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Shreya Swaminathan,1,* Jacob Ruzevick,1,* Vyshak Venur,2 Lia M Halasz,3 Jason Rockhill,3 Luis Gonzalez-Cuyar,4 Lee D Cranmer,2 Manuel Ferreira Jnr1 1Department of Neurological Surgery, The University of Washington School of Medicine, Seattle, WA, USA; 2Division of Medical Oncology, Department of Medicine, The University of Washington School of Medicine, Seattle, WA, USA; 3Department of Radiation Oncology, The University of Washington School of Medicine, Seattle, WA, USA; 4Department of Laboratory Medicine and Pathology, Division of Neuropathology, The University of Washington School of Medicine, Seattle, WA, USA*These authors contributed equally to this workCorrespondence: Lee D Cranmer, University of Washington School of Medicine, Division of Medical Oncology, 825 Eastlake Ave. East, LG-350, Seattle, WA, 98109, USA, Tel +1 206 606-7439, Email lcranmer@seattlecca.orgObjective: To provide benchmarks for further studies of solitary fibrous tumor/hemangiopericytoma (SFT/HPC) of the central nervous system (CNS), we investigated the association of baseline demographic, clinico-pathologic, and treatment factors with outcomes in those treated at our center.Methods: We conducted a retrospective, cohort analysis of patients treated for SFT/HPC at the University of Washington 1990– 2020. Kaplan-Meier and univariable Cox analyses assessed relationships between baseline variables and local or global CNS recurrence, extraneural recurrence, progression-free survival (PFS) and overall survival (OS).Results: Among 34 eligible patients, median duration of follow-up was 79 months (range 13– 318 months). Local and global CNS recurrence occurred at a median of 81 m (95% CI 48– 151) and 81 m (95% CI 47– 112), respectively. Extraneural metastases occurred at a median 248 m (95% CI 180-Not Reached) and only in grade 3 tumors. Median PFS and OS were 76 months (95% CI: 47– 109 months) and 210 months (95% CI 131– 306 months), respectively. Univariable Cox analyses showed that age at diagnosis was associated with local (p = 0.01) and global CNS relapse (p = 0.01), and PFS (p = 0.03). Gross total resection was associated with decreased local or global CNS relapse (p = 0.02) and improved PFS (p = 0.03); peri-operative radiation was associated with decreased local CNS relapse (p = 0.02).Conclusion: Following microsurgical resection of SFT/HPC, CNS relapse is common and associated with age, extent of resection, and adjuvant radiation. Extraneural relapse occurs in some patients. Delayed time-to-initial relapse justifies prolonged surveillance, but optimal approaches have not been defined.Keywords: solitary fibrous tumor, hemangiopericytoma, radiotherapy, embolization, adjuvant

Pediatric orbital and skull base pathologies encompass a spectrum of inflammatory, sporadic, syndromic, and neoplastic processes that require a broad and complex clinical approach for both medical and surgical treatment. Given their complexity and often multicompartment involvement, a multidisciplinary approach for diagnosis, patient and family counseling, and ultimately treatment provides the best patient satisfaction and clinical outcomes. Advances in minimally invasive surgical approaches, including endoscopic endonasal and transorbital approaches allows for more targeted surgical approaches through smaller corridors beyond more classic transcranial or transracial approaches., Competing Interests: Disclosure All authors confirm there are no commercial or financial conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: According to the 2017 World Health Organization classification of neuro-endocrine tumors, pituitary adenomas (PAs) are classified according to immunoexpression of the pituitary-specific transcription factors (TFs). A small subset of PAs exhibit multiple TF staining on immunohistochemistry and we present a series of 27 pathologically-confirmed cases of dual TF staining PAs (dsTF-PAs), and report clinically relevant implications., Methods: A retrospective chart review of a multi-institutional database of patients with PAs surgically resected between 2008-2021 was performed. PAs expressing immunopositivity 2+ TFs. Patient demographics, neuro-imaging characteristics, histopathologic findings, and clinical data were collected., Results: Twenty-seven patients had pathologically verified dsTF-PAs, of whom 17 were female (63%), with ages ranging from 20-84 years. Twenty-three (85.2%) patients harbored functional PAs, with acromegaly being the most common functional subtype (86.4%). The most common combination of TFs within a single tumor was PIT-1/SF-1 (85.2%). Six PAs exhibited Knosp cavernous sinus invasion grades of 3 or 4 and the Ki-67 labeling index was ≥3% in 6 patients (24.0%) and all stained for PIT-1/SF-1. Hormonal remission was achieved in 78% of functional dsTF-PAs. No PAs showed evidence of recurrence or progression over the mean follow-up period of 28.5 months., Conclusions: PAs exhibiting dsTF-PAs represent a small but clinically relevant diagnostic subset of PAs according to the 2021 World Health Organization criteria, as a majority are GH-producing. Precise classification using TF staining plays a key role in understanding the biology of these tumors. Favorable outcomes can be achieved in this subset of PAs with evolving TF classification., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion of human neocortex is marked by distinctive pyramidal neurons with extensive L1 branching, but whether L1 interneurons are similarly diverse is underexplored. Using Patch-seq recordings from human neurosurgical tissue, we identified four transcriptomic subclasses with mouse L1 homologs, along with distinct subtypes and types unmatched in mouse L1. Subclass and subtype comparisons showed stronger transcriptomic differences in human L1 and were correlated with strong morphoelectric variability along dimensions distinct from mouse L1 variability. Accompanied by greater layer thickness and other cytoarchitecture changes, these findings suggest that L1 has diverged in evolution, reflecting the demands of regulating the expanded human neocortical circuit.

