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Disparities in treatment and outcomes disproportionately affect minority ethnic and racial populations in many surgical fields. Although substantial research in racial disparities has focused on outcomes, little is known about how surgeon recommendations can be influenced by patient race. The aim of this study was to investigate racial and socioeconomic disparities in the surgical management of primary brain tumors.In this registry-based cohort study, we used data from the Surveillance, Epidemiology, and End Results (SEER) database (1975-2016) and the American College of Surgeons National Cancer Database (NCDB) in the USA for independent analysis. Adults (aged ≥20 years) with a new diagnosis of meningioma, glioblastoma, pituitary adenoma, vestibular schwannoma, astrocytoma, and oligodendroglioma, with information on tumour size and surgical recommendation were included in the analysis. The primary outcome of this study was the odds of a surgeon recommending against surgical resection at diagnosis of primary brain neoplasms. This outcome was determined using multivariable logistic regression with clinical, demographic, and socioeconomic factors.This study included US national data from the SEER (1975-2016) and NCDB (2004-17) databases of adults with a new diagnosis of meningioma (SEER n=63 674; NCDB n=222 673), glioblastoma (n=35 258; n=104 047), pituitary adenoma (n=27 506; n=87 772), vestibular schwannoma (n=11 525; n=30 745), astrocytoma (n=5402; n=10 631), and oligodendroglioma (n=3977; n=9187). Independent of clinical and demographic factors, including insurance status and rural-urban continuum code, Black patients had significantly higher odds of recommendation against surgical resection of meningioma (adjusted odds ratio 1·13, 95% CI 1·06-1·21, p0·0001), glioblastoma (1·14, 1·01-1·28, p=0·038), pituitary adenoma (1·13, 1·05-1·22, p0·0001), and vestibular schwannoma (1·48, 1·19-1·84, p0·0001) when compared with White patients in the SEER dataset. Additionally, patients of unknown race had significantly higher odds of recommendation against surgical resection for pituitary adenoma (1·80, 1·41-2·30, p0·0001) and vestibular schwannoma (1·49, 1·10-2·04, p=0·011). Performing a validation analysis using the NCDB dataset confirmed these significant results for Black patients with meningioma (1·18, 1·14-1·22, p0·0001), glioblastoma (1·19, 1·12-1·28, p0·0001), pituitary adenoma (1·21, 1·16-1·25, p0·0001), and vestibular schwannoma (1·19, 1·04-1·35, p=0·0085), and indicated and indicated that the findings are independent of patient comorbidities. When further restricted to the most recent decade in SEER, these inequities held true for Black patients, except those with glioblastoma (meningioma [1·18, 1·08-1·28, p0·0001], pituitary adenoma [1·20, 1·09-1·31, p0·0001], and vestibular schwannoma [1·54, 1·16-2·04, p=0·0031]).Racial disparities in surgery recommendations in the USA exist for patients with primary brain tumours, independent of potential confounders including clinical, demographic, and select socioeconomic factors. Further studies are needed to understand drivers of this bias and enhance equality in surgical care.None.

Tympanojugular paragangliomas (TJPs) are slow-growing tumors arising within the middle ear or jugular foramen. The development of modified skull base approaches and the increasing use of stereotactic radiosurgery have provided more modern techniques in the management of TJPs. Several factors dictating approach selection, and resulting clinical outcomes have been inconsistently described.A systematic review of the literature describing modern management of complex TJPs was performed and summarized. A random-effects meta-analysis was performed to describe the rate of tumor control, complications, and symptom improvement in patients undergoing radiosurgery or surgical resection.Nineteen studies were identified with a total of 852 TJP patients. A minority (153 patients) underwent radiosurgery while 699 underwent surgery. On meta-analysis, there was a 3.5% (95% confidence interval [CI]: 0.5%-6.4%) tumor growth rate following radiosurgery and 3.9% (95% confidence interval [CI]: 1.8%-6.0%) recurrence rate in surgical resection, with no significant moderator effect between the 2 groups (P = 0.9046). Complication rate for radiosurgery was 7.6% (95% CI: 2.8%-12.4%), differing significantly from surgical complication rates of 29.6% (95% CI: 17.1-42.0%, P = 0.0418).Stereotactic radiosurgery and surgical resection for TJPs have similar rates of tumor recurrence. Radiation is associated with less risk and lower morbidity, yet there is comparably modest reduction of the tumor size. In sum, the data suggest that radiosurgery is a reasonable management option for patients with minimal symptoms who are high risk for surgery. Microsurgical resection should be reserved for patients with lower cranial neuropathies or those who have failed radiation treatment.

