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OBJECTIVE The supplemented Spetzler-Martin (Supp-SM) grading system was developed to improve the predictive accuracy of surgical risk for patients with brain arteriovenous malformations (AVMs). The aim of this study was to apply the Supp-SM grading system to patients having stereotactic radiosurgery (SRS) for Spetzler-Martin (SM) intermediate- (grade III) or high-grade (grade IV–V) AVMs to enable comparison with published microsurgical series. METHODS In 219 patients who underwent SRS during the period from 1990 to 2016, the Supp-SM grade was calculated for SM grade III (n = 154) or SM grade IV–V (n = 65) AVMs. The Supp-SM grades in these patients were 4 (n = 14, 6%), 5 (n = 36, 16%), 6 (n = 67, 31%), 7 (n = 76, 35%), and 8–9 (n = 26, 12%). Sixty patients (27%) had deep AVMs (basal ganglia, thalamus, or brainstem). Thirty-nine patients (18%) had volume-staged SRS; 41 patients (19%) underwent repeat SRS. The median follow-up period was 69 months for SM grade III AVMs and 113 months for SM grade IV–V AVMs. RESULTS AVM obliteration was confirmed in 163 patients (74%) at a median of 38 months after initial SRS. The obliteration rates at 4 and 8 years were 59% and 76%, respectively. Thirty-one patients (14%) had post-SRS deficits from hemorrhage (n = 7, 3%) or radiation injury (n = 24, 11%). Six patients (3%) died after SRS (hemorrhage, n = 5; radiation injury, n = 1). The rates of neurological decline or death at 4 and 8 years were 11% and 18%, respectively. Factors predictive of nonobliteration were deep location (HR 0.57, 95% CI 0.39–0.82, p = 0.003) and increasing AVM volume (HR 0.96, 95% CI 0.93–0.99, p = 0.002). Increasing AVM volume was the only factor associated with neurological decline (HR 1.05, 95% CI 1.02–1.08, p = 0.002). The Supp-SM grading score did not correlate with either obliteration (HR 0.94, 95% CI 0.82–1.09, p = 0.43) or neurological decline (HR 1.15, 95% CI 0.84–1.56, p = 0.38). CONCLUSIONS The Supp-SM grading system was not predictive of outcomes after SRS of intermediate- or high-grade AVM. In a cohort that included a high percentage (47%) of "inoperable" AVMs according to Supp-SM grade (≥ 7), most patients had obliteration after SRS, although there was a high risk of neurological decline.

Background H3K27-altered diffuse midline glioma (DMG) is the deadliest pediatric brain tumor; despite intensive research efforts, every clinical trial to date has failed. Is this because we are choosing the wrong drugs? Or are drug delivery and other pharmacokinetic variables at play? We hypothesize that the answer is likely a combination, where optimization may result in a much needed novel therapeutic approach. Methods We used in vitro drug screening, patient samples, and shRNA knockdown models to identify an upregulated target in DMG. A single small molecule protein kinase inhibitor with translational potential was selected for systemic and direct, loco-regional delivery to patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM). Pharmacokinetic studies were conducted in non-tumor bearing rats. Results Aurora kinase (AK) inhibitors demonstrated strong antitumor effects in DMG drug screens. Additional in vitro studies corroborated the importance of AK to DMG survival. Systemic delivery of alisertib showed promise in subcutaneous PDX but not intracranial GEMM and PDX models. Repeated loco-regional drug administration into the tumor through convection-enhanced delivery (CED) was equally inefficacious, and pharmacokinetic studies revealed rapid clearance of alisertib from the brain. In an effort to increase the drug to tumor residence time, continuous CED over 7 days improved drug retention in the rodent brainstem and significantly extended survival in both orthotopic PDXs and GEMMs. Conclusions These studies provide evidence for increasing drug-tumor residence time of promising targeted therapies via extended CED as a valuable treatment strategy for DMG.

Background Gonadotroph pituitary adenoma (Gn-PA) may rarely cause ovarian hyperstimulation syndrome, leading to infertility in women, although this remains poorly described. Methods We present a quantitative systematic review including 2 patients from our institutional and 48 from the literature with Gn-PA causing ovarian hyperstimulation syndrome to thoroughly describe the clinical features and therapeutic outcomes from multidisciplinary aspects. Results The patients had a mean age of 31.5 years and a mean follicle-stimulating hormone level of 14.4 IU/L. Estradiol level was high in 82% of patients, at >350 pg/mL. The mean maximal adenoma diameter was 22 mm, with a Knosp grade ≥3 in 10 patients. Abdominal surgery preceded adenoma resection in 24 patients (48%). Among 25 patients for whom extent of resection was recorded, total adenoma resection was achieved in 12. Through a mean follow-up of 25 months, adenoma recurrence was observed in 5 patients, who were treated with re-resection (n = 2), radiation (n = 2), and medical therapy followed by bilateral oophorectomy (n = 1). Medical therapies were partially effective or ineffective, and adenoma shrinkage did not follow; gonadotropin-releasing hormone agonists/antagonists were partially effective in 20% of patients (2/10), dopamine agonists in 44% (8/18), and somatostatin analogues in 50% (1/2). Four experienced swelling of tumor/ovaries after gonadotropin-releasing hormone agonists/antagonists administration. Overall, chemical remission was obtained in 26 of 28 patients, normalization of ovaries in 25 of 27, and successful pregnancy in 12 of 14. Conclusions Adenoma resection is the main treatment, leading to reduction in ovarian size and biochemical remission, with a high likelihood of subsequent spontaneous pregnancy. Increased awareness of this rare condition may help avoid unnecessary abdominal procedures.

OBJECTIVEGlioblastoma (GBM) during infancy is rare, and the clinical outcomes of congenital GBM are not well understood. Correspondingly, the aim of this study was to present a long-term survivor case from the authors’ institution, and establish an integrated cohort of cases across the published literature to better understand the clinical course of this disease in this setting.METHODSThe authors report the outcomes of an institutional case of congenital GBM diagnosed within the first 3 months of life, and performed a comprehensive literature search for published cases from 2000 onward for an integrated survival analysis. All cases were integrated into 1 cohort, and Kaplan-Meier estimations, Fisher’s exact test, and logistic regression were used to interrogate the data.RESULTSThe integrated cohort of 40 congenital GBM cases consisted of 23 (58%) females and 17 (42%) males born at a median gestational age of 38 weeks (range 22–40 weeks). Estimates of overall survival (OS) at 1 month was 67%, at 1 year it was 59%, and at 10 years it was 45%, with statistically superior outcomes for subgroups in which patients survived to be treated by resection and chemotherapy. In the overall cohort, multivariable analysis confirmed resection (p < 0.01) and chemotherapy (p < 0.01) as independent predictors of superior OS. Gestational age > 38 weeks (p < 0.01), Apgar scores ≥ 7 at 5 minutes (p < 0.01), absence of prenatal hydrocephalus (p < 0.01), and vaginal delivery (p < 0.01) were associated with greater odds of surgical diagnosis versus autopsy diagnosis.CONCLUSIONSCongenital GBM can deviate from the expected poor prognosis of adult GBM in terms of OS. Both resection and chemotherapy confer statistically superior prognostic advantages in those patients who survive within the immediate postnatal period, and should be first-line considerations in the initial management of this rare disease.