Human cortex transcriptomic studies have revealed a hierarchical organization of γ-aminobutyric acid-producing (GABAergic) neurons from subclasses to a high diversity of more granular types. Rapid GABAergic neuron viral genetic labeling plus Patch-seq (patch-clamp electrophysiology plus single-cell RNA sequencing) sampling in human brain slices was used to reliably target and analyze GABAergic neuron subclasses and individual transcriptomic types. This characterization elucidated transitions between PVALB and SST subclasses, revealed morphological heterogeneity within an abundant transcriptomic type, identified multiple spatially distinct types of the primate-specialized double bouquet cells (DBCs), and shed light on cellular differences between homologous mouse and human neocortical GABAergic neuron types. These results highlight the importance of multimodal phenotypic characterization for refinement of emerging transcriptomic cell type taxonomies and for understanding conserved and specialized cellular properties of human brain cell types.

Introduction: Many patients with growth hormone-secreting pituitary adenoma (GHPA) fail to achieve biochemical remission, warranting investigation into epigenetic and molecular signatures associated with tumorigenesis and hormonal secretion. Prior work exploring the DNA methylome showed Myc-Associated Protein X (MAX), a transcription factor involved in cell cycle regulation, was differentially methylated between GHPA and nonfunctional pituitary adenoma (NFPA). We aimed to validate the differential DNA methylation and related MAX protein expression profiles between NFPA and GHPA., Methods: DNA methylation levels were measured in 52 surgically resected tumors (37 NFPA, 15 GHPA) at ~100,000 known MAX binding sites derived using ChIP-seq analysis from ENCODE. Findings were correlated with MAX protein expression using a constructed tissue microarray (TMA). Gene ontology analysis was performed to explore downstream genetic and signaling pathways regulated by MAX., Results: GHPA had more hypomethylation events across all known MAX binding sites. Of binding sites defined using ChIP-seq analysis, 1,551 sites had significantly different methylation patterns between the two cohorts; 432 occurred near promoter regions potentially regulated by MAX, including promoters of TNF and MMP9. Gene ontology analysis suggested enrichment in genes involved in oxygen response, immune system regulation, and cell proliferation. Thirteen MAX binding sites were within coding regions of genes. GHPA demonstrated significantly increased expression of MAX protein compared to NFPA., Conclusion: GHPA have significantly different DNA methylation and downstream protein expression levels of MAX compared to NFPA. These differences may influence mechanisms involved with cellular proliferation, tumor invasion and hormonal secretion., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Tucker et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Intraoperative use of the endoscope to assist in visualization of intracranial tumor pathology has expanded with increasing surgeon experience and improved instrumentation. The authors aimed to study how advancements in endoscopic technology have affected the evolution of endoscope use, with particular focus on blue light-filter modification allowing for discrimination of fluorescent tumor tissue following 5-ALA administration., Methods: A retrospective analysis of patients undergoing craniotomy for tumor resection at a single institution between February 2012 and July 2021 was performed. Patients were included if the endoscope was used for diagnostic tumor cavity inspection or therapeutic assistance with tumor resection following standard craniotomy and microsurgical tumor resection, with emphasis on those cases in which blue light endoscopy was used. Medical records were queried for patient demographics, operative reports describing the use of the endoscope and extent of resection, associations with tumor pathology, and postoperative outcomes. Preoperative and postoperative MR images were reviewed for radiographic extent of resection., Results: A total of 52 patients who underwent endoscope-assisted craniotomy for tumor were included. Thirty patients (57.7%) were men and the average age was 52.6 ± 16.1 years. Standard white light endoscopes were used for assistance with tumor resection in 28 cases (53.8%) for tumors primarily located in the ventricular system, parasellar region, and cerebellopontine angle. A blue light endoscope for detection of 5-ALA fluorescence was introduced into our practice in 2014 and subsequently used for assistance with tumor resection in 24 cases (46.2%) (intraaxial: n = 22, extraaxial: n = 2). Beyond the use of the surgical microscope as the primary visualization source, the blue light endoscope was used to directly perform additional tumor resection in 19/21 cases as a result of improved fluorescence detection as compared to the surgical microscope. No complications were associated with the use of the endoscope or with additional resection performed under white or blue light visualization., Conclusions: Endoscopic assistance to visualize intracranial tumors had previously been limited to white light, assisting mostly in the visualization of extraaxial tumors confined to intraventricular and cisternal compartments. Blue light-equipped endoscopes provide improved versatility and visualization of 5-ALA fluorescing tissue beyond the capability of the surgical microscope, thereby expanding its use into the realm of intraaxial tumor resections.

