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Sacroiliac (SI) joint pathology is a newly appreciated contributor to lower back pain. Sacroiliac joint fusion (SIJF) has grown rapidly in popularity in association with the advent of minimally-invasive surgical techniques. This has led to an explosion of new medical devices used for SIJF. The objective of this article is to outline clinical trends, summarize the current data, and categorize novel devices for SIJF.Trends in SI joint pathology and fusion were obtained via the Healthcare Cost and Utilization Project's (HCUP) National Inpatient Sample (NIS) database and Web of Science. To review literature on devices for SIJF, PubMed was searched using the Boolean phrase "sacroiliac joint AND (fusion OR arthrodesis)" since 2010. To establish a list of SIJF devices not represented in the literature, searches were performed on the FDA 510(k), premarket approval, and de novo databases, as well as Google and LinkedIn. Literature review yielded 11 FDA-approved devices for minimally invasive SIJF. Database query yielded an additional 22 devices for a total of 33 devices. Twenty-one devices used the lateral transiliac approach, six posterior allograft approach, three posterolateral approach, and three combined the lateral transiliac and posterolateral approaches. The evidence for the lateral transiliac approach is the most robust. Many novel devices have been developed for minimally invasive SIJF over the past 10 years. Further randomized comparative trials are warranted to evaluate different surgical approaches and novel devices at this time.

Objective. Cervical spondylotic myelopathy (CSM) is a degenerative disorder leading to progressive decline in spinal cord function. Cervical laminoplasty (CLP) and cervical laminectomy with fusion (CLF) are standard treatments for multilevel CSM. However, it is still unclear whether one procedure over the other provides better outcomes. Here, we performed a comprehensive review of published articles that compare the clinical outcomes and costs between CLP and CLF for CSM. Methods. A literature search was performed using PubMed, Web of Science, and Cochrane databases. Strict exclusion criteria were applied, and included articles were then assessed for publication year, study design, and significant differences in outcome variables. Results. From 519 studies identified with search terms, 38 studies were included for the qualitative analysis. Statistically significant differences in the clinical outcomes and costs were found in 18 studies. Eleven studies were prospective or retrospective, and 8 studies were meta-analyses. For the outcome variables of interest, results were reported by classifying into prospective studies, retrospective studies, and meta-analyses. Conclusion. CLP and CLF are 2 of the most commonly performed surgical procedures for the treatment of CSM. Although CLP and CLF each provide satisfactory clinical outcomes for patients with CMS, CLP may result in better cervical range of motion and less cost, length of stay, operation time, blood loss, paraspinal muscular atrophy, and rate of nerve palsies as compared to CLF. The major limitation of CLP versus CLF comparison studies includes the heterogeneity in techniques and preoperative criteria. Thus, further validation and investigations in larger cohorts will be required.

Background A number of minimally invasive sacroiliac (SI) joint fusion solutions for placing implants exist, with reduced post-operative pain and improved outcomes compared to open procedures. The objective of this study was to compare two MIS SI joint fusion approaches that place implants directly across the joint by comparing the ilium and sacrum bone characteristics and SI joint separation along the implant trajectories. Methods Nine cadaveric specimens (n = 9) were CT scanned and the left and right ilium and sacrum were segmented. The bone density, bone volume fraction, and SI joint gap distance were calculated along lateral and posterolateral trajectories and compared using analysis of variance between the two orientations. Results Iliac bone density, indicated by the mean Hounsfield Unit, was significantly greater for each lateral trajectory compared to posterolateral. The volume of cortical bone in the ilium was greater for the middle lateral trajectory compared to all others and for the top and bottom lateral trajectories compared to both posterolateral trajectories. Cortical density was greater in the ilium for all lateral trajectories compared to posterolateral. The bone fraction was significantly greater in all lateral trajectories compared to posterolateral in the ilium. No differences in cortical volume, cortical density, or cancellous density were found between trajectories in the sacrum. The ilium was significantly greater in density compared with the sacrum when compared irrespective of trajectory (p < 0.001). The posterolateral trajectories had a significantly larger SI joint gap than the lateral trajectories (p < 0.001). Conclusion Use of the lateral approach for minimally invasive SI fusion allows the implant to interact with bone across a significantly smaller joint space. This interaction with increased cortical bone volume and density may afford better fixation with a lower risk of pull-out or implant loosening when compared to the posterolateral approach.

Introduction Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread throughout the world with a large medical and economic impact. On March 12, 2020, the World Health Organization (WHO) classified SARS-CoV-2 as a pandemic. As a result of this worldwide public health crisis, politicians, elected officials, and healthcare professionals emergently began trialing hydroxychloroquine (HCQ) in efforts to treat and prevent the transmission of the virus. This meta-analysis was performed to assess the effects of HCQ on patients with COVID-19. Methods This meta-analysis adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMA) guidelines. Selected articles published between December 2019 and July 2020 were found utilizing the following search engines: PubMed, Google Scholar, Cochrane Library, DisasterLit, Clinicaltrials.gov, Medrxiv, and Embase. Two independent physician reviewers screened eligible articles that met the inclusion and exclusion criteria of the analysis. The outcome measures analyzed were mortality rate, rate of disease progression/improvement, rate of disease severity, and adverse effects of treatment. Six out of 14 studies that met the study’s eligibility criteria were selected and further analyzed, with a total of 381 participants (n= 381). Conclusion From the studies analyzed, it was found that groups treated with HCQ had an overall mortality rate that was 2.5 times greater than that of the control group. HCQ treated patients had higher rates of adverse clinical outcomes and side effects compared with the control populations. Lastly, there was a 1.2 times higher rate of improvement in the group of HCQ treated patients with mild to moderate symptoms as compared to the control group.

Study Design: An in vitro biomechanics study. Objective: To evaluate the efficacy of triangular titanium implants in providing mechanical stabilization to a sacroiliac joint with primary and revision sized implants. Methods: Ten lumbopelvic cadaveric specimens were tested in 4 stages: intact, pubic symphysis sectioned, primary, and simulated revision. Primary treatment was performed using 3 laterally placed triangular titanium implants. To simulate revision conditions before and after bone ingrowth and ongrowth on the implants, 7.5-mm and 10.75-mm implants were randomly assigned to one side of each specimen during the simulated revision stage. A 6 degrees of freedom spinal loading frame was used to load specimens in 4 directions: flexion extension, lateral bending, axial torsion, and axial compression. Biomechanical evaluation was based on measures of sacroiliac joint rotational and translational motion. Results: Both primary and revision implants showed the ability to reduce translational motion to a level significantly lower than the intact condition when loaded in axial compression. Simulated revision conditions showed no statistically significant differences compared with the primary implant condition, with the exception of flexion-extension range of motion where motions associated with the revised condition were significantly lower. Comparison of rotational and translation motions associated with the 7.5- and 10.75-mm implants showed no significant differences between the treatment conditions. Conclusions: These results indicate that implantation of laterally placed triangular titanium implants significantly reduces the motion of a sacroiliac joint using either the primary and revision sized implants. No statistically significant differences were detected when comparing the efficacy of primary, 7.5-mm revision, or 10.75-mm revision implants.