INTRODUCTION: Atypical teratoid rhabdoid tumor (ATRT) is a rare, often lethal brain tumor of childhood characterized by a complex epigenetic landscape amongst a simple genetic background. Recent molecular studies have defined key biologic events that contribute to tumorigenesis and molecular subtypes of ATRT. METHODS: Seminal studies on ATRT are reviewed with an emphasis on molecular pathogenesis and its relevance to novel therapeutics. RESULTS: In this review, we summarize the key clinicopathologic and molecular features of ATRT, completed and ongoing clinical trials and outline the translational potential of novel insights into the molecular pathogenesis of this tumor. CONCLUSIONS: SMARCB1 loss is the key genetic event in ATRT pathogenesis that leads to widespread epigenetic dysregulation and loss of lineage-specific enhancers. Current work is defining subtype-specific treatments that target underlying molecular derangements and drive tumorigenesis.

Hypoxia-inducible factors (HIFs) regulate oxygen sensing and expression of genes involved in angiogenesis and erythropoiesis. Polycythemia has been observed in patients with hepatocellular carcinoma (HCC), but the underlying molecular basis remains unknown. Liver tissues from 302 HCC patients, including 104 with polycythemia, were sequenced for HIF2A mutations. A germline HIF2A mutation was detected in one HCC patient with concurrent polycythemia. Three additional family members carried this mutation, but none exhibited polycythemia or were diagnosed with HCC. The gain-of-function mutation resulted in a HIF-2α protein that was transcribed normally but resistant to degradation. HIF-2α target genes EDN1, EPO, GNA14, and VEGF were significantly upregulated in the tumor bed but not in the surrounding liver tissue. Polycythemia resolved upon total resection of the tumor tissue. This newly described HIF2A mutation may promote HCC oncogenesis.

Background H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking. Methods We screened a library of drugs either FDA-approved or in clinical trial using a library of patient-derived H3K27M-mutant DMG cell lines with cell viability as the outcome. Results were validated for clinical relevance and mechanistic importance using patient specimens from biopsy and autopsy, patient-derived cell lines, inhibition by gene knockdown and small molecule inhibitors, and patient-derived xenografts. Results Kinase inhibitors were highly toxic to H3K27M-mutant DMG cells. Within this class, STAT3 inhibitors demonstrated robust cytotoxic activity in vitro. Mechanistic analyses revealed one form of activated STAT3, phospho-tyrosine- 705 STAT3 (pSTAT3), was selectively upregulated in H3K27M-mutant cell lines and clinical specimens. STAT3 inhibition by CRISPR/Cas9 knockout, shRNA or small molecule inhibition reduced cell viability in vitro, and partially restored expression of the polycomb repressive mark H3K27me3, which is classically lost in H3K27M-mutant DMG. Putative STAT3-regulated genes were enriched in an H3K27M-knockout DMG cell line, indicating relative gain of STAT3 signaling in K27M-mutant cells. Treatment of patient-derived intracranial xenografts with WP1066, a STAT3 pathway inhibitor currently in clinical use for pediatric brain tumors, resulted in stasis of tumor growth, and increased overall survival. Finally, pSTAT3(Y705) was detected in circulating plasma extracellular vesicles of patients with H3K27M-mutant DMG. Conclusions STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials.

OBJECTIVE Complex tethered spinal cord (cTSC) release in children is often complicated by surgical site infection (SSI). Children undergoing this surgery share many similarities with patients undergoing correction for neuromuscular scoliosis, where high rates of gram-negative and polymicrobial infections have been reported. Similar organisms isolated from SSIs after cTSC release were recently demonstrated in a single-center pilot study. The purpose of this investigation was to determine if these findings are reproducible across a larger, multicenter study. METHODS A multicenter, retrospective chart review including 7 centers was conducted to identify all cases of SSI following cTSC release during a 10-year study period from 2007 to 2017. Demographic information along with specific microbial culture data and antibiotic sensitivities for each cultured organism were collected. RESULTS A total of 44 SSIs were identified from a total of 655 cases, with 78 individual organisms isolated. There was an overall SSI rate of 6.7%, with 43% polymicrobial and 66% containing at least one gram-negative organism. Half of SSIs included an organism that was resistant to cefazolin, whereas only 32% of SSIs were completely susceptible to cefazolin. CONCLUSIONS In this study, gram-negative and polymicrobial infections were responsible for the majority of SSIs following cTSC surgery, with approximately half resistant to cefazolin. Broader gram-negative antibiotic prophylaxis should be considered for this patient population.

OBJECTIVE The profound immunosuppression found in glioblastoma (GBM) patients is a critical barrier to effective immunotherapy. Multiple mechanisms of tumor-mediated immune suppression exist, and the induction of immunosuppressive monocytes such as myeloid-derived suppressor cells (MDSCs) is increasingly appreciated as a key part of this pathology. GBM-derived extracellular vesicles (EVs) can induce the formation of MDSCs. The authors sought to identify the molecular consequences of these interactions in myeloid cells in order to identify potential targets that could pharmacologically disrupt GBM EV–monocyte interaction as a means to ameliorate tumor-mediated immune suppression. Heparin-sulfate proteoglycans (HSPGs) are a general mechanism by which EVs come into association with their target cells, and soluble heparin has been shown to interfere with EV-HSPG interactions. The authors sought to assess the efficacy of heparin treatment for mitigating the effects of GBM EVs on the formation of MDSCs. METHODS GBM EVs were collected from patient-derived cell line cultures via staged ultracentrifugation and cocultured with monocytes collected from apheresis cones from healthy blood donors. RNA was isolated from EV-conditioned and unconditioned monocytes after 72 hours of coculture, and RNA-sequencing analysis performed. For the heparin treatment studies, soluble heparin was added at the time of EV-monocyte coculture and flow cytometry analysis was performed 72 hours later. After the initial EV-monocyte coculture period, donor-matched T-cell coculture studies were performed by adding fluorescently labeled and stimulated T cells for 5 days of coculture. RESULTS Transcriptomic analysis of GBM EV–treated monocytes demonstrated downregulation of several important immunological and metabolic pathways, with upregulation of the pathways associated with synthesis of cholesterol and HSPG. Heparin treatment inhibited association between GBM EVs and monocytes in a dose-dependent fashion, which resulted in a concomitant reduction in MDSC formation (p < 0.01). The authors further demonstrated that reduced MDSC formation resulted in a partial rescue of immune suppression, as measured by effects on activated donor-matched T cells (p < 0.05). CONCLUSIONS The authors demonstrated that GBM EVs induce broad but reproducible reprogramming in monocytes, with enrichment of pathways that may portend an immunosuppressive phenotype. The authors further demonstrated that GBM EV–monocyte interactions are potentially druggable targets for overcoming tumor-mediated immune suppression, with heparin inhibition of EV-monocyte interactions demonstrating proof of principle.