BACKGROUND Gross total resection (GTR) of contrast-enhancing tumor is associated with increased survival in primary glioblastoma. Recently, there has been increasing interest in performing supratotal resections (SpTRs) for glioblastoma. OBJECTIVE To address the published results, which have varied in part due to lack of consensus on the definition and appropriate use of SpTR. METHODS A crowdsourcing approach was used to survey 21 neurosurgical oncologists representing 14 health systems nationwide. Participants were presented with 11 definitions of SpTR and asked to rate the appropriateness of each definition. Participants reviewed T1-weighed postcontrast and fluid-attenuated inversion-recovery magnetic resonance imaging for 22 anatomically distinct glioblastomas. Participants were asked to assess the tumor location's eloquence, the perceived equipoise of enrolling patients in a randomized trial comparing gross total to SpTR, and their personal treatment plans. RESULTS Most neurosurgeons surveyed (n = 18, 85.7%) agree that GTR plus resection of some noncontrast enhancement is an appropriate definition for SpTR. Overall, moderate inter-rater agreement existed regarding eloquence, equipoise, and personal treatment plans. The 4 neurosurgeons who had performed >10 SpTRs for glioblastomas in the past year were more likely to recommend it as their treatment plan (P

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

PURPOSE: Pituitary apoplexy is a rare endocrine emergency. The purpose of this study is to characterize physiological changes involved in pituitary apoplexy, especially during the acute phase. METHODS: A Cushing’s disease patient experienced corticotroph releasing hormone (CRH)-induced pituitary apoplexy during inferior petrosal sinus sampling (IPSS). The IPSS blood samples from the Cushing’s disease patient were retrospectively analyzed for cytokine markers. For comparison, we also analyzed cytokine markers in blood samples from two pituitary ACTH-secreting microadenoma patients and one patient with an ectopic ACTH-secreting tumor. RESULTS: Acute elevation of interleukin 6 (IL-6) and matrix metalloproteinase 9 (MMP9) was observed in the IPSS blood sample on the apoplectic hemorrhagic site of the tumor. In contrast, such a change was not observed in the blood samples from the contralateral side of the apoplexy patient and in other IPSS samples from two non-apoplexy Cushing’s disease patient and a patient with ectopic Cushing’s syndrome. CONCLUSION: IL-6 and MMP9 may be involved in the acute process of pituitary apoplexy in Cushing’s disease.

Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint Section on Tumors of the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS). The guidelines are created using the most current and clinically relevant evidence using systematic methodologies, which classify available data and provide recommendations for clinical practice. This update summarizes the Tumor Section Guidelines developed over the last five years for non-functioning pituitary adenomas, low grade gliomas, vestibular schwannomas, and metastatic brain tumors.

Background Balloon test occlusion is a widely used method for predicting tolerance of vessel occlusion in the treatment of aneurysms, fistulae, and head and neck neoplasms. However, the false-negative rate is variably reported due in part to the diversity of perfusion monitoring methods. Objective To evaluate the rate of symptomatic ischemic events after a negative balloon test occlusion and determine whether perfusion monitoring methods contribute to differences in these rates. Methods PubMed was systematically searched for studies between 1990 and 2020 that reported rates of ischemic outcomes of parental vessel occlusion in patients who passed balloon test occlusion. A generalized linear mixed model meta-analysis was performed. Results were expressed as the rate of symptomatic ischemic events after parental vessel occlusion without vessel bypass in patients who passed balloon test occlusion. Results Thirty-two studies met the inclusion criteria. The overall pooled rate of ischemic events after passing balloon test occlusion was 3.7% (95% confidence interval [CI]: 1.7–7.8). This rate was 3.8% (95% CI: 1.1–12.8) when monitored with angiography, 2.2% (95% CI: 0.4–10.2) when monitored by a form of computed tomography, and 5.3% (95% CI: 1.2–20.4) when monitored by 2 or more methods of perfusion assessment. The complication rate of balloon test occlusion was 0.8% (95% CI: 0.2–2.7). Conclusions Balloon test occlusion results in a low rate of subsequent ischemic events, without conclusive evidence of variation between methods of perfusion assessment. The choice of method should focus on reduction of complication risk, experience of the interventional team, and avoidance of prolonged test occlusion times.

OBJECTIVEThe authors conducted a study to identify clinical features of cranial base chondrosarcomas that will predict tumor progression after resection.METHODSThe authors performed a retrospective study at a tertiary referral cranial base center. Patients who underwent resection of cranial base chondrosarcomas between January 2004 and December 2018 were followed longitudinally. The main outcome measure was progression-free survival (PFS).RESULTSA total of 41 patients were treated for histopathologically proven “conventional” cranial base chondrosarcomas during the study period, and the median PFS was 123 months for the cohort. Univariate analysis was performed on clinical, anatomical, and radiographic parameters collected for each patient. Features that were statistically significant were fed into a multivariate regression model, which revealed two independent predictors of PFS: patient age and encasement of 3–4 major arteries (> 25% of the vessel wall surrounded by tumor). Using these two variables of age and multiple arterial vessel encasement, the authors generated a risk stratification model using a simple point system to predict PFS in patients with cranial base chondrosarcomas. Based on these two factors known preoperatively, this model could stratify patients into high-risk (10% of patients), intermediate-risk (68% of patients), and low-risk (22% of patients) subgroups corresponding to dramatically distinct median PFS (1.8 years, 10.2 years, and no progression, respectively).CONCLUSIONSIn patients with cranial base chondrosarcomas, age and artery encasement are variables known preoperatively that can powerfully predict tumor progression, define operative goals, and aid in selecting postoperative adjuvant therapy.