Candida auris (C. auris) is an opportunistic ascomycetous budding yeast that has been emerging as an invasive, multidrug-resistant pathogen over the past 10 years since its discovery. This fungi is the first to be labeled as a public health threat according to the Centers for Disease Control (CDC) and has since become a major problem in the United States. This serves as a detailed overview of the various factors contributing to the pathogenicity of C. auris.

Intracranial ependymomas are rare tumors in adults. Thus, factors affecting prognosis are poorly understood. We performed a study to investigate whether tumor location is an important prognostic factor in adults who undergo surgery for intracranial ependymomas. PubMed was searched to identify studies that reported clinical outcomes in adult patients with intracranial ependymoma. Data were extracted for patient and tumor characteristics, extent of resection, progression-free survival (PFS), and overall survival (OS). Tumors were categorized as supratentorial or infratentorial and extraventricular or intraventricular. Presenting clinical features and tumor characteristics were tabulated. Kaplan–Meier and multivariate Cox regression survival analyses were performed to determine PFS and OS by tumor location. Extent of resection was also analyzed by tumor location. A total of 183 patients were included in the metaanalysis. Patients presented at a mean of 8.2 months with a myriad of clinical features. The mean tumor size was 3.38 cm, and 19.3% of tumors were cystic. Supratentorial tumors were most commonly located in the frontal and parietal lobes, and infratentorial tumors in the fourth ventricle. Supratentorial tumors demonstrated significantly poorer PFS (p < 0.001) and OS (p = 0.003) than infratentorial tumors, despite a higher rate of gross total resection (GTR) for the supratentorial tumors (72.6% versus 42.1%). Extraventricular ependymomas displayed significantly poorer PFS than intraventricular ependymomas (p = 0.009). In summary, supratentorial ependymomas have significantly poorer PFS and OS than their infratentorial counterparts, despite being more conducive to GTR, suggesting increased clinical aggressiveness. Extraventricular location is also associated with significantly poorer PFS than intraventricular location.

BACKGROUND Ependymomas constitute approximately 40% of primary intraspinal tumors. Current World Health Organization (WHO) grading may not correlate with observed progression-free survival (PFS). OBJECTIVE This retrospective study of prospectively collected data examines whether PFS is influenced by the histological grade or by the extent of resection. It also analyzes the usage and effectiveness of postoperative adjuvant radiotherapy. METHODS We reviewed 134 consecutive patients with ependymomas of all grades. Pathology slides were re-reviewed and the histological grades were confirmed by a single neuropathologist. Postoperative residual or recurrence was evaluated with follow-up magnetic resonance imaging. RESULTS There were 85 male and 49 female patients, ranging from 10 to 79 (median 41) years of age. Thirty patients had WHO grade I tumors, 101 had grade II tumors, and 3 had grade III tumors. Kaplan-Meier analysis of PFS demonstrated a mean duration of 6 years for grade I, 14.9 years for grade II, and 3.7 years for grade III (P < .001). In grade II ependymomas, mean PFS was 11.2 years with subtotal resection and 17.8 years with gross total resection (P < .01). PFS of patients who underwent subtotal resection was not significantly changed by adjuvant radiotherapy (P < .36). CONCLUSION Patients with grade II ependymoma have significantly longer PFS than patients with grade I ependymoma. The extent of resection did not affect PFS in grade I ependymoma but it did in grade II. Contrary to its higher grade, WHO grade II ependymoma carries a better prognosis than WHO grade I ependymoma.

Diffusely infiltrative astrocytomas (World Health Organization [WHO] grades II–IV) are characterized by their potential to widely penetrate the normal brain parenchyma.1 Glioblastoma multiforme (GBM) is the highest-grade astrocytoma, and its patterns of dissemination have been directly linked to survival, where widespread dissemination is thought to give rise to more aggressive phenotypes.2 Increasing evidence suggests that all GBM tumors consist of heterogeneous populations of tumor cells in varied differentiation status,3 including well-differentiated tumor cells and less-differentiated stem cells. The less-differentiated stem cells from tumors are characterized by their expression of neural stem cell markers, such as CD133,4 nestin,5 and Sox2 (sex determining region Y-box 2).6 Functionally, these glioblastoma stem cells have been defined by their potent capacity for developing tumors when implanted in animals, as well as their ability to give rise to both stem cells and well-differentiated tumor cells.4,7–13 Thus, the less-differentiated tumor stem cells have also been called brain tumor-initiating cells (BTICs).4 In addition to their enhanced self-renewal and cell differentiation potential, BTICs have been shown to have increased resistance to chemo- and radiotherapy.4,7–13 Therefore, they have been identified as potentially important targets of GBM therapy. While increasing evidence suggests that they play a role in glioma pathogenesis, very little evidence exists to date characterizing the invasive potential of BTICs. Limited evidence, based primarily on in vitro experiments, initially suggested that BTICs might be more invasive than differentiated glioma cells.14–16 However, the mechanism of the elevated invasive potential of BTICs has not been clearly delineated. Conversely, there is also evidence that cancer stem cells are not always invasive, depending on their phenotype, which further complicates our understanding of cancer stem cell biology.17 Recent research suggests that gliomas utilize ion channels, including Na+/K+-ATPase, to support their unusual growth and invasion by adjusting their shape and volume rapidly as they invade the brain parenchyma.18 The various isoforms of the β-subunit of Na+/K+-ATPase have been shown to act in regulating cellular adhesion, particularly in the context of cancer progression.19–21 The β2 isoform, also known as the adhesion molecule on glia (AMOG), is a heavily glycosylated protein that plays a role in cellular adhesion in the CNS.22,23 It is diffusely expressed in the gray matter but is expressed in only perivascular astrocytes in the white matter.24 Although AMOG is highly expressed in the normal adult CNS, evidence suggests that it may be downregulated in GBM.25 However, given the heterogeneity that exists among GBM tumors, it is not known whether this is universally true of GBM. Initial functional data characterizing AMOG suggest that it plays an active role in cellular adhesion and migration in the normal CNS.22,26 While loss of AMOG has been implicated in glioma invasion and migration, currently there are no data characterizing its function in invasion and migration specifically in human glioma cells. To further our understanding of the role of AMOG in GBM and particularly in BTICs in the context of glioma migration and invasion, we specifically investigated (i) whether AMOG protein expression correlated with glioma grade, (ii) whether AMOG is globally downregulated in GBM, (iii) whether AMOG is differentially expressed in BTICs compared with differentiated GBM cells from patient-matched tumor tissues, (iv) whether overexpression of AMOG in low-expressing GBM cells decreases invasion and affects migration or proliferation, (v) whether AMOG knockdown increases invasion of normal glial cells, and (vi) whether downregulation of AMOG in GBM is associated with worse clinical outcome.