OBJECTIVE Arteriovenous malformations (AVMs) are a major cause of intracerebral hemorrhage in children, resulting in significant morbidity and mortality. Moreover, the rate of AVM recurrence in children is significantly higher than in adults. The aim of this study was to define the risk of delayed pediatric AVM (pAVM) recurrence following confirmed radiological obliteration. Further understanding of this risk could inform the role of long-term radiological surveillance. METHODS The authors conducted a retrospective review of ruptured and unruptured pAVM cases treated at a single tertiary care referral center between 1994 and 2019. Demographics, clinical characteristics, treatment modalities, and AVM recurrence were analyzed. RESULTS A total of 102 pediatric patients with intracranial AVMs, including 52 (51%) ruptured cases, were identified. The mean patient age at presentation was 11.2 ± 4.4 years, and 51 (50%) patients were female. The mean nidus size was 2.66 ± 1.44 cm. The most common Spetzler-Martin grades were III (32%) and II (31%). Stereotactic radiosurgery was performed in 69.6% of patients. AVM obliteration was radiologically confirmed in 68 (72.3%) of 94 patients with follow-up imaging, on angiography in 50 (73.5%) patients and on magnetic resonance imaging in 18 (26.5%). AVM recurrence was identified in 1 (2.3%) of 43 patients with long-term surveillance imaging over a mean follow-up of 54.7 ± 38.9 months (range 2–153 months). This recurrence was identified in a boy who had presented with a ruptured AVM and had been surgically treated at 5 years of age. The AVM recurred 54 months after confirmed obliteration on surveillance digital subtraction angiography. Two other cases of presumed AVM recurrence following resection in young children were excluded from recurrence analysis because of incomplete sets of imaging available for review. CONCLUSIONS AVM recurrence following confirmed obliteration on imaging is a rare phenomenon, though it occurs more frequently in the pediatric population. Regular long-term follow-up with dedicated surveillance angiography is recommended even after obliteration following resection.

It is generally accepted that larger saccular intracranial aneurysms are at greater risk to rupture. We investigated whether aneurysm location influences the effect of aneurysm size on the propensity of rupture.We reviewed patient and aneurysm characteristics in a consecutive series of patients with unruptured and ruptured aneurysms presenting to our institution between 2006 and 2018. Differences between unruptured and ruptured aneurysms at different locations were subsequently investigated.A total of 766 aneurysms in 568 patients were included, with 355 and 411 unruptured and ruptured aneurysms, respectively. There were significant differences in the distribution of aneurysm location between unruptured and ruptured aneurysms (P0.001). The most common locations of unruptured aneurysms were the middle cerebral artery (MCA) (27.6%) and paraclinoid internal carotid artery (ICA) (25.4%), whereas the most common locations of ruptured aneurysms were the anterior communicating artery (ACOM) (34.8%) and posterior communicating artery (17.8%). Ruptured aneurysms were larger than unruptured aneurysms at all locations except at the ACOM, where there was no difference in size between unruptured and ruptured aneurysms (5.4 vs. 5.8 mm, respectively; P = 0.40). Ruptured ACOM aneurysms were also smaller than ruptured aneurysms of the paraclinoid ICA (5.8 vs. 10.3 mm; P0.001), MCA (5.8 vs. 8.0 mm; P = 0.021), and basilar apex (5.8 vs. 10.5 mm; P0.001), respectively.We observed no difference in size between unruptured and ruptured ACOM aneurysms, possibly suggesting a greater susceptibility for ACOM aneurysms to rupture at smaller sizes.

BACKGROUND Superficial siderosis of the central nervous system is a rare syndrome notable for the presence of hemosiderin deposition due to chronic, repetitive hemorrhages into the subarachnoid space. OBSERVATIONS The authors presented a case of superficial siderosis in a 14-year-old girl. It arose as a late postoperative complication after resection of a medulloblastoma. Despite the patient being asymptomatic, surveillance imaging demonstrated diffuse hemosiderin deposition within the cerebellar folia and cisternal segments of cranial nerves VII and VIII on gradient echo (GRE) sequences. Formal audiometric testing demonstrated bilateral loss of high-frequency tone recognition consistent with early sensorineural hearing loss. A pseudomeningocele due to multiple dural defects was identified as the likely cause, and definitive surgical repair was performed. Intraoperatively, the presence of blood-tinged cerebrospinal fluid confirmed a diagnosis of superficial siderosis. LESSONS This case highlighted the potential need to routinely include GRE or susceptibility-weighted sequences in postoperative surveillance imaging after resection of pediatric posterior fossa tumors.

Background Successful management of pediatric low-grade glioma (pLGG) can be complicated by eloquent anatomical location, as well as specific pathologic and molecular features. Some authors have proposed using the VEGF inhibitor bevacizumab to improve disease control, but its safety and efficacy are poorly defined. Correspondingly, our aim was to pool systematically identified clinical data in the literature to assess the clinical utility of bevacizumab for pLGG at progression. Methods A systematic search of 7 electronic databases from inception to June 2019 was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. Articles were screened against prespecified criteria. Outcomes were then pooled by random-effects meta-analyses of proportions. Results Seven pertinent studies described the outcomes of 110 progressive pLGG patients managed with bevacizumab in largely multiagent regimens. While on treatment, the rate of clinical response was 58% (95% CI, 43%-72%), and the rate of response on imaging was 80% (95% CI, 58%-96%). The rate of grade 3 or higher toxicity was 8% (95% CI, 2%-17%), with proteinuria the most commonly described. In the off-treatment period up to median 1 year, the rate of progression was estimated to be 51% (95% CI, 28%-74%). Conclusions Bevacizumab has the potential to control clinical and radiographic disease with relatively low grade 3 or higher toxicity risk in progressive pLGG patients. However, the long-term off-treatment benefits of this therapy are not yet well defined. Heterogeneity in the literature precludes any formal recommendations regarding its use until larger, more standardized investigations can be performed.