INTRODUCTION Lactate dehydrogenase A (LDHA) encodes an enzyme that catalyzes the inter-conversion between pyruvate and lactate in glycolysis. Here, we demonstrate that LDHA mediates a novel role in DNA repair independent of this metabolic function. METHODS siRNA screen, The Cancer Genome Atlas (TCGA) survival analysis, ionizing radiation (IR), g-H2AX, and chromatin assays, site-directed mutagenesis. RESULTS In an orthogonal siRNA-informatic screen to identify genes 1) when silenced caused IR sensitivity in patient-derived glioblastoma lines and 2) lowered expression is associated with improved survival in TCGA, LDHA surfaced as the top candidate. The survival association was validated by LDHA immunohistochemical staining in an independent collection of glioblastoma samples. In vitro and in vivo, silencing of LDHA sensitized glioblastoma lines to IR and enhanced radiation-induced g-H2AX accumulation. Such sensitization was not observed after treatment with an LDHA inhibitor, suggesting the metabolic function of LDHA is distinct from its role in DNA repair. Supporting this hypothesis, truncation mutations that suppressed the LDHA glycolysis function minimally affected its role in DNA repair. Mechanistically, cytoplasmic LDHA translocates into the nucleus in response to IR. This translocation was associated with subsequent chromatin transition into an open conformation and enhanced homologous recombination. CONCLUSION The novel LDHA function in DNA repair suggests intricate crosstalks between glycolytic metabolism and DNA repair, offering a new platform for glioblastoma therapeutic development.

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

BACKGROUND AND IMPORTANCE Nerve root compression by an ectatic vertebral artery is a known but easily overlooked cause of cervical radiculopathy. Management options include nonoperative conservative therapies or surgical approaches designed to relieve the compression via anterior or posterior cervical approaches. CLINICAL PRESENTATION A 72-yr-old female presented with a 6-mo history of sharp, shooting pain in her right arm and shoulder and deltoid weakness. Imaging demonstrated a vertebral artery loop compressing the proximal right C5 nerve root. She previously underwent both nonoperative measures as well as posterior foraminotomy at this level with limited improvement in her pain. Therefore, we performed an anterolateral approach for vascular decompression of the C5 nerve root from the vertebral artery loop. Patient has been pain-free at 1 yr with full recovery of her deltoid weakness. CONCLUSION Vertebral artery loop formation is an uncommon cause of cervical radiculopathy, which can be readily treated by vascular decompression of the nerve root-vertebral artery loop complex. Although anomalous vertebral artery compression of a cervical nerve root is rare, it is increasingly being recognized as a readily treatable entity that can lead to lasting and full neurological recovery. We also include an operative video to illustrate the vascular decompression of an ectatic vertebral artery causing severe cervical radiculopathy.

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.

Background Pituitary apoplexy after resection of giant pituitary adenomas is a rare but often cited morbidity associated with devastating outcomes. It presents as hemorrhage and/or infarction of residual tumor in the postoperative period. Because of its rarity, its incidence and consequences remain ill defined. Objective The aim of this study is to estimate the rate of postoperative pituitary apoplexy after resection of giant pituitary adenomas and assess the morbidity and mortality associated with apoplexy. Methods A systematic review of literature was performed to examine extent of resection in giant pituitary adenomas based on surgical approach, rate of postoperative apoplexy, morbidities, and mortality. Advantages and disadvantages of each approach were compared. Results Seventeen studies were included in quantitative analysis describing 1,031 cases of resection of giant pituitary adenomas. The overall rate of subtotal resection ( Conclusion Postoperative pituitary apoplexy is uncommon but is associated with high rates of morbidity and mortality in subtotal resection cases. These findings highlight the importance in achieving a maximal resection in a time sensitive fashion to mitigate the severe consequences of postoperative apoplexy.