Object Ependymomas are primary central nervous system tumors that occur more frequently in the spines of adults than they do there in children. Previous studies consist mainly of retrospective single-institutional experiences or case studies. In this study, a comprehensive literature review was performed on reported cases of spinal ependymoma treated with resection to determine whether tumor location along the spinal axis conveys important prognostic information. Methods A PubMed search was performed to identify all papers that included data on patients with spinal ependymoma. Only cases involving adult patients who underwent ependymoma resection with a clearly reported tumor location were included for analysis. Tumor locations were separated into 6 groups: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus + cauda equina. Kaplan-Meier survival and Cox regression analyses were performed to determine the effect of tumor location on progression-free survival (PFS) and overall survival (OS). Results A total of 447 patients who underwent resection of spinal ependymomas with clearly indicated location of tumor were identified. The most common locations of spinal ependymomas were the cervical (32.0%) and conus + cauda equina (26.8%) regions. The thoracolumbar and cervicomedullary regions had the fewest tumors (accounting for, respectively, 5.1% and 3.4% of the total number of cases). The conus + cauda equina and thoracolumbar regions had the highest percentage of WHO Grade I tumors, while tumors located above these regions consisted of mostly WHO Grade II tumors. Despite the tendency for benign grades in the lower spinal regions, PFS for patients with spinal ependymomas in the lower 3 regions (thoracic, thoracolumbar, conus + cauda equina) was significantly shorter (p < 0.001) than for those with tumors in the upper regions (cervicomedullary, cervical, cervicothoracic), but the difference in OS did not achieve statistical significance (p = 0.131). Conclusions Spinal ependymomas along different regions of spinal axis have different characteristics and clinical behaviors. Tumor grade, extent of resection, and PFS varied by tumor location (upper vs lower spinal regions), while OS did not. Recurrence rates were higher for the lower spinal cord tumors, despite a greater prevalence of lower WHO grade lesions, compared with upper spinal cord tumors, suggesting that tumor location along the spinal axis is an important prognostic factor.

Object Ependymoma is a common CNS tumor in children, with spinal cord ependymomas making up 13.1% of all ependymomas in this age group. The clinical features that affect prognosis in pediatric spinal cord ependymomas are not well understood. A comprehensive literature review was performed to determine whether a tumor location along the spinal cord is prognostically significant in children undergoing surgery for spinal cord ependymomas. Methods A PubMed search was performed to identify all papers that contained data on patients with spinal cord ependymomas. Only pediatric patients (age < 18 years) who underwent resection with a clearly reported tumor location were included in the analysis. Myxopapillary tumors were excluded from study. Tumor location was subdivided into 6 regions: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus medullaris. Kaplan-Meier survival and Cox regression analyses were performed to determine the effects of tumor location on progression-free survival (PFS) and overall survival (OS). Results Fifty-eight patients who underwent resection of spinal cord ependymomas were identified. Ependymomas were located all along the spinal cord but occurred with the highest frequency in the cervical region (29.3%). Progression-free survival was significantly better in patients with tumors arising in the upper portion of the spinal cord (p = 0.031), which remained significant in the multivariate Cox regression analysis (p < 0.05). Moreover, OS was significantly better in patients with upper spinal cord ependymomas than in those harboring ependymomas in the lower spinal cord (p = 0.048). Conclusions Although more common in adults, spinal ependymomas can occur anywhere along the spinal cord in the pediatric population; however, tumors occurring in the lower half of the spinal cord carry a worse prognosis with shorter PFS and OS. By comparison, ependymomas in the upper spinal cord recur later and less frequently, with little or no mortality in this patient group.

The authors' object in this paper was to review the definition, epidemiology, biology, resistance mechanisms, and treatment options for dopamine agonist–resistant prolactinomas (DARPs). Prolactinomas are relatively unique among primary brain tumors in that medical treatment alone using dopamine agonists carries a high probability of disease control or even radiographic and endocrine remission, and thus has replaced surgery as the first line of therapy. Unfortunately, slightly less than 10% of patients with prolactinomas do not experience normalization of their prolactin levels in response to dopamine agonists, and harbor tumors that are resistant to dopamine agonist therapy. A literature review underscores that in male patients these DARPs are more likely to be invasive macroadenomas than dopamine agonist–responsive prolactinomas and that they are also more angiogenic, more proliferative, and more likely to exhibit cellular atypia. Estrogen receptor antagonists and temozolomide are the most commonly applied medical therapies in cases in which resection and radiosurgery have not induced remission of the hyperprolactinemia. Dopamine agonist–resistant prolactinomas exhibit aggressive behavior and tend to be large, invasive, hyperangiogenic tumors with high mitotic indices, which makes their management via surgery, radiosurgery, or alternative medical therapies challenging, thus underscoring the need for novel medical therapies or treatment regimens that target these lesions.

BACKGROUND AND IMPORTANCE: We report a patient with lumbar subdural hematoma secondary to intracranial subarachnoid hemorrhage (SAH) presenting with bilateral foot drop and describe our management. CLINICAL PRESENTATION: A 37-year-old woman presented with grade 4 SAH and hydrocephalus requiring emergent external ventricular drainage. Angiography demonstrated a left vertebral artery dissection and pseudoaneurysm that was treated with embolization of the vertebral artery. Six days after admission, her neurologic examination significantly improved. She was awake, alert, following commands, and moving all her extremities normally except for bilateral foot drop. An MRI scan revealed a lumbar subdural hematoma with severe thecal sac compression at L4-S1. The patient was initially treated with expectant management followed by surgery after she demonstrated only modest improvement. Evacuation of the hematoma was undertaken by an L5-S1 laminectomy and drainage of the liquefied clot in the subdural, extra-arachnoid space. Postoperatively, the patient demonstrated improved strength in all muscle groups except for left lower extremity eversion. CONCLUSION: We present a case of subdural hematoma that caused bilateral foot drop. Neurologic improvement occured after evacuation of the hematoma.

Induction of hippocampal long-term potentiation (LTP) requires activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), whereas maintenance of LTP additionally requires protein synthesis. We recently reported that CaMKII stimulates protein synthesis in depolarized hippocampal neurons through phosphorylation of the mRNA translation factor cytoplasmic polyadenylation element-binding protein (CPEB), and this phosphorylation is rapidly reversed by protein phosphatase 1 (PP1). Protein synthesis-dependent late-phase LTP (L-LTP) in the hippocampus requires calcium influx through the NMDA-type glutamate receptor (NMDA-R) to activate CaMKII as well as concomitant inhibition of PP1 mediated by protein kinase A. Therefore, we investigated the regulation of CPEB phosphorylation during L-LTP. Pharmacological stimulation of the NMDA-R in hippocampal slices to produce chemical long-term depression induced a brief dephosphorylation of CPEB. Modest LTP induction (once at 100 Hz), which induces a protein synthesis-independent early-phase LTP (E-LTP), resulted in a transient phosphorylation of CPEB. However, stronger stimulation (four times at 100 Hz), known to induce protein synthesis-dependent L-LTP, elicited a prolonged phosphorylation of CPEB. Furthermore, CPEB phosphorylation correlated with phosphorylation of PP1 inhibitor dopamine- and cAMP-regulated phosphoprotein, a known substrate for protein kinase A. These results evoke the hypothesis that bidirectional regulation of CPEB phosphorylation by CaMKII and protein phosphatases may serve as a mechanism to convert E-LTP into protein synthesis-dependent L-LTP by stimulating protein synthesis and thereby stabilizing synaptic enhancement.