A significant proportion of patients with subarachnoid hemorrhage have a normal cerebral angiogram. Patients with angiographically negative subarachnoid hemorrhage (anSAH) with either perimesencephalic- (panSAH) or aneurysmal-pattern hemorrhage (aanSAH, also known as diffuse anSAH) have an excellent prognosis, but only if underlying vascular abnormalities are completely excluded. The rate of occult aneurysms in patients with aanSAH varies widely across studies. The purpose of this study was to quantify the value of repeat DSA in these patients. We reviewed the records of all patients initially diagnosed with aanSAH after a screening DSA at a single tertiary neurovascular referral center from January 2006–April 2018. Patients with panSAH and traumatic SAH were excluded. We also performed a systematic review and meta-analysis of positive second DSAs in previously published case series of patients with aanSAH who underwent two serial DSAs. For meta-analysis, PubMed Central, MEDLINE and Cochrane Library databases were searched for pertinent studies up to November 2019. The rate of aneurysm detection on repeat angiography was extracted from each study. Pooled rates for positive second angiogram were calculated as untransformed proportions in a binary random-effects model meta-analysis. Inter-study heterogeneity was calculated using an I2 statistic. Three of 27 patients (11.1%) with aanSAH and at least two DSAs were subsequently found to have a cerebral aneurysm in our institutional dataset. Twenty-six studies in our systematic review met inclusion criteria, and the pooled rate of positive second angiogram was 10.4% (95% CI 7.3%—13.5%, P

Background Some patients with aneurysmal-pattern subarachnoid hemorrhage (SAH) have a normal digital subtraction angiogram (DSA). Patients with angiographically negative subarachnoid hemorrhage (anSAH), including those with either perimesencephalic (panSAH) or aneurysmal-pattern hemorrhage (aanSAH, also known as diffuse anSAH), have an excellent prognosis if underlying vascular lesions are definitively excluded. Many centers perform a second DSA in these patients, but the rate of aneurysm detection on repeat DSA varies between studies, and the timing of this study is debated. Methods All patients initially diagnosed with aanSAH after a screening DSA at a single tertiary neurovascular referral center January 2006 – April 2018 were included in this study. Patients with perimesencephalic-pattern, sulcal hemorrhage and traumatic SAH were excluded. A systematic review and meta-analysis of positive second DSA was performed on published case series of patients with aanSAH and at least two serial DSAs. The primary outcome for this analysis was pooled incidence using a binary random-effects model with studies weighted by size. I-squared statistics were calculated to assess heterogeneity. Results Three patients (11.1%) with aanSAH and multiple DSAs were found to have a cerebral aneurysm on repeat DSA at our institution. Each aneurysm was small (2 mm or smaller in maximum diameter). In a systematic review of 26 studies on the utility of repeat DSA for aanSAH, the pooled rate of positive second DSA was 10.4% (95% CI 7.3% – 13.5%, P Conclusions About one in 10 patients with aanSAH have a ruptured cerebral aneurysm that is not detectable on initial DSA. These aneurysms tend to be very small and difficult to visualize using other imaging techniques. In patients with aneurysmal-pattern SAH and no detectable aneurysm, there is good evidence to perform a second DSA. Disclosures C. Nesvick: None. S. Oushy: None. K. Ravindran: None. L. Rinaldo: None. P. Kerezoudis: None. E. Wijdicks: None. G. Lanzino: None. A. Rabinstein: None.

To determine whether biological effective dose (BED) was predictive of obliteration after stereotactic radiosurgery (SRS) for cerebral arteriovenous malformations (AVMs).We studied patients undergoing single-session AVM SRS between January 1, 1990, and December 31, 2014, with at least 2 years of imaging follow-up. Excluded were patients with syndromic AVM, previous SRS or embolization, and patients treated with volume-staged SRS. Biological effective dose was calculated using a mono-exponential model described by Jones and Hopewell. The primary outcome was likelihood of total obliteration defined by digital subtraction angiography or magnetic resonance imaging (MRI). Variables were analyzed as continuous and dichotomous variables based on the maximum value of (sensitivity-[1-specificity]).This study included 352 patients (360 AVM, median follow-up, 5.9 years). The median margin dose prescribed was 18.75 Gy (interquartile range [IQR]: 18 to 20 Gy). Two hundred fifty-nine patients (71.9%) had obliteration shown by angiography (n=176) or MRI (n=83) at a median of 36 months after SRS (IQR: 26 to 44 months). Higher BED was associated with increased likelihood of obliteration in univariate Cox regression analyses, when treated as either a dichotomous (≥133 Gy; hazard ratio [HR],1.52; 95% confidence interval [CI], 1.19 to 1.95; P.001) or continuous variable (HR, 1.00, 95% CI, 1.0002 to 1.005; P=.04). In multivariable analyses including dichotomized BED and location, BED remained associated with obliteration (P=.001).Biological effective dose ≥133 Gy was predictive of AVM obliteration after single-session SRS within the prescribed margin dose range 15 to 25 Gy. Further study is warranted to determine whether BED optimization should be considered as well as treatment dose for AVM SRS planning.

Glioblastoma (GBM) is the most common and deadly primary brain tumor. Novel therapeutic strategies are urgently needed to improve outcomes, but a number of disease-specific barriers pose challenges to innovation. Tumor-mediated immunosuppression is one such hurdle, and a growing body of evidence suggests that GBM-derived extracellular vesicles (EVs) play an important role in host immunosuppression. GBM-derived EVs have been shown to induce the formation of immunosuppressive monocytes, including myeloid-derived suppressor cells. Work by our group and others has increasingly shown that these immunosuppressive monocytes are a heterogenous group, and that many constellations of surface markers are inadequate to capture the changes wrought by EVs. In order to better understand the effects of GBM-EVs on monocytes, we conducted RNA-seq analysis on monocytes collected from four healthy donors treated with GBM-derived EVs harvested by ultracentrifugation from the patient-derived BT116 cell line. Following 72h of EV conditioning, total RNA was harvested from treated monocytes and untreated controls. RNA-seq was performed using the Illumina HiSeq4000 platform with paired end index reads. Analysis was performed using RNA STAR and the hg19 ENCODE reference sequence. Differential expression analysis was performed using DESeq2. Genes with a false-discovery rate (FDR)-corrected P value < 0.05 and a log2 fold-change value of >|1| were considered significantly different between groups. Pathway analysis was performed using ClueGO in Cytoscape (GO term fusion on, p< 0.05). Unsupervised clustering analysis of the top 500 most differentially-expressed genes demonstrated grouping of BT116 EV-treated monocytes together versus untreated monocytes. Pathway analysis upregulated genes in pathways important for heparan sulfate proteoglycan synthesis and cholesterol synthesis, which could potentially point to positive regulation of EV uptake. Downregulated pathways included regulation of T cell differentiation and chemoattractant activity, underscoring the induction of a potentially immunosuppressive phenotype by GBM-derived EVs.