INTRODUCTION Exceptional responders refer to the rare subset of patients who derive extraordinary benefits from a therapy compared to most treated patients. Understanding the basis for such responses represents a key pillar in the framework of precision medicine. OBJECTIVE Here, we examine the molecular basis underlying exceptional responses in glioblastoma patients who underwent concurrent radiation and temozolomide (TMZ) therapy. METHODS mRNA profiles derived from clinically annotated glioblastoma specimens were analyzed by Single sample gene set enrichment (ssGSEA) and Gene Cluster Expression Summary Score (GCESS). Key results were confirmed using cell-based assays and murine glioblastoma models. RESULTS Integrated, multi-platform analyses of RNA profiles derived from clinically annotated glioblastoma samples revealed decreased accumulation of microglia/macrophages in the tumor microenvironment of exceptional responders. Further analysis revealed that glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) activate a STAT3-MYC signaling axis in glioblastoma cells. This signaling facilitated glioblastoma transition into stem cell states that confer enhanced tumorigenicity as well as resistance to the TMZ. Pharmacologic inhibition or genetic inactivation of a myeloid cell restricted isoform of PI3K, PI3K-gamma, disrupted this signaling axis by suppressing microglia/macrophage accumulation and IL11 secretion in the glioblastoma microenvironment. Mirroring the clinical outcome of exceptional responders, PI3K-gamma inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3K-gamma in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. CONCLUSIONS Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3K-gamma inhibition as a glioblastoma therapy.

Gross total resection (GTR) of contrast-enhancing tumor is associated with significantly increased overall survival in primary glioblastoma (GBM). Even when achieved, recurrence is likely, in part due to malignant cells infiltrating outside enhanced regions. Subsequently, there has been increasing interest in performing supratotal resections (SpTRs) for GBM. Published results have varied in part due to a lack of consensus on the definition of SpTR in GBM and its appropriate use. A crowdsourcing approach was used to survey 21 academic neurosurgical oncologists representing 13 health systems nationwide. Participants’ demographics including fellowship training status, years of experience, and operative volume with various techniques was collected. Participants were presented with 11 definitions of SpTR from published, peer-reviewed studies and asked to rate the appropriateness of each definition. Subsequently, participants reviewed T1-weighed post-contrast and FLAIR MR imaging videos in the axial, coronal, and sagittal planes for 22 GBMs. Participants were asked to assess eloquence of the tumor’s location, perceived equipoise of enrolling patients in a randomized clinical trial comparing GTR to SpTR, and their own personal surgical treatment plans. Most neurosurgeons surveyed (n=18, 85.7%) agree or strongly agree that GTR plus resection of some non-contrast enhancement is an appropriate definition for SpTR. Overall, there was only moderate inter-rater agreement, measured using sample variance and the index of qualitative variation, regarding eloquence, equipoise, and personal treatment plans. Neurosurgeons who performed more than 10 SpTRs for GBMs in the past year were more likely than counterparts to recommend it as their personal treatment plan (p< 0.005). Anterior temporal and right frontal GBMs were considered the best randomization candidates. We established a consensus definition for SpTR of GBM and identified anatomically distinct locations deemed most amenable to SpTR. These results will be used to plan prospective trials further investigating the potential clinical utility of SpTR for GBMs.

Evidence-based, clinical practice guidelines in the management of central nervous system tumors (CNS) continue to be developed and updated through the work of the Joint Section on Tumors of the Congress of Neurological Surgeons (CNS) and the American Association of Neurological Surgeons (AANS).The guidelines are created using the most current and clinically relevant evidence using systematic methodologies, which classify available data and provide recommendations for clinical practice.This update summarizes the Tumor Section Guidelines developed over the last five years for non-functioning pituitary adenomas, low grade gliomas, vestibular schwannomas, and metastatic brain tumors.