BACKGROUND In 2003, Kanzaki and colleagues published a set of reporting standards for vestibular schwannoma (VS) to serve as a guide for future publication, with the specific purpose of promoting standardization of reporting results in VS. OBJECTIVE Here, the current published body of literature on VS cases treated with microsurgery was reviewed to determine its degree of adherence to consensus guidelines. METHODS A comprehensive search of the English language literature was performed to identify studies reporting outcome data in patients treated with microsurgery for VSs. Each publication was reviewed to determine whether it had properly reported each of the 7 items relevant to surgical management described in the Consensus Meeting reporting guidelines. The number of studies that had included each of the key items before and after the publication of the reporting guidelines was compared. RESULTS After the publication of the standards, there were a significantly greater proportion of studies that properly reported the nature of the tumor and facial nerve function. Since the publication of the Consensus Meeting Guidelines, there also were trends toward greater proportions of articles that properly reported the size, hearing function, preoperative symptoms, and postoperative complications of the patients treated. CONCLUSION Since the release of the reporting system guidelines for VS, the focus of the publications seems to have shifted away from basic clinical characteristics and toward posttreatment neurologic function. Future studies reporting the clinical characteristics and surgical outcomes for patients with VS cases should strive to include all the elements described in the Consensus Meeting guidelines.

G-protein coupled receptors (GPCRs) are among the most diverse and ubiquitous proteins in all of biology. The epidermal growth factorseven span transmembrane (EGF-TM7) subfamily of adhesion GPCRs is a small subset whose members are mainly expressed on the surface of leukocytes. The EGF domains on the N-terminus add significant size to these receptors and they are considered to be among the largest members of the TM7 family. Although not all of their ligands or downstream targets have been identified, there is evidence implicating the EGF-TM7 family diverse processes such as cell adhesion, migration, inflammation, and autoimmune disease. Recent studies have identified expression of EGF-TM7 family members on human neoplasms including those of the thyroid, stomach, colon, and brain. Their presence on these tissues is not surprising given the ubiquity of GPCRs, but because their functional significance and pathways are not completely understood, they are of tremendous clinical and scientific interest. Current evidence suggests that expression of certain EGF-TM7 receptors is correlated with tumor grade, confers a more invasive phenotype, and increases the likelihood of metastatic disease. In this review, we will discuss the structure, function, and regulation of these receptors. We also describe the expression of these receptors in human cancers and explore their potential mechanistic significance.

Choroid plexus carcinoma (CPCs) is a rare, malignant, primary brain tumor with a poor prognosis. Currently, there is no consensus on the use of adjuvant therapy, and few large-scale studies focus exclusively on the pediatric population. We performed a comprehensive systematic review of pediatric CPCs to determine the effects of various adjuvant therapy modalities on overall survival (OS). A literature search was performed to identify studies reporting children with CPC who underwent surgical resection. Only patients who had clearly received adjuvant therapy, or were described as not selected for adjuvant therapy were analyzed in our comparison groups. Kaplan-Meier and multivariate Cox regression survival analyses were performed to determine the effects of different types of adjuvant therapies on OS. A total of 135 children (age ≤ 18 years) with CPC who had known adjuvant therapy status and OS were identified from 53 articles. Kaplan-Meier analysis showed that while adjuvant therapy overall improved OS (p = 0.001), different modes of adjuvant therapies had varying effects on OS (p = 0.034). Specifically, combined chemo-radiotherapy as well as chemotherapy alone improved OS (p = 0.001), but radiation did not (p = 0.129). Multivariate Cox proportional hazard model adjusting for confounding factors showed that combined therapy was associated with better OS compared to chemotherapy alone (HR: 0.291, p = 0.027). Both chemotherapy alone and combined chemo-radiation improved OS independent of age, gender, tumor location and extent of resection, while radiation alone did not. © 2014 Springer Science+Business Media New York.

Object Ependymomas are a common type of CNS tumor in children, although only 13% originate from the spinal cord. Aside from location and extent of resection, the factors that affect outcome are not well understood. Methods The authors performed a search of an institutional neuropathology database to identify all patients with spinal cord ependymomas treated over the past 20 years. Data on patient age, sex, clinical presentation, symptom duration, tumor location, extent of resection, use of radiation therapy, surgical complications, presence of tumor recurrence, duration of follow-up, and residual symptoms were collected. Pediatric patients were defined as those 21 years of age or younger at diagnosis. The extent of resection was defined by the findings of the postoperative MR images. Results A total of 24 pediatric patients with spinal cord ependymomas were identified with the following pathological subtypes: 14 classic (Grade II), 8 myxopapillary (Grade I), and 2 anaplastic (Grade III) ependymomas. Both anaplastic ependymomas originated in the intracranial compartment and spread to the spinal cord at recurrence. The mean follow-up duration for patients with classic and myxopapillary ependymomas was 63 and 45 months, respectively. Seven patients with classic ependymomas underwent gross-total resection (GTR), while 4 received subtotal resection (STR), 2 received STR as well as radiation therapy, and 1 received radiation therapy alone. All but 1 patient with myxopapillary ependymomas underwent GTR. Three recurrences were identified in the Grade II group at 45, 48, and 228 months. A single recurrence was identified in the Grade I group at 71 months. The mean progression-free survival (PFS) was 58 months in the Grade II group and 45 months in the Grade I group. Conclusions Extent of resection is an important prognostic factor in all pediatric spinal cord ependymomas, particularly Grade II ependymomas. These data suggest that achieving GTR is more difficult in the upper spinal cord, making tumor location another important factor. Although classified as Grade I lesions, myxopapillary ependymomas had similar outcomes when compared with classic (Grade II) ependymomas, particularly with respect to PFS. Long-term complications or new neurological deficits were rare. Among patients with long-term follow-up, those who underwent GTR had a recurrence rate of 20% compared with 40% among those with STR or biopsy only, suggesting that extent of resection is perhaps a more important prognostic factor than histological grade in predicting PFS, which has been suggested by other data in the literature. Given the relative paucity of these lesions, collaborative multiinstitutional studies are needed, and such efforts should also focus on molecular and genetic analysis to refine the current classification system.

Choroid plexus carcinoma (CPC) is a rare, malignant, primary brain tumor with a poor prognosis. While previous reports have shown benefits of aggressive surgery, very few large-scale studies have focused exclusively on the pediatric population, for whom the risks of aggressive surgery must be weighed carefully against the benefits. We performed a comprehensive systematic review of pediatric CPCs to test the effects of gross total resection (GTR) on overall survival (OS) and progression-free survival (PFS). A Pubmed search was performed to identify children with CPC who underwent surgical resection. Only disaggregated clinical cases in which extent of resection was confirmed by CT or MRI were included for analysis. Kaplan-Meier and multivariate Cox regression survival analyses were performed to determine the effects of extent of resection on OS and PFS. Disaggregated clinical data from a total of 102 pediatric CPC patients (age≤18years) with known extent of resection and overall survival were analyzed. GTR was significantly associated with better OS by Kaplan-Meier analysis (logrank p&nbsp

Purpose: Prognostic factors affecting outcomes in pediatric spinal cord ependymomas are limited. We sought to investigate potential associations between extent of resection and histologic grade on progression-free survival (PFS) and overall survival (OS). Methods: A comprehensive literature search was performed to identify pediatric patients who underwent surgical resection for spinal cord ependymomas. Only manuscripts with clearly defined age, tumor grade, extent of resection, and clinical follow-up were included. Results: A total of 80 patients were identified with a histologic distribution as follows: 36 %25 myxopapillary (grade I), 54 %25 classical (grade II), and 10 %25 anaplastic (grade III). There was no association between tumor grade and PFS. The only factor associated with improved PFS was gross total resection (GTR), which remained significant in a multivariate model (hazard ratio (HR) = 0.248, p = 0.022). Moreover, older age (HR = 0.818, p = 0.026), GTR (HR = 0.042, p = 0.013), and anaplastic grade (HR = 19.847, p = 0.008) demonstrated a significant association with OS in a multivariate model. Conclusions: Among pediatric patients with spinal cord ependymomas, PFS did not differ across histologic grades but was prolonged among patients who underwent GTR. Age, extent of resection, and tumor grade were all significantly associated with survival. © 2013 Springer-Verlag Berlin Heidelberg.