Background: The abscopal effect is a rare phenomenon whereby local radiation induces a proposed immune-mediated anti-tumor effect at distant sites. Given the growing use of immunotherapies and systemic immune checkpoint inhibitors in neuro-oncologic practice, we aimed to review prior studies pertaining to this phenomenon in the context of tumor shrinkage both within the central nervous system as well as distant disease sites., Methods: A systematic review in accordance with the PRISMA guidelines was conducted to identify all studies which assessed the abscopal effect in patients with treated metastatic cancer to the brain and/or spine. Articles were included if they reported the abscopal effect in patients (case studies) or if the abscopal effect was explicitly analyzed in case series with cohorts of patients with metastatic brain or spine tumors. Laboratory investigations and clinical trials investigating new therapies were excluded., Results: Twenty reports met inclusion criteria [16 case reports, 4 case series ( n = 160), total n = 174]. Case reports of the abscopal effect were in relation to the following cancers: melanoma (6 patients), breast cancer (3), lung adenocarcinoma (2), non-small-cell lung cancer (2), hepatocellular carcinoma (1), and renal cell carcinoma (1). Eleven patients had irradiation to the brain and 2 to the spine. Patients undergoing whole brain radiotherapy (6) had an average dose of 33.6 Gy over 8-15 fractions, and those undergoing stereotactic radiosurgery (5) had an average dose of 21.5 Gy over 1-5 fractions. One patient had radiation to the body and an intracranial abscopal effect was observed. Most common sites of extracranial tumor reduction were lung and lymph nodes. Ten case studies (57%) showed complete resolution of extra-CNS tumor burden. Median progression-free survival was 13 months following radiation. Four papers investigated incidence of abscopal effects in patients with metastatic melanoma to the brain who received immune checkpoint inhibitor therapy ( n = 160); two papers found an abscopal effect in 35% and 52% of patients ( n = 16, 21 respectively), and two papers found no evidence of abscopal effects ( n = 61, 62)., Conclusions: Abscopal effects can occur following radiotherapy in patients with brain or spine metastases and is thought to be a result of increased anti-tumor immunity. The potential for immune checkpoint inhibitor therapy to be used in combination with radiotherapy to induce an abscopal effect is an area of active investigation., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Purpose: Patterns of extension of pituitary adenomas (PA) may vary according to PA subtype. Understanding extrasellar extension patterns in growth hormone PAs (GHPA) vis-a-vis nonfunctional PAs (NFPAs) may provide insights into the biology of GHPA and future treatment avenues., Methods: Preoperative MR imaging (MRI) in 179 consecutive patients treated surgically for NFPA (n = 139) and GHPA (n = 40) were analyzed to determine patterns of extrasellar growth. Extension was divided into two principal directions: cranio-caudal (measured by infrasellar/suprasellar extension), and lateral cavernous sinus invasion (CSI) determined by Knosp grading score of 3-4. Suprasellar extension was defined as tumor extension superior to the tuberculum sellae- dorsum sellae line, and inferior extension as invasion through the sellar floor into the sphenoid sinus or clivus. Categorical analysis was performed using Fisher's exact test., Results: GHPAs were overall more likely to remain purely intrasellar compared to NFPA (50% vs 26%, p < 0.001). GHPAs, however, were 7 times more likely to exhibit isolated infrasellar extension compared to NFPA (20% vs 2.8%, p = 0.001). Conversely, NFPAs were twice as likely to exhibit isolated suprasellar extension compared to GHPA (60% vs 28%, p < 0.001), as well as combined suprasellar/infrasellar extension (25% vs 3%, p = 0.011). There were no overall differences in CSI between the two subgroups., Discussion: GHPA and NFPA demonstrate distinct extrasellar extension patterns on MRI. GHPAs show proclivity for inferior extension with bony invasion, whereas NFPAs are more likely to exhibit suprasellar extension through the diaphragmatic aperture. These distinctions may have implications into the biology and future treatment of PAs., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: 5-Aminolevulinic acid (5-ALA)-enhanced fluorescence-guided resection of high-grade glioma (HGG) using microscopic blue light visualization offers the ability to improve extent of resection (EOR); however, few descriptions of HGG resection performed using endoscopic blue light visualization are currently available. In this report, the authors sought to describe their surgical experience and patient outcomes of 5-ALA-enhanced fluorescence-guided resection of HGG using primary or adjunctive endoscopic blue light visualization., Methods: The authors performed a retrospective review of prospectively collected data from 30 consecutive patients who underwent 5-ALA-enhanced fluorescence-guided biopsy or resection of newly diagnosed HGG was performed. Patient demographic data, tumor characteristics, surgical technique, EOR, tumor fluorescence patterns, and progression-free survival were recorded., Results: In total, 30 newly diagnosed HGG patients were included for analysis. The endoscope was utilized for direct 5-ALA-guided port-based biopsy (n = 9), microscopic to endoscopic (M2E; n = 18) resection, or exoscopic to endoscopic (E2E; n = 3) resection. All endoscopic biopsies of fluorescent tissue were diagnostic. 5-ALA-enhanced tumor fluorescence was visible in all glioblastoma cases, but only in 50% of anaplastic astrocytoma cases and no anaplastic oligodendroglioma cases. Gross-total resection (GTR) was achieved in 10 patients in whom complete resection was considered safe, with 11 patients undergoing subtotal resection. In all cases, endoscopic fluorescence was more avid than microscopic fluorescence. The endoscope offered the ability to diagnose and resect additional tumor not visualized by the microscope in 83.3% (n = 10/12) of glioblastoma cases, driven by angled lenses and increased fluorescence facilitated by light source delivery within the cavity. Mean volumetric EOR was 90.7% in all resection patients and 98.8% in patients undergoing planned GTR. No complications were attributable to 5-ALA or blue light endoscopy., Conclusions: The blue light endoscope is a viable primary or adjunctive visualization platform for optimization of 5-ALA-enhanced HGG fluorescence. Implementation of the blue light endoscope to guide resection of HGG glioma is feasible and ergonomically favorable, with a potential advantage of enabling increased detection of tumor fluorescence in deep surgical cavities compared to the microscope.