BACKGROUND: This is an update of the review originally published in 2011 and first updated in 2015. In most people with low‐grade gliomas (LGG), the primary treatment regimen remains a combination of surgery followed by postoperative radiotherapy. However, the optimal timing of radiotherapy is controversial. It is unclear whether to use radiotherapy in the early postoperative period, or whether radiotherapy should be delayed until tumour progression occurs. OBJECTIVES: To assess the effects of early postoperative radiotherapy versus radiotherapy delayed until tumour progression for low‐grade intracranial gliomas in people who had initial biopsy or surgical resection. SEARCH METHODS: Original searches were run up to September 2014. An updated literature search from September 2014 through November 2019 was performed on the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 11), MEDLINE via Ovid (September 2014 to November week 2 2019), and Embase via Ovid (September 2014 to 2019 week 46) to identify trials for inclusion in this Cochrane review update. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared early versus delayed radiotherapy following biopsy or surgical resection for the treatment of people with newly diagnosed intracranial LGG (astrocytoma, oligodendroglioma, mixed oligoastrocytoma, astroblastoma, xanthoastrocytoma, or ganglioglioma). Radiotherapy may include conformal external beam radiotherapy (EBRT) with linear accelerator or cobalt‐60 sources, intensity‐modulated radiotherapy (IMRT), or stereotactic radiosurgery (SRS). DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the trials for inclusion and risk of bias, and extracted study data. We resolved any differences between review authors by discussion. Adverse effects were also extracted from the study report. We performed meta‐analyses using a random‐effects model with inverse variance weighting. MAIN RESULTS: We included one large, multi‐institutional, prospective RCT, involving 311 participants; the risk of bias in this study was unclear. This study found that early postoperative radiotherapy was associated with an increase in time to progression compared to observation (and delayed radiotherapy upon disease progression) for people with LGG but did not significantly improve overall survival (OS). The median progression‐free survival (PFS) was 5.3 years in the early radiotherapy group and 3.4 years in the delayed radiotherapy group (hazard ratio (HR) 0.59, 95% confidence interval (CI) 0.45 to 0.77; P < 0.0001; 311 participants; 1 trial; low‐quality evidence). The median OS in the early radiotherapy group was 7.4 years, while the delayed radiotherapy group experienced a median overall survival of 7.2 years (HR 0.97, 95% CI 0.71 to 1.33; P = 0.872; 311 participants; 1 trial; low‐quality evidence). The total dose of radiotherapy given was 54 Gy; five fractions of 1.8 Gy per week were given for six weeks. Adverse effects following radiotherapy consisted of skin reactions, otitis media, mild headache, nausea, and vomiting. Rescue therapy was provided to 65% of the participants randomised to delayed radiotherapy. People in both cohorts who were free from tumour progression showed no differences in cognitive deficit, focal deficit, performance status, and headache after one year. However, participants randomised to the early radiotherapy group experienced significantly fewer seizures than participants in the delayed postoperative radiotherapy group at one year (25% versus 41%, P = 0.0329, respectively). AUTHORS' CONCLUSIONS: Given the high risk of bias in the included study, the results of this analysis must be interpreted with caution. Early radiation therapy was associated with the following adverse effects: skin reactions, otitis media, mild headache, nausea, and vomiting. People with LGG who underwent early radiotherapy showed an increase in time to progression compared with people who were observed and had radiotherapy at the time of progression. There was no significant difference in overall survival between people who had early versus delayed radiotherapy; however, this finding may be due to the effectiveness of rescue therapy with radiation in the control arm. People who underwent early radiation had better seizure control at one year than people who underwent delayed radiation. There were no cases of radiation‐induced malignant transformation of LGG. However, it remained unclear whether there were differences in memory, executive function, cognitive function, or quality of life between the two groups since these measures were not evaluated.

The endoscopic, endonasal transcribriform approach (EETA) is an important technique used to directly access the anterior skull base and is increasingly being used in the management of olfactory groove meningiomas (OGMs). As this approach requires removal of the cribriform plate and olfactory epithelium en route to the tumor, patients are anosmic postoperatively. Here, we report the development of phantosmia and dysgeusia in two patients who underwent EETAs for OGMs, which has not yet been reported in the literature. We hypothesize that phantosmia and dysgeusia may result from aberrant neuronal signals or misinterpretation centrally from the remaining distal portions of the olfactory and taste pathways. Since EETAs are newer than traditional open craniotomy-based techniques, reporting these outcomes will be important to appropriately counsel patients preoperatively.

Ventral masses of the craniocervical junction threaten the medulla and upper spinal cord leading to lower cranial nerve dysfunction and myelopathy. Traditional transoral and newer endonasal approaches can access ventral pathology in this region, though both remain challenging due to the competing goals of achieving sufficient decompression, yet mitigating risk to nearby critical neurovascular structures. Transoral approaches have traditionally been avoided for degenerative pseudotumor which generally slowly regresses following posterior fixation. Here, we present two cases of patients with significant retroodontoid degenerative pseudotumor and pannus causing dysphagia and myelopathy. The first patient was found with a large broad pannus requiring a wide decompression extending from lower clivus to inferior aspect of the C1 arch and odontoid process. The second patient had a more focal mass effect due to pannus and synovial cyst at the level of the inferior half of C1 and midodontoid. Both patients underwent an endoscopic endonasal transodontoid approach for immediate decompression followed by a posterior C1–C2 fusion. In these surgical videos, we highlight anatomic considerations in this critical area, demonstrate nuances of technique, and outline strategies to avoid complications and maximize exposure.The link to the video can be found at: https://youtu.be/19I-GQYGIr4.

Craniocervical instability due to chronic atlantoaxial dissociation presents the challenge of providing adequate decompression, reduction, and fixation to promote long-term stability while avoiding iatrogenic vertebral artery dissection or entrapment. The authors present one patient with chronic atlantoaxial dissociation and basilar invagination treated via Goel’s technique and with bilateral vertebral artery mobilization. There was substantial decompression and reduction postoperatively and the patient was discharged with a stable examination. Vertebral artery mobilization at the C1–2 junction can be safely performed via a standard midline suboccipital incision and dissection without vertebral artery injury.The video can be found here: https://youtu.be/VS1Mt1dBLO4.