G-protein coupled receptors (GPCRs) represent the most diverse and biologically ubiquitous protein receptors. The epidermal growth factor seven-span transmembrane (EGF-TM7) family consists of adhesion GPCRs with a diverse functional repertoire. CD97 is the most broadly expressed member with roles in cell adhesion, migration and regulation of intercellular junctions. CD97 is also expressed in a variety of human malignancies including those of the thyroid, stomach, colon and brain. CD97 confers an invasive phenotype and has been shown to correlate with tumor grade, lymph node invasion, metastatic spread and overall prognosis. More recently, CD97 was found to signal through Gα12/13, resulting in increased RHO-GTP levels. Proven roles in tumor invasion and signaling make CD97 an exciting novel therapeutic target. In this review, we will discuss the structure and function of this receptor, with a specific focus on its mechanistic significance in neoplastic diseases.

Mechanisms of invasion in glioblastoma (GBM) relate to differential expression of proteins conferring increased motility and penetration of the extracellular matrix. CD97 is a member of the epidermal growth factor seven-span transmembrane family of adhesion G-protein coupled receptors. These proteins facilitate mobility of leukocytes into tissue. In this study we show that CD97 is expressed in glioma, has functional effects on invasion, and is associated with poor overall survival. Glioma cell lines and low passage primary cultures were analyzed. Functional significance was assessed by transient knockdown using siRNA targeting CD97 or a non-target control sequence. Invasion was assessed 48 hours after siRNA-mediated knockdown using a Matrigel-coated invasion chamber. Migration was quantified using a scratch assay over 12 hours. Proliferation was measured 24 and 48 hours after confirmed protein knockdown. GBM cell lines and primary cultures were found to express CD97. Knockdown of CD97 decreased invasion and migration in GBM cell lines, with no difference in proliferation. Gene-expression based Kaplan-Meier analysis was performed using The Cancer Genome Atlas, demonstrating an inverse relationship between CD97 expression and survival. GBMs expressing high levels of CD97 were associated with decreased survival compared to those with low CD97 (p = 0.007). CD97 promotes invasion and migration in GBM, but has no effect on tumor proliferation. This phenotype may explain the discrepancy in survival between high and low CD97-expressing tumors. This data provides impetus for further studies to determine its viability as a therapeutic target in the treatment of GBM.

Choroid plexus papillomas are rare, benign tumors originating from the choroid plexus. Although generally found within the ventricular system, they can arise ectopically in the brain parenchyma or disseminate throughout the neuraxis. We sought to review recent advances in our understanding of the molecular biology and oncogenic pathways associated with this disease. A comprehensive PubMed literature review was conducted to identify manuscripts discussing the clinical, molecular, and genetic features of choroid plexus papillomas. Articles concerning diagnosis, treatment, and long-term patient outcomes were also reviewed. The introduction of atypical choroid plexus papilloma as a distinct entity has increased the need for accurate histopathologic diagnosis. Advances in immunohistochemical staining have improved our ability to differentiate choroid plexus papillomas from other intracranial tumors or metastatic lesions using combinations of key markers and mitotic indices. Recent findings have implicated Notch3 signaling, the transcription factor TWIST1, platelet-derived growth factor receptor, and the tumor necrosis factor–related apoptosis-inducing ligand pathway in choroid plexus papilloma tumorigenesis. A combination of commonly occurring chromosomal duplications and deletions has also been identified. Surgical resection remains the standard of care, although chemotherapy and radiotherapy may be considered for recurrent or metastatic lesions. While generally considered benign, these tumors possess a complex biology that sheds insight into other choroid plexus tumors, particularly malignant choroid plexus carcinomas. Improving our understanding of the molecular biology, genetics, and oncogenic pathways associated with this tumor will allow for the development of targeted therapies and improved outcomes for patients with this disease.

Ependymomas are primary central nervous system tumors that occur more frequently in the spines of adults than they do there in children. Previous studies consist mainly of retrospective single-institutional experiences or case studies. In this study, a comprehensive literature review was performed on reported cases of spinal ependymoma treated with resection to determine whether tumor location along the spinal axis conveys important prognostic information.A PubMed search was performed to identify all papers that included data on patients with spinal ependymoma. Only cases involving adult patients who underwent ependymoma resection with a clearly reported tumor location were included for analysis. Tumor locations were separated into 6 groups: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus + cauda equina. Kaplan-Meier survival and Cox regression analyses were performed to determine the effect of tumor location on progression-free survival (PFS) and overall survival (OS).A total of 447 patients who underwent resection of spinal ependymomas with clearly indicated location of tumor were identified. The most common locations of spinal ependymomas were the cervical (32.0%) and conus + cauda equina (26.8%) regions. The thoracolumbar and cervicomedullary regions had the fewest tumors (accounting for, respectively, 5.1% and 3.4% of the total number of cases). The conus + cauda equina and thoracolumbar regions had the highest percentage of WHO Grade I tumors, while tumors located above these regions consisted of mostly WHO Grade II tumors. Despite the tendency for benign grades in the lower spinal regions, PFS for patients with spinal ependymomas in the lower 3 regions (thoracic, thoracolumbar, conus + cauda equina) was significantly shorter (p0.001) than for those with tumors in the upper regions (cervicomedullary, cervical, cervicothoracic), but the difference in OS did not achieve statistical significance (p = 0.131).Spinal ependymomas along different regions of spinal axis have different characteristics and clinical behaviors. Tumor grade, extent of resection, and PFS varied by tumor location (upper vs lower spinal regions), while OS did not. Recurrence rates were higher for the lower spinal cord tumors, despite a greater prevalence of lower WHO grade lesions, compared with upper spinal cord tumors, suggesting that tumor location along the spinal axis is an important prognostic factor.

Despite the relatively low-grade of most central neurocytomas (CN), evidence suggests the existence of an aggressive subset with a propensity for recurrence. Recent studies have found the MIB-1 labeling index to be a prognostic indicator in CN. Here we review our experience with CN to analyze the relationships between extent of resection, adjuvant therapy, tumor histology, and clinical outcomes based on aggressive histology, as defined by MIB-1 labeling. A retrospective review was performed on histologically proven CN surgically resected from 1993 to 2009 at the University of California at San Francisco. Recurrence rates were analyzed using the Kaplan-Meier method with respect to MIB-1 labeling and extent of resection. All MIB-1 labeling indices were analyzed. A total of 18 patients were identified with a mean age of 30 years (range 17-58 years) and median follow-up of 40 months (5-173 months). The treatments were: gross total resection (GTR) alone (17% of patients), subtotal resection (STR) alone (50% of patients), STR plus radiotherapy (XRT: external beam or stereotactic radiosurgery: 28% of patients), or STR plus chemotherapy (5% of patients). The extent of resection and a MIB-1 labeling index >4% was predictive of recurrence (p4% with median time to recurrence of 23.5 months. The 2-year and 4-year recurrence rates in patients with MIB-1 labeling >4% were 50% and 75% respectively. No patient with a MIB-1 labeling index 4% can be a clinically useful prognostic indicator and can help guide adjuvant treatment.

