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Small cell lung cancer (SCLC) has a propensity for brain metastases, which is associated with poor prognosis. We sought to determine predictors of overall survival (OS) and brain progression-free survival (bPFS) in SCLC patients with synchronous brain metastases at the time of initial SCLC diagnosis. A total of 107 SCLC patients with synchronous brain metastases treated at a single institution were included in this retrospective analysis. These patients had brain lesions present on initial staging imaging. Survival was estimated using the Kaplan-Meier method with log-rank test. Factors predictive of OS and bPFS were analyzed using Cox proportional hazards regression model. Median OS for the entire cohort was 9 months (interquartile range, 4.2-13.8 months) and median bPFS was 7.3 months (interquartile range, 3.5-11.1 months). OS was 30.3% at 1 year and 14.4% at 2 years, while bPFS was 22.0% at 1 year and 6.9% at 2 years. The median number of brain lesions at diagnosis was 3 (interquartile range, 2-8), and the median size of the largest metastasis was 2.0 cm (interquartile range, 1.0-3.3 cm). Increased number of brain lesions was significantly associated with decreased OS. Patients who received both chemotherapy and whole brain radiation therapy (WBRT) had improved OS (P=0.02) and bPFS (P=0.005) compared to those who had either chemotherapy or WBRT alone. There was no significant difference in OS or bPFS depending on the sequence of therapy or the dose of WBRT. Thirteen patients underwent upfront brain metastasis resection, which was associated with improved OS (P=0.02) but not bPFS (P=0.09) compared to those who did not have surgery. The combination of chemotherapy and WBRT was associated with improved OS and bPFS compared to either modality alone. Upfront brain metastasis resection was associated with improved OS but not bPFS compared to those who did not have surgery., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-641/coif). T.R.H. reports receiving consulting fees from Medtronics which is not relevant to the work in this paper. T.B. reports funding from National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) as national principle investigator (PI) of a clinical trial 04/22-3/23, which is not relevant to this study. A.D. reports participation in data safety monitoring board or advisory board on Ipsen, Amgen, Jazz, BMS, Astra Zeneca. S.C. reports receiving funding from the National Institutes of Health 01/20-11/23 (grant No. K12CA076917 to S.C. for salary support and research funds); participation in advisory boards for Telix Pharmaceuticals, Seagen Inc. and GT Medical. A.E.S. reports funding from U01 CS236215 06/19-5/23 (PI: Sloan), R01 CA 217956 06/17-05/22 (PI: Brady-Kalnay), R21 CA256573 01/21-12/22 (PI: Sloan), P01 CA CA245705-01 09/20-08/25 (PI: Lathia), Merck Case 3316 12/17-11/21 (PI: Sloan), Coulter Translational Research Fund 09/17-08/22 (PI: Brady-Kalnay), Jobs Ohio 5/22-11/23 (PI: Brady-Kalnay); options for <1% of company shares of Surgical Theater; consulting fees from Medtronic (Visualase), Monteris Medical Inc. and Surgical Theater; patents on the usage of PS-Binding CAR-T Cells and the procoagulant function of cancer stem cells. The other authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Objective: Neurosurgery has remained relatively homogeneous in terms of racial and gender diversity, trailing behind national demographics. Less than 5% of practicing neurosurgeons in the United States identify as Black/African American (AA). Research and academic productivity are highly emphasized within the field and are crucial for career advancement at academic institutions. They also serve as important avenues for mentorship and recruitment of diverse trainees and medical students. This study aimed to summarize the academic accomplishments of AA neurosurgeons by assessing publication quantity, h-index, and federal grant funding., Methods: One hundred thirteen neurosurgery residency training programs accredited by the Accreditation Council for Graduate Medical Education in 2022 were included in this study. The American Society of Black Neurosurgeons registry was reviewed to analyze the academic metrics of self-identified Black or AA academic neurosurgeons. Data on the academic rank, leadership position, publication quantity, h-index, and race of neurosurgical faculty in the US were obtained from publicly available information and program websites., Results: Fifty-five AA and 1393 non-AA neurosurgeons were identified. Sixty percent of AA neurosurgeons were fewer than 10 years out from residency training, compared to 37.4% of non-AA neurosurgeons (p = 0.001). AA neurosurgeons had a median 32 (IQR 9, 85) publications compared to 52 (IQR 22, 122) for non-AA neurosurgeons (p = 0.019). AA neurosurgeons had a median h-index of 12 (IQR 5, 24) compared to 16 (IQR 9, 31) for non-AA colleagues (p = 0.02). Following stratification by academic rank, these trends did not persist. No statistically significant differences in the median amounts of awarded National Institutes of Health funding (p = 0.194) or level of professorship attained (p = 0.07) were observed between the two cohorts., Conclusions: Racial disparities between AA and non-AA neurosurgeons exist in publication quantity and h-index overall but not when these groups are stratified by academic rank. Given that AA neurosurgeons comprise more junior faculty, it is expected that their academic accomplishments will increase as more enter academic practice and current neurosurgeons advance into more senior positions.