Summary Ribonucleoprotein enzymes require dynamic conformations of their RNA constituents for regulated catalysis. Human telomerase employs a non-coding RNA (hTR) with a bipartite arrangement of domains—a template-containing core and a distal three-way junction (CR4/5) that stimulates catalysis through unknown means. Here, we show that telomerase activity unexpectedly depends upon the holoenzyme protein TCAB1, which in turn controls conformation of CR4/5. Cells lacking TCAB1 exhibit a marked reduction in telomerase catalysis without affecting enzyme assembly. Instead, TCAB1 inactivation causes unfolding of CR4/5 helices that are required for catalysis and for association with the telomerase reverse-transcriptase (TERT). CR4/5 mutations derived from patients with telomere biology disorders provoke defects in catalysis and TERT binding similar to TCAB1 inactivation. These findings reveal a conformational "activity switch" in human telomerase RNA controlling catalysis and TERT engagement. The identification of two discrete catalytic states for telomerase suggests an intramolecular means for controlling telomerase in cancers and progenitor cells.

Object Moyamoya disease/syndrome (MMD/S) is a progressive, occlusive vasculopathy of the intracranial vasculature that leads to ischemic and hemorrhagic strokes. Significant debate exists regarding the role of indirect cerebrovascular bypass surgery in its management. The authors review their institution's experience with indirect bypass in the surgical management of patients with MMD/S. Methods The authors conducted a retrospective review of patients with MMD/S who underwent encephaloduroarteriosynangiosis (EDAS), a form of indirect bypass, from 1996 to 2013. Results A total of 37 patients (52 hemispheres) underwent an EDAS procedure for MMD/S; 21 patients received revascularization of both hemispheres. Patients presented with the following: 49% with stroke, 35% with transient ischemic attack, 13% with hemorrhage, and 3% with seizure. The mean Suzuki grade was 3.46. The number of patients with a modified Rankin Scale score of 0–1 improved from 21 to 29 (p = 0.002) from the time of surgery to the time of last follow-up. The number of neurological events (i.e., transient ischemic attacks, strokes, and hemorrhages) decreased from a mean of 1.7 events per patient to 0.14 (p < 0.001). The mean length of follow-up was 32.8 months. Conclusions This series demonstrates that EDAS is an effective procedure for MMD/S in a North American cohort of patients.

Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME).We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses., National Cancer Institute (U.S.) (Grant P30-CA14051)

This 25-year-old woman presented after a second hemorrhage from a mesencephalic cavernous malformation. High-definition fiber tracking demonstrated lateral displacement of the corticospinal tracts, making a midline approach ideal. The lesion appeared to present to the third ventricle, but a transcallosal approach was abandoned due to the posterior third ventricular location and after FIESTA imaging revealed a superior and medial rim of normal parenchyma that would have to be transgressed to access the malformation. An endoscopic endonasal approach with interdural pituitary hemitransposition was performed. The interpeduncular cistern was accessed and the thalamoperforating arteries dissected to access the cavernous malformation that was completely removed in a piecemeal fashion. The patient’s preexisting internuclear ocular palsies and hemiparesis were slightly worsened after surgery as predicted by a drop in anterior tibialis motor evoked potentials. Postoperative MRI showed no infarct, and the hemiparesis was back to baseline at 1-month follow-up.The video can be found here: https://youtu.be/e6203R9HHmk.

Objective For multisession radiosurgery, no published data relate the volume and dose of cochlear irradiation to quantified risk of hearing loss. We conducted a retrospective, dosimetric study to evaluate the relationship between hearing loss after stereotactic radiosurgery (SRS) and the dose-volume of irradiated cochlea. Methods Cochlear dose data were retrospectively collected on consecutive patients who underwent SRS (18 Gy in 3 sessions) for vestibular schwanoma between 1999 and 2005 at Stanford University Hospital. Inclusion criteria included Gardner-Robertson (GR) grade I or II hearing prior to radiosurgical treatment, complete audiograms, and magnetic resonance imaging (MRI) follow-up. A cochlea dose-volume histogram was generated for each of the 94 patients who qualified for this study. Results GR grade I-II hearing posttreatment was maintained in 74% of patients (70/94). Median time to last follow-up audiogram was 2.4 years (range 0.4–8.9) and to last MRI was 3.6 years (range 0.5–9.4). Each higher level of cochlear irradiation was associated with increased risk of hearing loss. Larger cochlear volume was associated with lower risk of hearing loss. Controlling for differences in cochlear volume among subjects, each additional mm 3 of cochlea receiving 10 to 16 Gy (single session equivalent doses of 6.6–10.1 Gy 3 ) significantly increased the odds of hearing loss by approximately 5%. Conclusions Larger cochlear volume is associated with lower risk of hearing loss following trisession SRS for vestibular schwannoma. Controlling for this phenomenon, higher radiation dose and larger irradiated cochlear volume are significantly associated with higher risk of hearing loss. This study confirms and quantifies the risk of hearing loss following trisession SRS for vestibular schwannoma.