// Chao Zhang 1,2,* , Chunzhang Yang 3,* , Michael J. Feldman 4 , Herui Wang 4 , Ying Pang 2 , Dominic M. Maggio 4 , Dongwang Zhu 4 , Cody L. Nesvick 4 , Pauline Dmitriev 4 , Petra Bullova 2,5 , Prashant Chittiboina 4 , Roscoe O. Brady 4 , Karel Pacak 2 and Zhengping Zhuang 4 1 Department of Orthopedics, Xinqiao Hospital, The Third Military Medical University, Chongqing, China 2 Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA 3 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA 4 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA 5 Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia * These authors have contributed equally to this work Correspondence to: Karel Pacak, email: // Zhengping Zhuang, email: // Keywords : HDACi, Hsp90, SAHA, HIF, hypoxia Received : December 14, 2016 Accepted : April 10, 2017 Published : May 23, 2017 Abstract Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi. Through an in-vitro and in-vivo approach utilizing cell lines for hepatocellular carcinoma (HCC), osteosarcoma (OS), and glioblastoma (GBM), we demonstrate that SAHA potently inhibits HIF-a nuclear translocation via direct acetylation of its associated chaperone, heat shock protein 90 (Hsp90). In the presence of SAHA we found elevated levels of acetyl-Hsp90, decreased interaction between acetyl-Hsp90 and HIF-a, decreased nuclear/cytoplasmic HIF-α expression, absent HIF-α association with its nuclear karyopharyin Importin, and markedly decreased HIF-a transcriptional activity. These changes were associated with downregulation of downstream hypoxia molecules such as endothelin 1, erythropoietin, glucose transporter 1, and vascular endothelial growth factor. Findings were replicated in an in-vivo Hep3B HRE-Luc expressing xenograft, and were associated with significant decreases in xenograft tumor size. Altogether, this study highlights a novel mechanism of action of an important class of chemotherapeutic.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare CNS cancer that typically occurs in children younger than 3 years of age. Histologically, AT/RTs are embryonal tumors that contain a rhabdoid component as well as areas with primitive neuroectodermal, mesenchymal, and epithelial features. Compared to other CNS tumors of childhood, AT/RTs are characterized by their rapid growth, short symptomatic prodrome, and large size upon presentation, often leading to brain compression and intracranial hypertension requiring urgent intervention. For decades, the mainstay of care has been a combination of maximal safe surgical resection followed by adjuvant chemotherapy and radiotherapy. Despite advances in each of these modalities, the relative paucity of data on these tumors, their inherently aggressive course, and a lack of molecular data have limited advances in treatment over the past 3 decades. Recent large-scale, multicenter interdisciplinary studies, however, have significantly advanced our understanding of the molecular pathogenesis of these tumors. Multiple clinical trials testing molecularly targeted therapies are underway, offering hope for patients with AT/RT and their families.

Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system cancer of infancy and early childhood that may occur anywhere along the neuraxis and is associated with a high rate of mortality. While contemporary multimodal therapeutic approaches have significantly improved overall survival, targeted therapy remains elusive, and treatment is often associated with significant morbidity. ATRT is unique in its genomic stability, with the only recurrent genetic abnormality being bi-allelic loss of the SMARCB1 gene, which encodes a core subunit of the BAF chromatin remodeling complex. The epigenetic mechanisms by which SMARCB1 loss leads to tumorigenesis are not yet well-defined and addressing this gap in understanding is necessary for creating efficacious, targeted therapeutics. To better understand the epigenetic features gained and lost in ATRT, we re-expressed SMARCB1 in a library of patient-derived and established ATRT cell lines of multiple molecular subtypes. SMARCB1 restoration significantly reduced or eliminated the proliferative and clonogenic capacity of each cell line. We performed assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) and RNA sequencing (RNA-Seq) to define putative transcriptional regulatory networks that are gained and lost in ATRT. SMARCB1 restoration was associated with global changes in chromatin openness consistent with the creation of new regulatory elements throughout the genome, and these were associated with induction of a diverse developmental transcriptional signature. Motif enrichment analysis of regions with increased accessibility defined a small but consistent number of centrally enriched transcription factor motifs across cell lines indicative of putative pioneer factors whose functions may be lost in ATRT. Pertinent chromatin immunoprecipitation with sequencing (ChIP-Seq) data will be discussed in the context of lost and gained transcriptional regulatory networks in ATRT and normal cellular development.

OBJECTIVE Paraplegia and paraparesis following aortic aneurysm repair occur at a substantially high rate and are often catastrophic to patients, their families, and the overall health care system. Spinal cord injury (SCI) following open thoracoabdominal aortic aneurysm (TAAA) repair is reported to be as high as 20% in historical controls. The goal of this study was to determine the impact of CSF drainage (CSFD) on SCI following TAAA repair. METHODS In August 2015 a systematic literature search was performed using clinicaltrials.gov, the Cochrane Library, PubMed/MEDLINE, and Scopus that identified 3478 articles. Of these articles, 10 met inclusion criteria. Random and fixed-effect meta-analyses were performed using both pooled and subset analyses based on study type. RESULTS The meta-analysis demonstrated that CSFD decreased SCI by nearly half (relative risk 0.42, 95% confidence interval 0.25–0.70; p = 0.0009) in the pooled analysis. This effect remained in the subgroup analysis of early SCI but did not remain significant in late SCI. CONCLUSIONS This meta-analysis showed that CSFD could be an effective strategy in preventing SCI following aortic aneurysm repair. Care should be taken to prevent complications related to overdrainage. No firm conclusions can be drawn about the newer endovascular procedures at the current time.

Metabolomics has shown significant potential in identifying small molecules specific to tumor phenotypes. In this study we analyzed resected tissue metabolites using capillary electrophoresis-mass spectrometry and found that tissue hypotaurine levels strongly and positively correlated with glioma grade. In vitro studies were conducted to show that hypotaurine activates hypoxia signaling through the competitive inhibition of prolyl hydroxylase domain-2. This leads to the activation of hypoxia signaling as well as to the enhancement of glioma cell proliferation and invasion. In contrast, taurine, the oxidation metabolite of hypotaurine, decreased intracellular hypotaurine and resulted in glioma cell growth arrest. Lastly, a glioblastoma xenograft mice model was supplemented with taurine feed and exhibited impaired tumor growth. Taken together, these findings suggest that hypotaurine is an aberrantly produced oncometabolite, mediating tumor molecular pathophysiology and progression. The hypotaurine metabolic pathway may provide a potentially new target for glioblastoma diagnosis and therapy.