Background: Improving and fostering diversity within the neurosurgical workforce has become a high priority. This cross-sectional study aims to provide data on the diversity of neurosurgical oncology faculty (NSOF) in the US., Methods: All 115 neurosurgery (NS) Accreditation Council for Graduate Medical Education (ACGME) accredited programs were included in this study. The academic rank, academic and clinical title(s), gender, race, and hiring date of neurosurgical faculty with a primary focus on neurosurgical oncology (NSOF) were recorded. Geographical distribution and "top 10" programs were tabulated according to published data. Underrepresented minorities in medicine (URiM) faculty were identified according to the AAMC definition., Results: The NSOF workforce constitutes 21% of the total NS faculty. Of these, 10.1% are women and 9.9% are URiM (P < .001). Currently, 58% of neurosurgery programs (NSP) do not have URiM and/or women NSOF. The top 10 ranked NSP, according to Blue Ridge Institute for Medical Research, had a significantly less URiM NSOF (P = .019) than nontop 10 ranked programs. There was a decreasing trend in the proportion of URiM at higher academic ranks (P = .019). All of the URiM department chairs (3/113)-all men-and 1/3 women department chairs nationwide subspecialized in neurosurgical oncology., Conclusions: Neurosurgical oncology is a sought-after subspecialty attracting a fifth of neurosurgeons practicing in ACGME-accredited training programs. Changing demographics and the benefits of workforce diversity represent a great opportunity for our field to continue leading inclusion efforts and attracting the best and brightest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The sigma 2 receptor (σ 2 R) was recently identified as an endoplasmic reticulum (ER) membrane protein known as transmembrane protein 97 (TMEM97). Studies have shown that σ 2 R/TMEM97 binding compounds are neuroprotective, suggesting a role of σ 2 R/TMEM97 in neurodegenerative processes. To understand the function of σ 2 R/TMEM97 in neurodegeneration pathways, we characterized ischemia-induced retinal ganglion cell (RGC) degeneration in TMEM97 -/- mice and found that RGCs in TMEM97 -/- mice are resistant to degeneration. In addition, intravitreal injection of a selective σ 2 R/TMEM97 ligand DKR-1677 significantly protects RGCs from ischemia-induced degeneration in wildtype mice. Our results provide conclusive evidence that σ 2 R/TMEM97 plays a role to facilitate RGC death following ischemic injury and that inhibiting the function of σ 2 R/TMEM97 is neuroprotective. This work is a breakthrough toward elucidating the biology and function of σ 2 R/TMEM97 in RGCs and likely in other σ 2 R/TMEM97 expressing neurons. Moreover, these findings support future studies to develop new neuroprotective approaches for RGC degenerative diseases by inhibiting σ 2 R/TMEM97., (© 2022. The Author(s).)