Glioblastoma, the most common and aggressive malignant brain tumor, is propagated by stem-like cancer cells refractory to existing therapies. Understanding the molecular mechanisms that control glioblastoma stem cell (GSC) proliferation and drug resistance may reveal opportunities for therapeutic interventions. Here we show GSCs can reversibly transition to a slow-cycling, persistent state in response to targeted kinase inhibitors. In this state, GSCs upregulate primitive developmental programs and are dependent upon Notch signaling. This transition is accompanied by widespread redistribution of repressive histone methylation. Accordingly, persister GSCs upregulate, and are dependent on, the histone demethylases KDM6A/B. Importantly, slow-cycling cells with high Notch activity and histone demethylase expression are present in primary glioblastomas before treatment, potentially contributing to relapse. Our findings illustrate how cancer cells may hijack aspects of native developmental programs for deranged proliferation, adaptation, and tolerance. They also suggest strategies for eliminating refractory tumor cells by targeting epigenetic and developmental pathways.

Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny1. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.

Human tumors are complex systems containing cells with diverse phenotypes, genotypes and epigenetic states; but current treatment strategies and models do not adequately reflect tumor composition in patients. High-grade gliomas are particularly heterogeneous tumors and currently represent the most common cause of cancer-related death in children. Increasing evidence indicates that treatment failure and resistance are at least in part due to this heterogeneity. We used single-cell RNA sequencing (scRNA-seq) to profile the transcriptome of thousands of single cells in pediatric high-grade glioma and reconstructed their cellular architecture. We found restricted expression of neural stem/progenitor expression programs in distinct subsets of cells, and observed that cellular programs evolve during genetic evolution. This suggests that both genetic and superimposed developmental programs contribute to tumor heterogeneity. These results provide unparalleled insight into the cellular composition of pediatric high-grade gliomas at the level of single-cell resolution, and open up new avenues for discovering novel therapeutic targets.

Telomerase is a ribonucleoprotein (RNP) complex that synthesizes telomere repeats in tissue progenitor cells and cancer cells. Active human telomerase consists of at least three principal subunits, including the telomerase reverse transcriptase, the telomerase RNA (TERC), and dyskerin. Here, we identify a holoenzyme subunit, TCAB1 (telomerase Cajal body protein 1), that is notably enriched in Cajal bodies, nuclear sites of RNP processing that are important for telomerase function. TCAB1 associates with active telomerase enzyme, established telomerase components, and small Cajal body RNAs that are involved in modifying splicing RNAs. Depletion of TCAB1 by using RNA interference prevents TERC from associating with Cajal bodies, disrupts telomerase-telomere association, and abrogates telomere synthesis by telomerase. Thus, TCAB1 controls telomerase trafficking and is required for telomere synthesis in human cancer cells.

Telomerase maintains cell viability and chromosomal stability through the addition of telomere repeats to chromosome ends. The reactivation of telomerase through the upregulation of TERT, the telomerase protein subunit, is an important step during cancer development, yet TERT protein function and regulation remain incompletely understood. Despite its close sequence similarity to human TERT (hTERT), we find that mouse TERT (mTERT) does not immortalize primary human fibroblasts. Here we exploit these differences in activity to understand TERT protein function by creating chimeric mouse-human TERT proteins. Through the analysis of these chimeric TERT proteins, we find that sequences in the human carboxy-terminal domain are critical for telomere maintenance in human fibroblasts. The substitution of the human carboxy-terminal sequences into the mouse TERT protein is sufficient to confer immortalization and maintenance of telomere length and function. Strikingly, we find that hTERT protein accumulates to markedly higher levels than does mTERT protein and that the sequences governing this difference in protein regulation also reside in the carboxy-terminal domain. These elevated protein levels, which are characteristic of hTERT, are necessary but not sufficient for telomere maintenance because stabilized mTERT mutants cannot immortalize human cells. Thus, the TERT carboxy terminus contains sequences that regulate TERT protein levels and determinants that are required for productive action on telomere ends.