Diffuse midline glioma (DMG) is a lethal brain tumor that typically occurs in children. Numerous studies have demonstrated the central role of the H3K27M mutation and secondary loss of H3K27 trimethylation (H3K27me3) in DMG tumorigenesis. Understanding how the H3K27M mutation alters the epigenetic landscape of the cell is necessary for revealing molecular targets that are critical to tumorigenesis. To investigate the epigenetic effects of H3K27M mutation in DMG, we developed revertant DMG cell lines with the mutant methionine residue reverted to wildtype (i.e., M27K). Revertant cells were analyzed for epigenetic changes and phenotypic differences in vitro and in vivo. H3M27K DMG cells grew in culture but displayed diminished proliferative capacity. H3M27K cells demonstrated total loss of H3K27M expression and restored trimethylation of H3K27 and H3K4. Furthermore, consistent with the hypothesis that the H3K27M mutation impacts H3 phosphorylation via expression of Aurora Kinase during mitosis, H3M27K cells demonstrated reduced expression of both Aurora Kinase A and phosphorylation of H3 serine residues 10 and 28. In line with the critical role of H3S10 phosphorylation in chromatin segregation, H3M27K cells also demonstrated restored chromosome segregation compared to H3K27M cells. In vivo data will be discussed. Revertance of the H3K27M mutation reduces tumorigenesis in DMG tumors. Isogenic H3M27K cells display reversal of key epigenetic changes associated with oncogenesis in DMG. The revertant H3M27K DMG model is a useful tool to investigate the downstream epigenetic reprogramming specific to H3K27M mutation in these tumors.

Motocross is a competitive outdoor extreme sport in which motorcyclists race across vast courses of jumps, berms and long straightaways of unpredictable terrain. While the sport has gained notoriety in adult popular culture through contests like the X Games, motocross is also increasingly popular among youth in the Unites States and beyond. In the setting of contemporary discussions on traumatic brain injury, this poses an obvious challenge to those advising children and parents on the risks of motocross to the developing brain and spine. The available literature demonstrates that even when practiced with appropriate protective equipment, motocross poses an increased risk for acquiring major trauma to the brain, spine and limbs for which the long-term consequences have been poorly studied. Riders and parents should be counseled about the risks of these injuries prior to participation and in accordance with state laws. Furthermore, formal return-to-play guidelines following concussions should be developed.

OBJECTIVEAlthough ventricular shunting is an effective therapy for idiopathic normal pressure hydrocephalus (iNPH), the effect of shunt valve type on the incidence of revision surgery is not well defined. To address this issue, shunt revision rates between patients with iNPH receiving a fixed-setting valve (FSV) versus a programmable valve (PV) were compared.METHODSPatients with iNPH treated with ventricular shunting between 2001 and 2017 were included for analysis. The incidence of shunt revision was noted and risk factors for revision were identified using a Cox proportional hazards model. Costs associated with admission for ventricular shunt procedures were obtained from the Vizient national database.RESULTSThere were 348 patients included for analysis, with 98 patients (28.1%) receiving a PV. Shunt revision occurred in 73 patients (21.0%), with 12 patients (3.4%) undergoing multiple revisions. Overall revision rates were lower in patients receiving a PV (13.3% vs 24.0%; p = 0.027), as was the incidence of multiple revisions (0.0% vs 4.8%; p = 0.023). Patients with initial placement of an FSV were also more likely to undergo valve exchange during follow-up (12.4% vs 2.0%; p = 0.003). Patients with a PV were less likely to undergo revision due to persistent symptoms without obstruction (2.0% vs 8.8%; p = 0.031) and distal obstruction (1.0% vs 6.8%; p = 0.030). In a multivariate Cox proportional hazards model, initial placement of a PV was associated with reduced risk of revision due to persistent symptoms without obstruction (OR 0.27, 95% CI 0.04–0.93; p = 0.036). PVs were associated with more frequent shunt series (1.3 vs 0.6; p < 0.001) and head CT scans (3.6 vs 2.7; p = 0.038) during follow-up. There was no significant difference in mean total costs between patients receiving an FSV and a PV ($24,282.50 vs $24,396.90; p = 0.937).CONCLUSIONSThe authors’ results suggest that PVs lead to reduced rates of shunt revision in patients with iNPH, and decreased risk of revision due to persistent symptoms of iNPH, thereby justifying the higher upfront cost of PVs despite similar overall treatment costs between these devices.

ObjectiveTo define the in-hospital course, complications, short- and long-term functional outcomes of patients with angiographically negative subarachnoid hemorrhage (anSAH), particularly those with aneurysmal-pattern anSAH (aanSAH).MethodsRetrospective cohort study of patients with aneurysmal subarachnoid hemorrhage (aSAH), aanSAH, and perimesencephalic-pattern anSAH (panSAH) treated at a single tertiary referral center between January 2006 and April 2018. Ninety-nine patients with anSAH (33 aanSAH and 66 panSAH) and 464 patients with aSAH were included in this study. Outcomes included symptomatic hydrocephalus requiring CSF drainage, need for ventriculoperitoneal shunt, radiographic vasospasm, delayed cerebral ischemia (DCI), radiographic infarction, disability level within 1 year of ictus, and at last clinical follow-up as defined by the modified Rankin Scale.ResultsPatients with aanSAH and panSAH had similar rates of DCI and radiologic infarction, and patients with aanSAH had significantly lower rates compared to aSAH (p ≤ 0.018). Patients with aanSAH were more likely than those with panSAH to require temporary CSF diversion and ventriculoperitoneal shunt (p ≤ 0.03), with similar rates to those seen in aSAH. Only one patient with anSAH died in the hospital. Compared to those with aSAH, patients with aanSAH were significantly less likely to have a poor functional outcome within 1 year of ictus (odds ratio 0.26, 95% confidence interval 0.090–0.75) and at last follow-up (hazard ratio 0.30, 95% confidence interval 0.19–0.49, p = 0.002).ConclusionsDCI is very uncommon in anSAH, but patients with aanSAH have a similar need for short- and long-term CSF diversion to patients with aSAH. Nevertheless, patients with aanSAH have significantly better short- and long-term outcomes.

Gliosarcoma is an uncommon variant of glioblastoma, which commonly demonstrates dural attachment. However, skull base invasion is rarely seen with this entity. Herein, we report a 44-year-old female patient diagnosed with primary intracranial gliosarcoma extensively invading the skull base and muscles of mastication. She presented to our institution with a three-month history of difficult right jaw opening and retro-orbital pressure and one week of severe right-sided postauricular headache. Head CT demonstrated a 6 cm mass with marked bony erosion. Brain MRI at a one-week interval more clearly characterized tumor extension through the right orbit and muscles of mastication, with overall growth to 7 cm and worsening midline shift. The patient underwent a right frontotemporal craniotomy for gross total resection. Pathology confirmed the diagnosis of gliosarcoma, IDH-wildtype (WHO grade IV). Her postoperative course was uneventful and she was discharged at preoperative neurologic baseline. To our knowledge, this is the third reported case of a primary intracranial gliosarcoma with direct invasion of skull base, brain parenchyma, and extracranial compartment. However, this is the first report case of primary GS invading the surrounding musculature and orbit. This case report highlights the rapid aggressiveness of gliosarcomas and further a prior undescribed radiographic and anatomic finding of skull base invasion with this entity.