Ependymoma is a common CNS tumor in children, with spinal cord ependymomas making up 13.1% of all ependymomas in this age group. The clinical features that affect prognosis in pediatric spinal cord ependymomas are not well understood. A comprehensive literature review was performed to determine whether a tumor location along the spinal cord is prognostically significant in children undergoing surgery for spinal cord ependymomas.A PubMed search was performed to identify all papers that contained data on patients with spinal cord ependymomas. Only pediatric patients (age18 years) who underwent resection with a clearly reported tumor location were included in the analysis. Myxopapillary tumors were excluded from study. Tumor location was subdivided into 6 regions: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus medullaris. Kaplan-Meier survival and Cox regression analyses were performed to determine the effects of tumor location on progression-free survival (PFS) and overall survival (OS).Fifty-eight patients who underwent resection of spinal cord ependymomas were identified. Ependymomas were located all along the spinal cord but occurred with the highest frequency in the cervical region (29.3%). Progression-free survival was significantly better in patients with tumors arising in the upper portion of the spinal cord (p = 0.031), which remained significant in the multivariate Cox regression analysis (p0.05). Moreover, OS was significantly better in patients with upper spinal cord ependymomas than in those harboring ependymomas in the lower spinal cord (p = 0.048).Although more common in adults, spinal ependymomas can occur anywhere along the spinal cord in the pediatric population; however, tumors occurring in the lower half of the spinal cord carry a worse prognosis with shorter PFS and OS. By comparison, ependymomas in the upper spinal cord recur later and less frequently, with little or no mortality in this patient group.

Esthesioneuroblastoma (EN) is a rare sinonasal tumor with varied aggressiveness and potential for intracranial invasion. EN is staged anatomically with radiographic evaluation using the Kadish staging system (stages A, B, and C) and histologically by using Hyam's criteria (grades 1-4). Here we show that despite radiographic evidence of aggressive features, the prognosis of patients with Kadish stage C EN is best predicted by tumor histology using Hyam's criteria. We retrospectively analyzed patients with EN with Kadish stage C who were evaluated and treated at our institution between 1995 and 2009. Clinical information was collected using patient medical records, imaging, and review of pathological specimens. Twenty patients with Kadish stage C EN were identified with mean age of 51 years (31-70 years) with a median follow-up of 41.4 months (1.3-175 months). Upon pathological review, 44.4% of patients had low-grade (1/2) and 55.6% had high-grade (3/4) histology. About 37.5% of patients with low-grade EN had undergone gross total resection (GTR) and the remaining 62.5% had GTR and adjuvant radiation, whereas 50% of patients with high-grade ER had undergone GTR, 20% had undergone GTR and adjuvant radiation, and 30% had been treated with a subtotal resection (STR) and adjuvant radiation. The 5-year and 10-year survival in patients with low-grade EN was 86% in comparison to 56% and 28% with high-grade EN, respectively. In patients with low-grade EN, the 2-year progression free survival (PFS) was 86% and the 5-year PFS was 65% in comparison to 73% and 49% in patients with high-grade EN, respectively. The patient's tumor histology (Hyam's criteria) appeared to be the best way of predicting the prognosis and for selecting patients for adjuvant radiotherapy.

Background. Ependymoma is the most common glial tumor of the adult spinal cord. Current consensus recommends surgical resection with gross total resection (GTR) whenever possible. We performed a comprehensive review of the literature to evaluate whether adjuvant radiotherapy after subtotal resection (STR) has any benefit. Methods. A PubMed search was performed to identify adult patients with spinal cord ependymoma who underwent surgical resection. Only patients who had clearly defined extent of resection with or without adjuvant radiotherapy were included for analysis. Kaplan-Meier and multivariate Cox regression survival analyses were performed to determine the effects of adjuvant radiotherapy on progression-free survival (PFS) and overall survival (OS). Results. A total of 348 patients underwent surgical resection of spinal cord ependymomas, where GTR was obtained in 77.0% (268/348) of patients. Among those who received STR, 58.8% (47/80) received adjuvant radiotherapy. PFS was significantly prolonged among those who received adjuvant radiotherapy after STR (log rank; P , .001). This prolonged PFS with adjuvant radiotherapy remained significant in multivariate Cox regression analysis (STR versus STR + RT group; hazard ratio (HR) ¼ 2.26, P ¼ .047). By contrast, improved OS was only associated with GTR (GTR versus STR + RT group; HR ¼ 0.07, P ¼ .001) and benign ependymomas (HR ¼ 0.16, P ¼ .001). Conclusions. Surgery remains the mainstay treatment for spinal cord ependymomas, where GTR provides optimal outcomes with longest PFS and OS. Adjuvant radiotherapy prolongs PFS after STR significantly, and OS is improved by GTR and benign tumor grade only.

Although the World Health Organization (WHO) categorizes spinal ependymomas into three histological grades, difference in surgical outcomes between WHO grades I and II tumors are unclear. For these benign tumors, prognosis may be best determined by factors other than tumor grade alone, such as extent of resection. To analyze the effects of the extent of resection on different grades of spinal ependymomas, we performed a comprehensive literature review to identify adult spinal ependymoma patients who received surgical resection with a clearly identifiable WHO grade. A total of 175 patients were identified. While grade III tumors carried the worst prognosis as expected (p

Pituitary carcinomas are defined as malignant primary neoplasms of the adenohypophysis with either systemic or craniospinal metastases. Although pituitary adenomas are common, pituitary carcinomas only make up 0.1% to 0.2% of all pituitary tumors. Prognosis is very poor with approximately 66% mortality in the first year of diagnosis. Although effective medical and surgical treatments are available for pituitary adenomas, pituitary carcinomas require a multimodality treatment including surgery, hormonal therapy, cytotoxic chemotherapy, and radiation with limited success. Here we review the clinical behavior and pathologic characteristics of pituitary carcinomas and the recent advances in potential therapies for this malignant disease.

Prolactinomas are the most common hormone-secreting pituitary adenomas, comprising 40% of all pituitary tumors. Prolactinomas present a unique challenge for clinicians, as these tumors are amenable to either medical or surgical treatments based on patients' comorbidities, tolerance to medical treatment, and the response of tumors to medical treatment. Rare prolactinomas that are unresponsive to either medical or surgical treatment modalities may be responsive to radiation therapy. This article reviews the recent advancements in the management of prolactinomas.

