblastoma: practical insights for neurosurgeons.

The prognosis for glioblastoma (GBM) remains exceedingly poor despite state-of-the-art multimodal therapy. Immunotherapy, particularly with cytotoxic T cells, represents a promising alternative. Perhaps the most prominent T-cell technology is the chimeric antigen receptor (CAR), which in 2017 received accelerated approval from the Food and Drug Administration for the treatment of hematological malignancies. Several CARs for GBM have been recently tested in clinical trials with exciting results. The authors review these clinical data and discuss areas of ongoing research.

Post-operative imaging assessment of non-functioning pituitary adenomas.

BACKGROUND: Non-functioning pituitary adenomas (NFAs) are the most common pituitary tumors. There is significant variability in clinical practice in terms of post-operative imaging evaluation. The objective of this manuscript is to provide an exhaustive review of published articles pertaining to the post-operative imaging evaluation of NFAs. METHODS: The MEDLINE database was queried for studies investigating imaging for the post-operative evaluation of pituitary adenomas. From an initial search of 5589 articles, 37 articles were evaluated in detail and included in this review. RESULTS: Magnetic resonance imaging (MRI) is the gold standard for post-operative monitoring of NFAs, although functional imaging modalities may improve identification of residual tumor in conjunction with MRI. The residual tumor can be distinguished from post-operative changes by experienced practitioners using high-resolution MRI in the immediate post-operative setting (within 1 week of surgery). However, continued imaging evolution in the appearance of residual tumor or resection cavity is expected up to 3 months post-operatively. CONCLUSIONS: Post-operative imaging appearance of the pituitary gland, optic apparatus, and pneumocephalus patterns, correlated with the clinical outcomes. Long-term, lifetime follow-up is warranted for NFA patients who underwent surgical resection.

Impact of medical academic genealogy on publication patterns: An analysis of the literature for surgical resection in brain tumor patients.

"Academic genealogy" refers to the linking of scientists and scholars based on their dissertation supervisors. We propose that this concept can be applied to medical training and that this "medical academic genealogy" may influence the landscape of the peer-reviewed literature. We performed a comprehensive PubMed search to identify US authors who have contributed peer-reviewed articles on a neurosurgery topic that remains controversial: the value of maximal resection for high-grade gliomas (HGGs). Training information for each key author (defined as the first or last author of an article) was collected (eg, author's medical school, residency, and fellowship training). Authors were recursively linked to faculty mentors to form genealogies. Correlations between genealogy and publication result were examined. Our search identified 108 articles with 160 unique key authors. Authors who were members of 2 genealogies (14% of key authors) contributed to 38% of all articles. If an article contained an authorship contribution from the first genealogy, its results were more likely to support maximal resection (log odds ratio = 2.74, p < 0.028) relative to articles without such contribution. In contrast, if an article contained an authorship contribution from the second genealogy, it was less likely to support maximal resection (log odds ratio = -1.74, p < 0.026). We conclude that the literature on surgical resection for HGGs is influenced by medical academic genealogies, and that articles contributed by authors of select genealogies share common results. These findings have important implications for the interpretation of scientific literature, design of medical training, and health care policy.

Survival trends of oligodendroglial tumor patients and associated clinical practice patterns: a SEER-based analysis.

There is limited information on the management strategies and survival trends for oligodendroglioma patients. Here we used the Surveillance, Epidemiology and End Results (SEER, 1999-2012) database to analyze the historical trends of oligodendroglioma patient survival and correlate these trends to evolving clinical practice of radiation therapy (RT) use and surgical practice of gross total resection (GTR). We identified 2689 World Health Organization (WHO) grade II oligodendroglioma (abbreviated as O2) and 1191 WHO grade III oligodendroglioma (abbreviated as O3). Time-trend analyses were performed for overall survival, radiation treatment (RT) use, and extent of surgical resection (EOR). In multivariable Cox models that accounted for age, race, sex, tumor size, tumor location, EOR, and RT status, the hazard of dying from O3 has significantly decreased over the study period (p  <  0.01), while the hazard of dying from O2 has remained largely unchanged. A search of the published literature revealed articles reporting results largely supportive of these observations. The pattern of surgical practice and RT for O3 patients remained unchanged throughout the study period, suggesting that the survival improvement may be related to evolving patterns of medical management. Results from the SEER database indicate significant gains have been made in survival for O3 patients between 1999 and 2012. Such gains were not observed for O2 patients during this study period.

Clinical efficacy and safety of surface imaging guided radiosurgery (SIG-RS) in the treatment of benign skull base tumors.

Frameless, surface imaging guided radiosurgery (SIG-RS) is a novel platform for stereotactic radiosurgery (SRS) wherein patient positioning is monitored in real-time through infra-red camera tracking of facial topography. Here we describe our initial clinical experience with SIG-RS for the treatment of benign neoplasms of the skull base. We identified 48 patients with benign skull base tumors consecutively treated with SIG-RS at a single institution between 2009 and 2011. Patients were diagnosed with meningioma (n = 22), vestibular schwannoma (n = 20), or nonfunctional pituitary adenoma (n = 6). Local control and treatment-related toxicity were retrospectively assessed. Median follow-up was 65 months (range 61-72 months). Prescription doses were 12-13 Gy in a single fraction (n = 18), 8 Gy × 3 fractions (n = 6), and 5 Gy × 5 fractions (n = 24). Actuarial tumor control rate at 5 years was 98%. No grade ≥3 treatment-related toxicity was observed. Grade ≤2 toxicity was associated with symptomatic lesions (p = 0.049) and single fraction treatment (p = 0.005). SIG-RS for benign skull base tumors produces clinical outcomes comparable to conventional frame-based SRS techniques while enhancing patient comfort.