OBJECTMalignant tumors of the brainstem, excluding classic diffuse intrinsic pontine gliomas (DIPGs), are a very rare, heterogeneous group of neoplasms that have been infrequently described in the literature. In this paper, the authors present their experiences with treating these unique cancers.METHODSA retrospective chart review was conducted to identify eligible cases over a 15-year period. All tumors involving the pons were, by consensus, felt not to be DIPGs based on their neuroimaging features. Demographic information, pathological specimens, neuroimaging characteristics, surgical and nonsurgical management plans, and survival data were gathered for analysis.RESULTSBetween January 2000 and December 2014, 29 patients were identified. The mean age at diagnosis was 8.4 years (range 2 months to 25 years), and 17 (59%) patients were male. The most common presenting signs and symptoms were cranial neuropathies (n = 24; 83%), hemiparesis (n = 12; 41%), and ataxia or gait disturbance (n = 10; 34%). There were 18 glial and 11 embryonal tumors. Of the glial tumors, 5 were radiation-induced and 1 was a malignant transformation of a previously known low-grade tumor. Surgical intervention consisted of biopsy alone in 12 patients and some degree of resection in another 15 patients. Two tumors were diagnosed postmortem. The median overall survival for all patients was 196 days (range 15 to 3999 days). There are currently 5 (17%) patients who are still alive: 1 with an anaplastic astrocytoma and the remaining with embryonal tumors.CONCLUSIONSIn general, malignant non-DIPG tumors of the brainstem carry a poor prognosis. However, maximal cytoreductive surgery may be an option for select patients with focal tumors. Long-term survival is possible in patients with nonmetastatic embryonal tumors after multimodal treatment, most importantly maximal resection.

BACKGROUND Ventricular shunt placement for treating hydrocephalus is one of the most common neurosurgical procedures. The rate of shunt failure, however, has not appreciably changed with time. OBJECTIVE To investigate whether intraoperative image guidance using ultrasound or stereotaxy contributes to accurate shunt catheter placement and survival. METHODS We performed a systematic literature review using PubMed and MEDLINE databases for studies that use ultrasound and frameless stereotaxy for ventricular catheter placement for hydrocephalus. All articles assessed the accuracy of catheter tip placement and/or overall shunt survival, and the rate of accurate shunt catheter placement, the overall failure rate, and the average time to shunt failure were extracted for analysis. RESULTS Although each modality (ultrasound/stereotaxy) did not increase catheter placement accuracy, a combined random-effects meta-analysis of 738 catheters (136 guided by ultrasound, 168 guided by frameless stereotaxy, and 434 freehand) demonstrated a weak benefit of image guidance (risk ratio: 1.19, 95% confidence interval: 1.02-1.39, P = .02), but this result was limited by considerable heterogeneity among studies (I² = 86%, P < .001 by Cochrane's Q test). A meta-analysis could not be performed for shunt survival due to heterogeneity in data reporting. CONCLUSION Although image guidance offers a promising solution to lower the risk of inaccurate catheter placement, which could lead to lower premature failure of ventricular shunts, our review demonstrated that there is not yet a clear benefit of these technologies. Current literature is limited to case series and cohort studies, and significant between-study heterogeneity in methodology and reporting currently limits a higher order analysis.

Background Schwannomas arising from the cranial nerves controlling extraocular eye movements are very rare and usually present with some degree of diplopia. Case Presentation We report a 50-year-old woman who presented with isolated left-sided trigeminal neuralgia of 6 months' duration. Imaging demonstrated a homogeneously enhancing mass in the left ambient cistern, and the patient was brought to the operating room for resection. A retrosigmoid approach was used, and the mass was directly visualized arising from the trochlear nerve and compressing the dorsal root entry zone of the trigeminal nerve. A gross total resection of the mass was achieved, and microvascular decompression of the trigeminal nerve was performed. The tumor was pathologically confirmed as a schwannoma. At 3-month follow-up, the patient's facial pain was resolved, and her extraocular eye movements were intact. Conclusions A total of 32 pathology-confirmed cases of trochlear schwannoma have been previously reported in the English-language literature. Most of these tumors arose from the cisternal segment of the nerve, and most patients presented with frank trochlear nerve palsy on exam. We report the first case of trochlear schwannoma presenting with isolated trigeminal neuralgia.

Object Observational studies, such as cohort and case-control studies, are valuable instruments in evidence-based medicine. Case-control studies, in particular, are becoming increasingly popular in the neurosurgical literature due to their low cost and relative ease of execution; however, no one has yet systematically assessed these types of studies for quality in methodology and reporting. Methods The authors performed a literature search using PubMed/MEDLINE to identify all studies that explicitly identified themselves as “case-control” and were published in the JNS Publishing Group journals (Journal of Neurosurgery, Journal of Neurosurgery: Pediatrics, Journal of Neurosurgery: Spine, and Neurosurgical Focus) or Neurosurgery. Each paper was evaluated for 22 descriptive variables and then categorized as having either met or missed the basic definition of a case-control study. All studies that evaluated risk factors for a well-defined outcome were considered true case-control studies. The authors sought to identify key features or phrases that were or were not predictive of a true case-control study. Those papers that satisfied the definition were further evaluated using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. Results The search detected 67 papers that met the inclusion criteria, of which 32 (48%) represented true case-control studies. The frequency of true case-control studies has not changed with time. Use of odds ratios (ORs) and logistic regression (LR) analysis were strong positive predictors of true case-control studies (for odds ratios, OR 15.33 and 95% CI 4.52–51.97; for logistic regression analysis, OR 8.77 and 95% CI 2.69–28.56). Conversely, negative predictors included focus on a procedure/intervention (OR 0.35, 95% CI 0.13–0.998) and use of the word “outcome” in the Results section (OR 0.23, 95% CI 0.082–0.65). After exclusion of nested case-control studies, the negative correlation between focus on a procedure/intervention and true case-control studies was strengthened (OR 0.053, 95% CI 0.0064–0.44). There was a trend toward a negative association between the use of survival analysis or Kaplan-Meier curves and true case-control studies (OR 0.13, 95% CI 0.015–1.12). True case-control studies were no more likely than their counterparts to use a potential study design “expert” (OR 1.50, 95% CI 0.57–3.95). The overall average STROBE score was 72% (range 50–86%). Examples of reporting deficiencies were reporting of bias (28%), missing data (55%), and funding (44%). Conclusions The results of this analysis show that the majority of studies in the neurosurgical literature that identify themselves as “case-control” studies are, in fact, labeled incorrectly. Positive and negative predictors were identified. The authors provide several recommendations that may reverse the incorrect and inappropriate use of the term “case-control” and improve the quality of design and reporting of true case-control studies in neurosurgery.