Background Activating variants in platelet-derived growth factor receptor beta (PDGFRB), including a variant we have previously described (p.Tyr562Cys [g.149505130T>C [GRCh37/hg19]; c.1685A>G]), are associated with development of multiorgan pathology, including aneurysm formation. To investigate the association between the allele fraction genotype and histopathologic phenotype, we performed an expanded evaluation of post-mortem normal and aneurysmal tissue specimens from the previously published index patient. Methods and Results Following death due to diffuse subarachnoid hemorrhage in a patient with mosaic expression of the above PDGFRB variant, specimens from the intracranial, coronary, radial and aortic arteries were harvested. DNA was extracted and alternate allele fractions (AAF) of PDGFRB were determined using digital droplet PCR. Radiographic and histopathologic findings, together with genotype expression of PDGFRB were then correlated in aneurysmal tissue and compared to non-aneurysmal tissue. The PDGFRB variant was identified in the vertebral artery, basilar artery, and P1 segment aneurysms (AAF: 28.7%, 16.4%, and 17.8%, respectively). It was also identified in the coronary and radial artery aneurysms (AAF: 22.3% and 20.6%, respectively). In phenotypically normal intracranial and coronary artery tissues, the PDGFRB variant was not present. The PDGFRB variant was absent from lymphocyte DNA and normal tissue, confirming it to be a non-germline somatic variant. Primary cell cultures from a radial artery aneurysm localized the PDGFRB variant to CD31-, non-endothelial cells. Conclusions Constitutive expression of PDGFRB within the arterial wall is associated with the development of human fusiform aneurysms. The role of targeted therapy with tyrosine kinase inhibitors in fusiform aneurysms with PDGFRB mutations should be further studied.