Moyamoya disease/syndrome (MMD/S) is a progressive, occlusive vasculopathy of the intracranial vasculature that leads to ischemic and hemorrhagic strokes. Significant debate exists regarding the role of indirect cerebrovascular bypass surgery in its management. The authors review their institution's experience with indirect bypass in the surgical management of patients with MMD/S.The authors conducted a retrospective review of patients with MMD/S who underwent encephaloduroarteriosynangiosis (EDAS), a form of indirect bypass, from 1996 to 2013.A total of 37 patients (52 hemispheres) underwent an EDAS procedure for MMD/S; 21 patients received revascularization of both hemispheres. Patients presented with the following: 49% with stroke, 35% with transient ischemic attack, 13% with hemorrhage, and 3% with seizure. The mean Suzuki grade was 3.46. The number of patients with a modified Rankin Scale score of 0-1 improved from 21 to 29 (p = 0.002) from the time of surgery to the time of last follow-up. The number of neurological events (i.e., transient ischemic attacks, strokes, and hemorrhages) decreased from a mean of 1.7 events per patient to 0.14 (p0.001). The mean length of follow-up was 32.8 months.This series demonstrates that EDAS is an effective procedure for MMD/S in a North American cohort of patients.

SummaryTelomere maintenance by telomerase is impaired in the stem cell disease dyskeratosis congenita and during human aging. Telomerase depends upon a complex pathway for enzyme assembly, localization in Cajal bodies, and association with telomeres. Here, we identify the chaperonin CCT/TRiC as a critical regulator of telomerase trafficking using a high-content genome-wide siRNA screen in human cells for factors required for Cajal body localization. We find that TRiC is required for folding the telomerase cofactor TCAB1, which controls trafficking of telomerase and small Cajal body RNAs (scaRNAs). Depletion of TRiC causes loss of TCAB1 protein, mislocalization of telomerase and scaRNAs to nucleoli, and failure of telomere elongation. DC patient-derived mutations in TCAB1 impair folding by TRiC, disrupting telomerase function and leading to severe disease. Our findings establish a critical role for TRiC-mediated protein folding in the telomerase pathway and link proteostasis, telomere maintenance, and human disease.

Nerve sheath tumors (NSTs) arise from Schwann precursor cells and include neurofibromas, schwannomas, and malignant peripheral NSTs. More recently, hybrid NST with pathological features of both neurofibromas and schwannomas have been described. NSTs can present as sporadic solitary tumors or can present in the setting of neurofibromatosis 1 and 2, and schwannomatosis. This article summarizes the presentation, genetics, imaging, and treatment of these common tumors.

Mucormycosis is an invasive fungal infection associated with a high mortality. Cerebral mucor abscesses can result secondary to rhinocerebral or hematogenous spread. Amphotericin B, posaconazole, and aggressive surgical resection are the hallmarks of treatment. While amphotericin is typically administered intravenously, less is known about the use of intrathecal amphotericin B. We describe a 42-year-old man who developed a cerebellar mucor abscess after undergoing hematopoietic stem cell transplant for the treatment of myelodysplastic syndrome. In the post-operative period he was admitted to the neurocritical care unit and received liposomal amphotericin B intravenously and through an external ventricular drain. This patient demonstrates that utilization of an external ventricular drain for intrathecal antifungal therapy in the post-operative period may warrant further study in patients with difficult to treat intracranial fungal abscesses.

Because pial artery dilation during a 20- or 40-min hypoxic exposure was less than that observed during a 5- or 10-min exposure, stimulus duration determines the vascular response to hypoxia. Dynorphin (Dyn) modulates hypoxic pial dilation and contributes to decremented dilation during longer hypoxic exposures. This study was designed to determine whether vasopressin (VP) contributes to Dyn modulation of hypoxic pial dilation in newborn pigs equipped with a closed cranial window. Moderate (M) and severe (S) hypoxia (arterial [Formula: see text] ∼ 35 and 25 mmHg, respectively) had no effect on cerebrospinal fluid VP during a 5-min exposure but increased its concentration during longer exposure periods. The VP antagonist [β-mercapto-β,β-cyclopentamethylenepropionyl1, O-Me-Tyr2,Arg8]vasopressin (MEAVP) had no influence on pial dilation during the 5-min exposure but potentiated the 20- and 40-min M and S hypoxic exposure dilations: 21 ± 2 vs. 29 ± 3% and 23 ± 2 vs. 33 ± 2% for 20- and 40-min S hypoxic dilation before and after MEAVP. Topical VP during 5 min of hypoxia elicited dilation that was reversed to vasoconstriction during 20 min of S and 40 min of M and S hypoxia. Similarly, during 5 min of hypoxia, Dyn elicited dilation that was reversed to vasoconstriction during longer hypoxic periods. MEAVP blunted this Dyn-induced vasoconstriction. These data show that VP modulates hypoxic pial dilation in a stimulus duration-dependent manner and that VP contributes to the reversal of Dyn from a dilator to a constrictor during prolonged hypoxia. Finally, these data suggest that VP contributes to Dyn modulation of hypoxic cerebrovasodilation.