Establishment of a diverse neurosurgical workforce includes increasing the recruitment of women in neurosurgery. The impact of pregnancy on the training and career trajectory of female neurosurgeons poses a barrier to recruitment and retention of women in neurosurgery. A recent Women in Neurosurgery survey evaluated female neurosurgeons' perception and experience regarding childbearing of female neurosurgeons and identified several recommendations regarding family leave policies. Additionally, pregnancy may carry higher risk in surgical fields, yet little guidance exists to aid both the pregnant resident and her training program in optimizing the safety of the training environment with specific considerations to risks inherent in neurosurgical training. This review of current literature aims to address best practices that can be adopted by pregnant neurosurgery residents and their training programs to improve the well-being of these residents while considering the impact on their education and the educational environment for their colleagues.

Objective: Stereotactic radiosurgery (SRS) has recently emerged as a minimally invasive alternative to resection for treating multiple brain metastases. Given the lack of consensus regarding the application of SRS versus resection for multiple brain metastases, the authors aimed to conduct a systematic literature review of all published work on the topic., Methods: The PubMed, OVID, Cochrane, Web of Science, and Scopus databases were used to identify studies that examined clinical outcomes after resection or SRS was performed in patients with multiple brain metastases. Radiological studies, case series with fewer than 3 patients, pediatric studies, or national database studies were excluded. Data extracted included patient demographics and mean overall survival (OS). Weighted t-tests and ANOVA were performed., Results: A total of 1300 abstracts were screened, 450 articles underwent full-text review, and 129 studies met inclusion criteria, encompassing 20,177 patients (18,852 treated with SRS and 1325 who underwent resection). The OS for the SRS group was 10.2 ± 6 months, and for the resection group it was 6.5 ± 3.8 months. A weighted ANOVA test comparing OS with covariates of age, sex, and publication year revealed that the treatment group (p = 0.045), age (p = 0.034), and publication year (0.0078) were all independently associated with OS (with SRS, younger age, and later publication year being associated with longer survival), whereas sex (p = 0.95) was not., Conclusions: For patients with multiple brain metastases, SRS and resection are effective treatments to prolong OS, with published data suggesting that SRS may have a trend toward lengthened survival outcomes. The authors encourage additional work examining outcomes of treatments for multiple brain metastases.

Huntington's disease (HD) is a genetic neurodegenerative disease caused by an expanded CAG repeat in the Huntingtin ( HTT ) gene that encodes for an expanded polyglutamine (polyQ) repeat in exon-1 of the human mutant huntingtin (mHTT) protein. The presence of this polyQ repeat results in neuronal degeneration, for which there is no cure or treatment that modifies disease progression. In previous studies, we have shown that small molecules that bind selectively to σ 2 R/TMEM97 can have significant neuroprotective effects in models of Alzheimer's disease, traumatic brain injury, and several other neurodegenerative diseases. In the present work, we extend these investigations and show that certain σ 2 R/TMEM97-selective ligands decrease mHTT-induced neuronal toxicity. We first synthesized a set of compounds designed to bind to σ 2 R/TMEM97 and determined their binding profiles ( K i values) for σ 2 R/TMEM97 and other proteins in the central nervous system. Modulators with high affinity and selectivity for σ 2 R/TMEM97 were then tested in our HD cell model. Primary cortical neurons were cultured in vitro for 7 days and then co-transfected with either a normal HTT construct (Htt N-586-22Q/GFP) or the mHTT construct Htt-N586-82Q/GFP. Transfected neurons were treated with either σ 2 R/TMEM97 or σ 1 R modulators for 48 h. After treatment, neurons were fixed and stained with Hoechst, and condensed nuclei were quantified to assess cell death in the transfected neurons. Significantly, σ 2 R/TMEM97 modulators reduce the neuronal toxicity induced by mHTT, and their neuroprotective effects are not blocked by NE-100, a selective σ 1 R antagonist known to block neuroprotection by σ 1 R ligands. These results indicate for the first time that σ 2 R/TMEM97 modulators can protect neurons from mHTT-induced neuronal toxicity, suggesting that targeting σ 2 R/TMEM97 may lead to a novel therapeutic approach to treat patients with HD.

