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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

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.

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.

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.

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.

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.

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)

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.

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.

INTRODUCTION:Gliomas are among the most lethal malignancies and their histogenesis in humans remains unresolved. IDH1 mutational status and co-occurring genetic alterations define major clinical and prognostic classes of gliomas that closely mirror their histologic classification into astrocytic or

Telomerase serves a critical role in stem cell function and tissue homeostasis. This role depends on its ability to synthesize telomere repeats in a manner dependent on the reverse transcriptase (RT) function of its protein component telomerase RT (TERT), as well as on a novel pathway whose mechanism is poorly understood. Here, we use a TERT mutant lacking RT function (TERTci) to study the mechanism of TERT action in mammalian skin, an ideal tissue for studying progenitor cell biology. We show that TERTci retains the full activities of wild-type TERT in enhancing keratinocyte proliferation in skin and in activating resting hair follicle stem cells, which triggers initiation of a new hair follicle growth phase and promotes hair synthesis. To understand the nature of this RT-independent function for TERT, we studied the genome-wide transcriptional response to acute changes in TERT levels in mouse skin. We find that TERT facilitates activation of progenitor cells in the skin and hair follicle by triggering a rapid change in gene expression that significantly overlaps the program controlling natural hair follicle cycling in wild-type mice. Statistical comparisons to other microarray gene sets using pattern-matching algorithms revealed that the TERT transcriptional response strongly resembles those mediated by Myc and Wnt, two proteins intimately associated with stem cell function and cancer. These data show that TERT controls tissue progenitor cells via transcriptional regulation of a developmental program converging on the Myc and Wnt pathways., Author Summary Stem cells and progenitor cells within a tissue are required to maintain tissue homeostasis and to repair tissues after injury by giving rise to differentiated daughter cells. Many progenitor cells express telomerase, a reverse transcriptase enzyme that adds DNA repeats to telomeres, the protective structures that cap chromosome ends. Telomere addition by telomerase is important for normal progenitor cell function and is crucial for enabling cancer cells to divide an unlimited number of times. In addition to its telomere-lengthening function, telomerase reverse transcriptase (TERT) can directly activate quiescent epidermal stem cells. However, the mechanism underlying this novel function for TERT is still not understood. In this study, we demonstrate that the catalytic activity of TERT is dispensable for its ability to activate tissue progenitor cells in vivo. Furthermore, using gene microarrays, we show that TERT controls a developmental program that overlaps the natural transcriptional program of hair follicle cycling in mouse skin. Using pattern-matching algorithms, we find that the TERT-controlled genetic program significantly resembles programs regulated by Myc and Wnt, two pathways critical for stem cell function and tumorigenesis. This paper reveals critical new insights into novel mechanisms of non-telomerase functions of TERT, identifying TERT as a developmental regulator linked to control of transcriptional responses.

Telomerase is a multi-subunit ribonucleoprotein (RNP) complex that adds telomere repeats to the ends of linear chromosomes. Three essential telomerase components have been identified thus far: the telomerase reverse transcriptase (TERT), the telomerase RNA component (TERC), and the TERC-binding protein dyskerin. Few other proteins are known to be required for human telomerase function, significantly limiting our understanding of both telomerase regulation and mechanisms of telomerase action. Here, we identify the ATPases pontin and reptin as telomerase components through affinity purification of TERT from human cells. Pontin interacts with both TERT and dyskerin, and the amount of TERT bound to pontin and reptin peaks in S phase, evidence for dynamic cell cycle-dependent regulation of TERT. Depletion of pontin and reptin markedly impairs accumulation of the telomerase RNP, indicating an essential role in telomerase assembly. These findings reveal an unanticipated requirement for additional enzymes in telomerase RNP biogenesis and suggest new approaches for inhibiting telomerase in human cancer.