Transcription factors that induce epithelial-mesenchymal transition (EMT) promote invasion, chemoresistance and a stem-cell phenotype in epithelial tumors, but their roles in central nervous system tumors are not well-understood. We hypothesized these transcription factors have a functional impact in grades II-III gliomas. Using the National Cancer Institute (NCI) Repository for Molecular Brain Neoplasia Data (REMBRANDT) and the Cancer Genome Atlas (TCGA) Lower-Grade Glioma (LGG) data, we determined the impact of EMT-promoting transcription factors (EMT-TFs) on overall survival in grades II-III gliomas, compared their expression across common genetic subtypes and subsequently validated these findings in a set of 31 tumors using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. Increased expression of the gene coding for the transcriptional repressor Zinc Finger E box-binding Homeobox 1 (ZEB1) was associated with a significant increase in overall survival (OS) on Kaplan-Meier analysis. Genetic subtype analysis revealed that ZEB1 expression was relatively increased in IDH1/2-mutant gliomas, and IDH1/2-mutant gliomas expressed significantly lower levels of many ZEB1 transcriptional targets. Similarly, IDH1/2-mutant tumors expressed significantly higher levels of targets of microRNA 200C (MIR200C), a key regulator of ZEB1. In a validation study, ZEB1 mRNA was significantly increased in IDH1-mutant grades II-III gliomas, and ZEB1 protein expression was more pronounced in these tumors. Our findings demonstrate a novel relationship between IDH1/2 mutations and expression of ZEB1 and its transcriptional targets. Therapy targeting ZEB1-associated pathways may represent a novel therapeutic avenue for this class of tumors.

Although schwannoma and neurofibroma tumors are generally reported as distinct pathologic diagnoses, sporadic schwannoma/neurofibroma hybrid nerve sheath tumors have been reported in the general population with components of both entities. We report the clinicopathological features of these hybrid nerve sheath tumors in patients with neurofibromatosis type 2 (NF2). A retrospective review of nerve sheath tumor surgical specimens from patients with NF2 enrolled at the National Institutes of Health was performed. Those specimens reported to have schwannoma-like and neurofibromalike features were selected for further characterization by morphology, immunohistochemical panel (CD34, S100, neurofilament triplet protein (immunostain) (NFTP), epithelial membrane antigen (EMA)), and confirmation as hybrid tumors. Of 43 total NF2 patients undergoing resection of nerve sheath tumors, 11 specimens from 11 (26%) patients were found to be benign nerve sheath tumors exhibiting hybrid features of both neurofibroma and schwannoma. Immunohistochemical studies showed the schwannoma component to be S100+, CD 34- while the neurofibroma component was CD34+, variable S100+. Our experience emphasizes the importance of including this distinct tumor subtype, the schwannoma/neurofibroma hybrid tumor, in the differential diagnosis of nerve sheath tumors in NF2 patients and suggests that the relationship between neurofibroma and schwannoma tumors is closer than previously suspected..

Desmoplastic infantile ganglioglioma (DIG; also known as desmoplastic infantile astrocytoma, DIA) is a rare, World Health Organization (WHO) grade-I central nervous system tumor that most often arises in very young children, often with rapidly enlarging head circumference. We reviewed the records of all infants diagnosed with pathology-confirmed DIG/DIA at Mayo Clinic from 1997 to 2016. Immunohistochemical staining was performed on tumor specimens to assess expression of IDH1 R132H, BRAF V600E, H3K27me3 and INI1. Seven patients were included in this study: age range was 2 - 9 months, and four were male. Six patients presented with rapidly enlarging head circumference, and one presented with isolated seizures. On immunohistochemical analysis, all tumors were negative for R132H-mutant IDH1. INI1 expression was retained in all specimens, and BRAF V600E expression was negative or only very focally positive. H3K27me3 expression was partly lost in four tumors. Three tumors were located in the suprasellar region, and four were located in the lateral cerebral hemispheres. All patients underwent surgery for tumor resection; a gross total resection was achieved in the lateral cerebral tumors, and a subtotal resection was achieved in the suprasellar tumors. At 2-year follow-up, none of the patients with a hemispheric tumor developed long-term sequelae from their surgery, but each patient with a supresellar tumor had a neurologic or endocrinologic deficit from tumor progression or surgery, including visual impairment, panhypopituitarism and/or hemiparesis. These results highlight the importance of tumor location in prognosticating these challenging tumors, suggesting that suprasellar location is associated with a poorer prognosis.

Subependymal giant cell astrocytomas (SEGAs) are rare central nervous system tumors that are almost pathognomonic of tuberous sclerosis complex (TSC). These lesions are World Health Organization (WHO) grade-I tumors that arise in the lateral ventricles near the foramen of Monro and almost always contain detectable mutations in TSC1 or TSC2. We present three children with TSC in whom a diagnosis of SEGA was the presenting feature and who displayed a mild TSC phenotype. All patients underwent surgery for tumor resection. Following surgical resection, germline testing for TSC1 and TSC2 mutations was performed, and pathologic specimens subsequently underwent molecular analysis using chromosomal microarray and a 50-gene next-generation sequencing. There were two males and one female with an age range of 12 to 18 years. All patients had evidence of cortical tubers on brain MRI, and two had hypomelanotic macules; no other manifestations of TSC were present. None of these patients were found to have detectable germline mutations in TSC1 or TSC2. One tumor specimen contained copy-neutral loss of heterozygosity (cnLOH) of chromosome 9q34 affecting TSC1 and NOTCH1. The second specimen contained cnLOH of chromosome 16p12-13 affecting TSC2; DNA sequencing confirmed a known pathogenic mutation in TSC2 in this patient. A third specimen was cytogenetically normal but contained a missense mutation in NOTCH2 of unknown significance. These data demonstrate that SEGAs in patients with a mild TS phenotype are molecularly heterogeneous, sometimes containing genetic alterations in TSC1 or TSC2 but also containing mutations in other pathways associated with growth, development and neoplasia.

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), can attenuate tumor-associated edema and improve patient symptoms but based on magnetic resonance imaging, is associated with non-enhancing tumor progression and possibly gliosarcoma differentiation. To gain insight into these findings, we investigated the role of hypoxia and epithelial-mesenchymal transition (EMT)-associated proteins in GBM. Tumor markers of hypoxia and EMT were upregulated in bevacizumab-treated tumors from GBM patients compared to untreated counterparts. Exposure of glioma cells to 1% oxygen tension increased cell proliferation, expression of EMT-associated proteins and enhanced cell migration in vitro. These phenotypic changes were significantly attenuated by pharmacologic knockdown of hypoxia-inducible Factor 1α (HIF1α) or HIF2α, indicating that HIFs represent a therapeutic target for mesenchymal GBM cells. These findings provide insights into potential development of novel therapeutic targeting of angiogenesis-specific pathways in GBM.