Glioblastoma multiforme (GBM) is a grade IV malignant brain tumor with high mortality and has been well known to involve many molecular pathways, including G-protein coupled receptor (GPCR)-mediated signaling (such as epithelial growth factor receptor [EGFR] and platelet derived growth factor receptor [PDGFR]). G protein-coupled receptor kinases (GRK) directly regulate GPCR activity by phosphorylating activated agonist-bound receptors to desensitize signaling and internalize receptors through beta-arrestins. Recent studies in various cancers, including prostate and breast cancer, have highlighted the role of change in GRK expression to oncogenesis and tumor proliferation. In this study, we evaluated the expression of GRK5 in grade II to grade IV glioma specimens using immunohistochemistry and found that GRK5 expression levels are highly correlated with aggressiveness of glioma. We used culture conditions to selectively promote the growth of either glioblastoma cells with stem cell markers (GSC) or differentiated glioblastoma cells (DGC) from fresh GBM specimens. GSC are known to be highly invasive and mobile, and have the capacity to self-renew and are more resistant to chemotherapy and radiation compared to differentiated populations of GBM. We examined the expression of GRK5 in these two sets of culturing conditions for GBM cells and found that GRK5 expression is upregulated in GSC compared to differentiated GBM cells. To better understand the role of GRK5 in GBM-derived stem cells, we created stable GRK5 knockdown and evaluated the proliferation rate. Using an ATP chemiluminescence assay, we show, for the first time, that knocking down the expression of GRK5 decreased the proliferation rate of GSC in contrast to control.

Choroid plexus carcinoma (CPC) is a World Health Organization (WHO) grade III brain tumor with a poor prognosis that occurs mainly in children. Gross total resection of CPC is highly recommended and is associated with improved overall survival, although it is often associated with increased morbidity. The use of adjuvant therapies has yet to be standardized, although evidence suggests that for patients with incompletely resected CPCs, a combination of chemotherapy and radiation therapy may be beneficial. The use of radiation therapy for younger children (

Tuberculosis is among the oldest and most devastating infectious diseases worldwide. Nearly one third of the world's population has active or latent disease, resulting in 1.5 million deaths annually. Central nervous system involvement, while rare, is the most severe form of tuberculosis. Manifestations include tuberculoma and tuberculous meningitis, with the majority of cases occurring in children and immunocompromised patients. Despite advancements in imaging and laboratory diagnostics, tuberculomas of the central nervous system remain a diagnostic challenge due to their insidious nature and nonspecific findings. On imaging studies tuberculous meningitis is characterized by diffuse basal enhancement, but tuberculomas may be indistinguishable from neoplasms. Early diagnosis is imperative, since clinical outcomes are largely dependent on timely treatment. Stereotactic biopsy with histopathological analysis can provide a definitive diagnosis, but is only recommended when non-invasive methods are inconclusive. Standard medical treatment includes rifampicin, isoniazid, pyrazinamide, and streptomycin or ethambutol. In cases of drug resistance, revision of the treatment regimen with second-line agents is recommended over the addition of a single drug to the first-line regimen. Advances in genomics have identified virulent strains of tuberculosis and are improving our understanding of host susceptibility. Neurosurgical referral is advised for patients with elevated intracranial pressure, seizures, or brain or spinal cord compression. This review synthesizes pertinent findings in the literature surrounding central nervous system tuberculoma in an effort to highlight recent advances in pathophysiology, diagnosis, and treatment.

Choroid plexus papillomas are rare neuroepithelial tumors found mainly in children. Although well studied in the pediatric population, there is a paucity of literature focusing specifically on adults. We sought to assess the relative advantage of gross total resection (GTR) and further characterize the natural history of this disease in adults. A comprehensive PubMed search was performed to identify adults who underwent surgical resection for choroid plexus papillomas with clearly reported age, tumor location, and extent of resection. Kaplan-Meier analysis was used to assess progression-free survival (PFS) and overall survival (OS). Multivariate analysis was performed using Cox proportional hazards models. A total of 193 patients were identified with a mean age of 39.9 ± 1.1 years. GTR was achieved in 72% of patients with subtotal resection (STR) in 28%. GTR was associated with a significant increase in both PFS (p = 0.015) and OS (p = 0.004) compared to STR. In a multivariate Cox proportional hazards model we found that only GTR was associated with recurrence (hazard ratio [HR] = 0.47, 95% confidence interval [CI] 0.25-0.90), while both age (HR = 1.03, 95% CI 1.00-1.05) and GTR (HR = 0.36, 95% CI 0.17-0.78) were associated with OS. Interestingly, our observed recurrence and death rates were higher than those in previously published studies. These findings demonstrate the benefit of GTR for the treatment of choroid plexus papillomas in adults. Our analysis suggests that these lesions are not as indolent as previously thought and while GTR is preferred, it is not always curative.

Supratentorial hemangioblastoma is a rare form of hemangioblastoma; little information is available regarding prognosis, treatment, and clinical characteristics, because the available literature is primarily composed of case reports and small case series. Therefore, we performed a systematic review of the literature to analyze clinical characteristics, disease progression, and surgical outcomes with respect to survival for supratentorial hemangioblastomas. The rate of progression-free survival (PFS) was determined using Kaplan-Meier analysis. Differences in categorical factors, including location of tumor and diagnosis of von Hippel-Lindau (VHL) disease, were analyzed using the Pearson χ2 test. A total of 106 articles met the search criteria, which combined for a total of 132 patients. Of the patients with supratentorial tumors, 60% had VHL disease, and 31 (84%) of 37 patients with tumors in the sellar/suprasellar region had associated VHL (χ2, P < .001). Five-year PFS for gross-total resection and subtotal resection were 100% and 53%, respectively (Log rank, P < .01). On the basis of our analysis of the literature on published cases of supratentorial hemangioblastoma, gross-total resection appears to be superior to other treatment modalities in extending PFS. Von Hippel–Lindau disease is positively correlated with supratentorial hemangioblastoma when compared with non-supratentorial CNS hemangioblastomas, particularly when present in the sellar/suprasellar region.

In an effort to promote a uniform standard for reporting clinical results, the Consensus Meeting on Systems for Reporting Results in Acoustic Neuroma was convened in 2001, and the results of this meeting have been summarized by Kanzaki et al. in 2003. We describe publication compliance to these reporting parameters in a systematic analysis of publications obtained through a comprehensive literature search on patients with vestibular schwannoma (VS) treated with stereotactic radiosurgery (SRS). Each publication was scored based on whether it had properly reported each of eight elements described in the Consensus Meeting Reporting Guidelines (Guidelines). We compared the proportions of studies and cases that included each of the eight items prior to, and after, publication of the Guidelines. A significantly greater proportion of studies appropriately reported the size of the tumor after the release of the Guidelines (98% compared to 85%, p = 0.04). A significantly greater number of cases were reported properly adhering to the Guidelines in seven of the eight elements, with the exception of the cystic nature of the tumor. Report of post-treatment neurologic symptoms and complications saw the greatest degree of increase from before to after the publication of the Guidelines (47% to 68% of cases published, p < 0.001). Our findings suggest a potentially significant impact of the Guidelines on the quality of the information included in studies.

Glioblastoma multiforme (GBM), the most aggressive form of primary brain tumors, contain small population of tumor cells that carry cancer stem cell properties. These brain tumor stem cells (BTSCs) are highly invasive and mobile, have the capacity to self-renew, and are more resistant to radiation and chemotherapy. BTSCs can migrate away from the primary tumor sites and form microsatellite tumors. Thus, BTSCs have been proposed to play a key role in tumor progression, metastasis, and recurrence. Recent studies indicate that neural stem cells have the innate ability to track down tumor cells and may even slow tumor growth and progression. Thus, therapeutic neural stem cells can be developed by “arming” normal neural stem cells with genes cytotoxic to glioma cells and, more importantly, to BTSCs. Studies are currently underway to explore this new therapeutic approach to treat GBM using neural stem cells.