Objective: The utility of robotic instrumentation is expanding in neurosurgery. Despite this, successful examples of robotic implementation for endoscopic endonasal or skull base neurosurgery remain limited. Therefore, the authors performed a systematic review of the literature to identify all articles that used robotic systems to access the sella or anterior, middle, or posterior cranial fossae., Methods: A systematic review of MEDLINE and PubMed in accordance with PRISMA guidelines performed for articles published between January 1, 1990, and August 1, 2021, was conducted to identify all robotic systems (autonomous, semiautonomous, or surgeon-controlled) used for skull base neurosurgical procedures. Cadaveric and human clinical studies were included. Studies with exclusively otorhinolaryngological applications or using robotic microscopes were excluded., Results: A total of 561 studies were identified from the initial search, of which 22 were included following full-text review. Transoral robotic surgery (TORS) using the da Vinci Surgical System was the most widely reported system (4 studies) utilized for skull base and pituitary fossa procedures; additionally, it has been reported for resection of sellar masses in 4 patients. Seven cadaveric studies used the da Vinci Surgical System to access the skull base using alternative, non-TORS approaches (e.g., transnasal, transmaxillary, and supraorbital). Five cadaveric studies investigated alternative systems to access the skull base. Six studies investigated the use of robotic endoscope holders. Advantages to robotic applications in skull base neurosurgery included improved lighting and 3D visualization, replication of more traditional gesture-based movements, and the ability for dexterous movements ordinarily constrained by small operative corridors. Limitations included the size and angulation capacity of the robot, lack of drilling components preventing fully robotic procedures, and cost. Robotic endoscope holders may have been particularly advantageous when the use of a surgical assistant or second surgeon was limited., Conclusions: Robotic skull base neurosurgery has been growing in popularity and feasibility, but significant limitations remain. While robotic systems seem to have allowed for greater maneuverability and 3D visualization, their size and lack of neurosurgery-specific tools have continued to prevent widespread adoption into current practice. The next generation of robotic technologies should prioritize overcoming these limitations.

Background: While it has been suspected that different primary cancers have varying predilections for metastasis in certain brain regions, recent advances in neuroimaging and spatial modeling analytics have facilitated further exploration into this field., Methods: A systematic electronic database search for studies analyzing the distribution of brain metastases (BMs) from any primary systematic cancer published between January 1990 and July 2020 was conducted using PRISMA guidelines., Results: Two authors independently reviewed 1957 abstracts, 46 of which underwent full-text analysis. A third author arbitrated both lists; 13 studies met inclusion/exclusion criteria. All were retrospective single- or multi-institution database reviews analyzing over 8227 BMs from 2599 patients with breast (8 studies), lung (7 studies), melanoma (5 studies), gastrointestinal (4 studies), renal (3 studies), and prostate (1 study) cancers. Breast, lung, and colorectal cancers tended to metastasize to more posterior/caudal topographic and vascular neuroanatomical regions, particularly the cerebellum, with notable differences based on subtype and receptor expression. HER-2-positive breast cancers were less likely to arise in the frontal lobes or subcortical region, while ER-positive and PR-positive breast metastases were less likely to arise in the occipital lobe or cerebellum. BM from lung adenocarcinoma tended to arise in the frontal lobes and squamous cell carcinoma in the cerebellum. Melanoma metastasized more to the frontal and temporal lobes., Conclusion: The observed topographical distribution of BM likely develops based on primary cancer type, molecular subtype, and genetic profile. Further studies analyzing this association and relationships to vascular distribution are merited to potentially improve patient treatment and outcomes., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland., (© 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.)

Emerging evidence suggest WHO grade III meningiomas that arise de novo as opposed to dedifferentiating from a lower grade may harbor differing prognoses. To investigate this, a single institution retrospective analysis of prospectively acquired patients between 1999 and 2018 was performed. Clinical data and radiographic parameters were reviewed to calculate progression free survival and overall survival in patients undergoing microsurgical resection. Next generation targeted sequencing of meningioma associated genes was performed on 11 tumors. Eighteen patients were identified as undergoing surgical resection of WHO grade III meningioma. Nine patients (50%) had de novo arising tumors and nine patients had secondary progressive tumors. To compare outcomes, only those patients undergoing gross total resection (Simpson grade I) were included for survival analysis. There was an improvement in median progression free survival for de novo resected tumors as compared to secondary progressive tumors (p = 0.02). Median overall survival for patients with de novo tumors was not statistically improved compared to that of secondary progressive tumors (p = 0.22). Next generation sequencing of targeted genes (NF2, BAP1, TRAF7, KLF4, SMO and AKT) revealed 5/11 tumors containing mutations in the NF2 gene, 2/11 containing BAP1 mutations, and a single tumor containing mutations in both NF2 and TRAF7. More mutations in NF2 and BAP1 were seen in the secondary progressive tumors. In conclusion, patients undergoing gross total resection for de novo arising grade III meningiomas showed improved progression free survival, though similar overall survival, as compared to those patients with secondary progressive tumors. Further studies focused on tumor associated genes and other associated risk factors are needed to improve risk-stratification., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Meningiomas are a heterogeneous group of tumors, defined histo-pathologically by World Health Organization (WHO) grading. The WHO grade of meningiomas does not always correlate with clinical aggressiveness. Despite maximal surgical resection and adjuvant radiation, a subset of tumors are clinically aggressive; displaying early recurrence and invasion. Current methods for identifying aggressive meningiomas solely focus on genomics, proteomics, or epigenetics and not a combination of all for developing a real-time clinical biomarker. Improved methods for the identification of these outlying tumors can facilitate better classification and potentially adjuvant treatment planning. Understanding the pathways of oncogenesis using multiple markers driving aggressive meningiomas can provide a foundation for targeted therapies, which currently do not exist., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare., (Copyright: © 2020 Nazem et al.)

Background: Intracranial hypotension is an underrecognized cause of spontaneous subdural hematoma. Failure to identify this entity and treat the underlying etiology can result in profoundly dangerous clinical consequences, prolonged and costly hospitalization, and caregiver fatigue, as seen in the case presented here., Case Description: We present a case of intracranial hypotension associated with a spontaneous cerebrospinal fluid (CSF) leak in the cervical spine leading to consistently reproducible herniation syndrome with head of bed elevation, and bilateral subdural hematomas as a result of a pressure gradient favoring downward migration of intracranial contents resulting in traction on bridging veins. This gradient promoted transtentorial herniation with resultant brainstem compression, leading to a prolonged intensive care unit stay, recurrent respiratory failure, and severe deconditioning. An exhaustive diagnostic workup uncovered a cervical root CSF leak with a nuclear medicine CSF flow study, which was successfully treated with nerve root ligation and dural closure. The patient recovered well postprocedurally and was able to return to baseline level of function., Conclusions: This case demonstrates the importance of considering intracranial hypotension in cases of positional herniation syndrome and the necessity for early and aggressive attempts at identifying and treating the underlying cause to prevent unnecessary neurologic dysfunction and protracted medical care., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To report on intra- and perioperative complications associated with working channel endoscopic spine surgery., Methods: This study is a retrospective chart review of a multi-institutional patient cohort operated on by surgeons within the Endoscopic Spine Study Group between May 2010 and June 2017., Results: Our study cohort consists of a total of 553 consecutive cases with an average age of 57 years. The most common procedure was an endoscopic discectomy (n = 377, 68%) followed by foraminotomy (n = 156, 28.2%), unilateral laminotomy for bilateral decompression (n = 55, 9.9%), and lateral recess decompression (n = 29, 5.2%). Overall, the rate of intra- and perioperative complications was 2.7%. There were 3 durotomies (0.54%), 2 epidural hematomas (0.36%), 2 patients developed a complex pain disorder (0.36%), 4 recurrent disc herniations within 3 months (1.1%), 4 systemic complications (1.1%), and no wound infections. No risk factors were identified with regards to age, sex, approach, or number of segments., Conclusions: Endoscopic spine surgery is associated with a favorable rate of intra- and perioperative complications compared with reported rates of minimally invasive ortraditional open spine surgeries. Our report proposes safe and effective strategies for management of these complications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Electric fields are known to produce biological effects. Depending on specific frequency, they can stimulate healing, directly damage tissues, or produce anti-mitotic activity. Frequencies of 100-300 KHz have been shown to disrupt mitosis and lead to cellular death. Growth of cancer cell lines, both in vitro and in vivo, was shown to be inhibited by application of the electric fields. In the clinical setting, electric fields are available for treatment of brain tumors, specifically glioblastoma (GBM), through a portable device producing so-called tumor treating fields (TTF). Clinical trials conducted in patients with recurrent and newly diagnosed GBM indicated that this novel treatment modality is active and associated with minimal toxicity. This manuscript will review the available evidence supporting the use of TTF in neuro-oncologic practice.

Head and neck paragangliomas are rare neuroendocrine tumors that arise from paraganglion cells of the parasympathetic nervous system. Paragangliomas arising from the midline skull base have only rarely been reported. Surgery is the mainstay of treatment and adjuvant radiation is often recommended. These tumors can rarely secrete metanephrines and normetanephrines which can complicate operative management. Here we present two cases of clival paragangliomas with unique clinical presentations and review the previous literature on skull base paragangliomas.

Purpose: Immune responses to antigens originating in the central nervous system (CNS) are generally attenuated, as collateral damage can have devastating consequences. The significance of this finding for the efficacy of tumor-targeted immunotherapies is largely unknown., Experimental Design: The B16 murine melanoma model was used to compare cytotoxic responses against established tumors in the CNS and in the periphery. Cytokine analysis of tissues from brain tumor-bearing mice detected elevated TGFβ secretion from microglia and in the serum and TGFβ signaling blockade reversed tolerance of tumor antigen-directed CD8 T cells. In addition, a treatment regimen using focal radiation therapy and recombinant Listeria monocytogenes was evaluated for immunologic activity and efficacy in this model., Results: CNS melanomas were more tolerogenic than equivalently progressed tumors outside the CNS as antigen-specific CD8 T cells were deleted and exhibited impaired cytotoxicity. Tumor-bearing mice had elevated serum levels of TGFβ; however, blocking TGFβ signaling with a small-molecule inhibitor or a monoclonal antibody did not improve survival. Conversely, tumor antigen-specific vaccination in combination with focal radiation therapy reversed tolerance and improved survival. This treatment regimen was associated with increased polyfunctionality of CD8 T cells, elevated T effector to T regulatory cell ratios, and decreased TGFβ secretion from microglia., Conclusions: These data suggest that CNS tumors may impair systemic antitumor immunity and consequently accelerate cancer progression locally as well as outside the CNS, whereas antitumor immunity may be restored by combining vaccination with radiation therapy. These findings are hypothesis-generating and warrant further study in contemporary melanoma models as well as human trials., (©2015 American Association for Cancer Research.)