Recent studies in stem cell biology have refined our understanding of the origin and progression of cancer. Identification and characterization of endogenous neural stem cells (NSCs), especially those in the adult human brain, have inspired new ideas for selectively targeting and destroying malignant gliomas. Gliomas consist of a heterogeneous population of cells, and some of these cells have characteristics of cancer stem cells. These brain tumor stem cells (BTSCs) share certain characteristics with normal NSCs. It is still unclear, however, whether malignant gliomas in human patients originate from these aberrant BTSCs. Nonetheless, the cellular and molecular similarities between BTSCs and normal NSCs suggest a common research landscape underlying both normal and cancer stem cell biology, wherein findings of one field are relevant to the other. Furthermore, the natural tropism of NSCs to gliomas has generated the idea that modified NSCs can deliver modified genes to selectively destroy malignant brain tumor cells, and even BTSCs, while leaving healthy surrounding neurons intact. These studies and others on the basic biology of both BTSCs and NSCs will be crucial to expanding our treatment strategies for malignant gliomas.

Ca(2+)-permeable AMPA receptors (CP-AMPARs) at central glutamatergic synapses are of special interest because of their unique biophysical and signaling properties that contribute to synaptic plasticity and their roles in multiple neuropathologies. However, intracellular signaling pathways that recruit synaptic CP-AMPARs are unknown, and involvement of CP-AMPARs in hippocampal region CA1 synaptic plasticity is controversial. Here, we report that intracellular infusion of active CaM-kinase I (CaMKI) into cultured hippocampal neurons enhances miniature EPSC amplitude because of recruitment of CP-AMPARs, likely from an extrasynaptic pool. The ability of CaMKI, which regulates the actin cytoskeleton, to recruit synaptic CP-AMPARs was blocked by inhibiting actin polymerization with latrunculin A. CaMK regulation of CP-AMPARs was also confirmed in hippocampal slices. CA1 long-term potentiation (LTP) after theta bursts, but not high-frequency tetani, produced a rapid, transient expression of synaptic CP-AMPARs that facilitated LTP. This component of TBS LTP was blocked by inhibition of CaM-kinase kinase (CaMKK), the upstream activator of CaMKI. Our calculations show that adding CP-AMPARs numbering

Activity-dependent changes in the strength of excitatory synapses are a cellular mechanism for the plasticity of neuronal networks that is widely recognized to underlie cognitive functions such as learning and memory. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs) are the main transducers of rapid excitatory transmission in the mammalian CNS, and recent discoveries indicate that the mechanisms which regulate AMPARs are more complex than previously thought. This review focuses on recent evidence that alterations to AMPAR functional properties are coupled to their trafficking, cytoskeletal dynamics and local protein synthesis. These relationships offer new insights into the regulation of AMPARs and synaptic strength by cellular signalling.

Enhancement of synaptic transmission, as occurs in long-term potentiation (LTP), can result from several mechanisms that are regulated by phosphorylation of the AMPA-type glutamate receptor (AMPAR). Using a quantitative assay of net serine 845 (Ser-845) phosphorylation in the GluR1 subunit of AMPARs, we investigated the relationship between phospho-Ser-845, GluR1 surface expression, and synaptic strength in hippocampal neurons. About 15% of surface AMPARs in cultured neurons were phosphorylated at Ser-845 basally, whereas chemical potentiation (forskolin/rolipram treatment) persistently increased this to 60% and chemical depression (N-methyl-D-aspartate treatment) decreased it to 10%. These changes in Ser-845 phosphorylation were paralleled by corresponding changes in the surface expression of AMPARs in both cultured neurons and hippocampal slices. For every 1% increase in net phospho-Ser-845, there was 0.75% increase in the surface fraction of GluR1. Phosphorylation of Ser-845 correlated with a selective delivery of AMPARs to extrasynaptic sites, and their synaptic localization required coincident synaptic activity. Furthermore, increasing the extrasynaptic pool of AMPA receptors resulted in stronger theta burst LTP. Our results support a two-step model for delivery of GluR1-containing AMPARs to synapses during activity-dependent LTP, where Ser-845 phosphorylation can traffic AMPARs to extrasynaptic sites for subsequent delivery to synapses during LTP.

GluR1 and GluR2 subunits compose AMPA receptors (AMPARs) in the mature hippocampus, and both the GluR1 subunit and Ca2+/calmodulin-dependent protein kinase II (CaMKII) are required for synaptic plasticity, memory and learning. Although GluR1 phosphorylationby CaMKII is preserved, the functional regulation of AMPARs by phosphorylation is lost in the presence of the GIuR2 subunit. Our findings define a previously unknown, dominant role of the GluR2 subunit in signaling mediated by CaMKII at AMPARs.

Glioblastoma multiforme is the most malignant type of primary brain tumor with a poor prognosis. These tumors consist of a heterogeneous population of malignant cells, including well-differentiated tumor cells and less differentiated cells with stem cell properties. These cancer stem cells, known as brain tumor initiating cells, likely contribute to glioma recurrence, as they are highly invasive, mobile, resistant to radiation and chemotherapy, and have the capacity to self-renew. Glioblastoma tumor cells release excitotoxic levels of glutamate, which may be a key process in the death of peritumoral neurons, formation of necrosis, local inflammation, and glioma-related seizures. Moreover, elevated glutamate levels in the tumor may act in paracrine and autocrine manner to activate glutamate receptors on glioblastoma tumor cells, resulting in proliferation and invasion. Using a previously described culturing condition that selectively promotes the growth of brain tumor initiating cells, which express the stem cell markers nestin and SOX-2, we characterize the expression of α-amino-3-hydroxy-5-methyl-4-isozolepropionic acid (AMPA)-type glutamate receptor subunits in brain tumor initiating cells derived from glioblastomas. Here we show for the first time that glioblastoma brain tumor initiating cells express high concentrations of functional calcium-permeable AMPA receptors, compared to the differentiated tumor cultures consisting of non-stem cells. Up-regulated calcium-permeable AMPA receptor expression was confirmed by immunoblotting, immunocytochemistry, and intracellular calcium imaging in response to specific agonists. Our findings raise the possibility that glutamate secretion in the GBM tumor microenvironment may stimulate brain tumor derived cancer stem cells.

Avoidance of facial nerve injury is one of the major goals of vestibular schwannoma (VS) surgery because functional deficits of the facial nerve can lead to physical, cosmetic, and psychological consequences for patients. Clinically, facial nerve function is assessed using the House-Brackmann grading scale, which also allows physicians to track the progress of a patient's facial nerve recovery. Because the facial nerve is a peripheral nerve, it has the ability to regenerate, and the extent of its functional recovery depends largely on the location and nature of its injury. In this report, the authors first describe the facial nerve anatomy, the House-Brackmann grading system, and factors known to be predictors of postoperative facial nerve outcome. The mechanisms and pathophysiology of facial nerve injury during VS surgery are then discussed, as well as factors affecting facial nerve regeneration after surgery.