Immune checkpoints have come to the forefront of cancer therapies as a powerful and promising strategy to stimulate antitumor T cell activity. Results from recent preclinical and clinical studies demonstrate how checkpoint inhibition can be utilized to prevent tumor immune evasion and both local and systemic immune suppression. This review encompasses the key immune checkpoints that have been found to play a role in tumorigenesis and, more specifically, gliomagenesis. The review will provide an overview of the existing preclinical and clinical data, antitumor efficacy, and clinical applications for each checkpoint with respect to GBM, as well as a summary of combination therapies with chemotherapy and radiation.

Background: The orbitozygomatic craniotomy is a fundamental procedure in neurosurgery, allowing access to orbital and skull base pathology., Objective: Determine the feasibility of using an ultrasonic osteotome to safely perform orbitozygomatic osteotomies in patients with intracranial pathology., Methods: The medical records of patients undergoing orbitozygomatic craniotomy using an ultrasonic osteotome (Aesculap BoneScalpel™) for tumor resection at Johns Hopkins Hospital between November 2009 and March 2013 were retrospectively reviewed., Results: Six patients underwent orbitozygomatic craniotomy for tumor resection using an ultrasonic osteotome at the Johns Hopkins Hospital during the study period. All patients were female and the average age was 53.2 years. Patients were followed for an average of 375 days. There were two cases of transient diplopia. There were no cases of periorbital violation, orbital injury, enophthalmos, or orbital hematoma. Post-operative imaging showed the cuts were well opposed and no cosmetic issues were encountered., Conclusion: Use of an ultrasonic osteotome allows for precise cuts under direct visualization with minimal risk to critical adjacent structures in our cohort of patients undergoing a two-piece orbitozygomatic craniotomy. This appears to be a safe instrument for osteotomy creation in skull base approaches., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Although uncommon, esthesioneuroblastomas may produce clinically significant amounts of catecholamines., Methods: We report a patient with a catecholamine-secreting esthesioneuroblastoma who developed an intraoperative hypertensive crisis., Results: A patient with a history of hypertension was referred to our skull base center for management of a residual esthesioneuroblastoma. A staged endonasal endoscopic approach was planned. At the conclusion of the first stage, a hypertensive crisis occurred. Workup revealed elevated levels of serum and urinary catecholamines. The patient was treated with alpha adrenoceptor blockade before the second stage. Serum catecholamine levels after this second stage were normal. On immunohistochemical analysis, the tumor cells were found to be positive for tyrosine hydroxylase, the rate limiting enzyme in catecholamine synthesis, and achaete-scute homologue 1, a transcription factor essential in the development of olfactory and sympathetic neurons., Conclusion: Catecholamine production should be considered in the differential of unexpected extreme hypertension during surgical resection of esthesioneuroblastoma., (© 2015 Wiley Periodicals, Inc.)

Pituitary adenomas are among the most common central nervous system tumors. They represent a diverse group of neoplasms that may or may not secrete hormones based on their cell of origin. Epidemiologic studies have documented the incidence of pituitary adenomas within the general population to be as high as 16.7%. A growing body of work has helped to elucidate the pathogenesis of these tumors. Each subtype has been shown to demonstrate unique cellular changes potentially leading to tumorigenesis. Surgical advancements over several decades have included microsurgery and the employment of the endoscope for surgical resection. These advancements increase the likelihood of gross-total resection and have resulted in decreased patient morbidity.

Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas.

The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.

Background: Glioblastoma (GBM) is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA-4) blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137) is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model., Methods: GL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain-infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors., Results: Mice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long-term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response., Conclusion: Combination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy improves survival in an orthotopic mouse model of glioma by a CD4+ T cell dependent mechanism and generates antigen-specific memory.

A familiar challenge for neuroradiologists and neuro-oncologists is differentiating between radiation treatment effect and disease progression in the CNS. Both entities are characterized by an increase in contrast enhancement on MRI and present with similar clinical signs and symptoms that may occur either in close temporal proximity to the treatment or later in the disease course. When radiation-related imaging changes or clinical deterioration are mistaken for disease progression, patients may be subject to unnecessary surgery and/or a change from otherwise effective therapy. Similarly, when disease progression is mistaken for treatment effect, a potentially ineffective therapy may be continued in the face of progressive disease. Here we describe the three types of radiation injury to the brain based on the time to development of signs and symptoms--acute, subacute and late--and then review specific imaging changes after intensity-modulated radiation therapy, stereotactic radiosurgery and brachytherapy. We provide an overview of these phenomena in the treatment of a wide range of malignant and benign CNS illnesses. Finally, we review the published data regarding imaging techniques under investigation to address this well-known problem.

Background and Purpose: Extravascular optical coherence tomography (OCT), as a noninvasive imaging methodology with micrometer resolution, was evaluated in a murine model of carotid atherosclerosis by way of assessing the efficacy of pravastatin therapy., Methods: An OCT device was engineered for extravascular plaque imaging. Wild-type mice and apolipoprotein E-deficient (ApoE(-/-)) mice were randomized to 3 treatment groups: (1) wild-type on a diet of standard rodent chow (n=13); (2) ApoE(-/-) on a high-fat, atherosclerotic diet (HFD; n=13); and (3) ApoE(-/-) on a HFD given daily pravastatin (n=13). Mice were anesthetized and the left common carotid was surgically exposed. Three-dimensional (3D; 2 spatial dimensions+time) and 4D (3 spatial dimensions+time) OCT images of the vessel lumen patency were evaluated. After perfusion, in situ OCT imaging was performed for statistical comparison with the in vivo results and final histology., Results: Intraoperative OCT imaging positively identified carotid plaque in 100% of ApoE(-/-) mice on HFD. ApoE(-/-) mice on HFD had a significantly decreased lumen patency when compared with that in wild-type mice (P<0.001). Pravastatin therapy was found to increase lumen patency significantly in ApoE(-/-) mice on HFD (P<0.01; compared with ApoE(-/-) on HFD). The findings were confirmed with OCT imaging after perfusion and histology., Conclusions: OCT imaging offers the potential for real-time, detailed vessel lumen evaluation, potentially improving surgical accuracy and outcomes during cerebrovascular neurosurgical procedures. Pravastatin significantly increases vessel lumen patency in the ApoE(-/-) mouse on HFD.

Stereotactic radiosurgery has become standard adjuvant treatment for patients with metastatic intracranial lesions. There has been a growing appreciation for benign imaging changes following radiation that are difficult to distinguish from true tumor progression. These imaging changes, termed pseudoprogression, carry significant implications for patient management. In this review, we discuss the current understanding of pseudoprogression in metastatic brain lesions, research to differentiate pseudoprogression from true progression, and clinical implications of pseudoprogression on treatment decisions.

Signal transducer and activator of transcription 3 (STAT3) is a potent regulator of gliomagenesis through its induction of angiogenesis, host immunosuppression, and tumor invasion. Gain of function mutations result in constitutive activation of STAT3 in glioma cells, making STAT3 an attractive target for inhibition in cancer therapy. Nevertheless, some studies show that STAT3 also participates in terminal differentiation and apoptosis of various cell lines and in glioma with phosphatase and tensin homolog (PTEN)-deficient genetic backgrounds. In light of these findings, the utility of STAT3 as a prognostic indicator and as a target of drug therapies will be contingent on a more nuanced understanding of its pro- and anti-tumorigenic effects.

Chordomas are rare primary bone tumors that occur along the neuraxis. Primary treatment is surgery, often followed by radiotherapy. Treatment options for patients with recurrence are limited and, notably, there are no FDA approved therapeutic agents. Development of therapeutic options has been limited by the paucity of preclinical model systems. We have established and previously reported the initial characterization of the first patient-derived chordoma xenograft model. In this study, we further characterize this model and demonstrate that it continues to resemble the original patient tumor histologically and immunohistochemically, maintains nuclear expression of brachyury, and is highly concordant with the original patient tumor by whole genome genotyping. Pathway analysis of this xenograft demonstrates activation of epidermal growth factor receptor (EGFR). In vitro studies demonstrate that two small molecule inhibitors of EGFR, erlotinib and gefitinib, inhibit proliferation of the chordoma cell line U-CH 1. We further demonstrate that erlotinib significantly inhibits chordoma growth in vivo. Evaluation of tumors post-treatment reveals that erlotinib reduces phosphorylation of EGFR. This is the first demonstration of antitumor activity in a patient-derived chordoma xenograft model and these findings support further evaluation of EGFR inhibitors in this disease.

Purpose: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model., Methods and Materials: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen., Results: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms., Conclusions: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM., (Copyright © 2013 Elsevier Inc. All rights reserved.)