Objective: Many neurosurgeons resect nonenhancing low-grade gliomas (LGGs) by using an inside-out piecemeal resection (PMR) technique. At the authors' institution they have increasingly used a circumferential, perilesional, sulcus-guided resection (SGR) technique. This technique has not been well described and there are limited data on its effectiveness. The authors describe the SGR technique and assess the extent to which SGR correlates with extent of resection and neurological outcome., Methods: The authors identified all patients with newly diagnosed LGGs who underwent resection at their institution over a 22-year period. Demographics, presenting symptoms, intraoperative data, method of resection (SGR or PMR), volumetric imaging data, and postoperative outcomes were obtained. Univariate analyses used ANOVA and Fisher's exact test. Multivariate analyses were performed using multivariate logistic regression., Results: Newly diagnosed LGGs were resected in 519 patients, 208 (40%) using an SGR technique and 311 (60%) using a PMR technique. The median extent of resection in the SGR group was 84%, compared with 77% in the PMR group (p = 0.019). In multivariate analysis, SGR was independently associated with a higher rate of complete (100%) resection (27% vs 18%) (OR 1.7, 95% CI 1.1-2.6; p = 0.03). SGR was also associated with a statistical trend toward lower rates of postoperative neurological complications (11% vs 16%, p = 0.09). A subset analysis of tumors located specifically in eloquent brain demonstrated SGR to be as safe as PMR., Conclusions: The authors describe the SGR technique used to resect LGGs and show that SGR is independently associated with statistically significantly higher rates of complete resection, without an increase in neurological complications, than with PMR. SGR technique should be considered when resecting LGGs.

This study describes general methods for the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates through dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation of vinyl heterocycles with aryl- or heteroaryldiazoacetates. The reactions are highly diastereoselective and high asymmetric induction could be achieved using either ( R )-pantolactone as a chiral auxiliary or chiral dirhodium tetracarboxylate catalysts. For meta - or para -substituted aryl- or heteroaryldiazoacetates the optimum catalyst was Rh 2 ( R-p -Ph-TPCP) 4 . In the case of ortho -substituted aryl- or heteroaryldiazoacetates, the optimum catalyst was Rh 2 ( R -TPPTTL) 4 . For a highly enantioselective reaction with the ortho -substituted substrates, 2-chloropyridine was required as an additive in the presence of either 4 Å molecular sieves or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Under the optimized conditions, the cyclopropanation could be conducted in the presence of a variety of heterocycles, such as pyridines, pyrazines, quinolines, indoles, oxadiazoles, thiophenes and pyrazoles., Competing Interests: The authors declare the following competing financial interests., (This journal is © The Royal Society of Chemistry.)

Background: The objective of this study was to explore racial/ethnic factors that may be associated with survival in patients with glioblastoma by querying the National Cancer Database (NCDB)., Methods: The NCDB was queried for patients diagnosed with glioblastoma between 2004 and 2014. Patient demographic variables included age at diagnosis, sex, race, ethnicity, Charlson-Deyo score, insurance status, and rural/urban/metropolitan location of zip code. Treatment variables included surgical treatment, extent of resection, chemotherapy, radiation therapy, type of radiation, and treatment facility type. Outcomes included 30-day readmission, 30- and 90-day mortality, and overall survival. Multivariable Cox regression analyses were performed to evaluate variables associated with race and overall survival., Results: A total of 103 652 glioblastoma patients were identified. There was a difference in the proportion of patients for whom surgery was performed, as well as the proportion receiving radiation, when stratified by race ( P < .001). Black non-Hispanics had the highest rates of unplanned readmission (7.6%) within 30 days (odds ratio [OR]: 1.39 compared to White non-Hispanics, P < .001). Asian non-Hispanics had the lowest 30- (3.2%) and 90-day mortality (9.8%) when compared to other races (OR: 0.52 compared to White non-Hispanics, P = .031). Compared to White non-Hispanics, we found Black non-Hispanics (hazard ratio [HR]: 0.88, P < .001), Asian non-Hispanics (HR: 0.72, P < .001), and Hispanics (HR: 0.69, P < .001) had longer overall survival., Conclusions: Differences in treatment and outcomes exist between races. Further studies are needed to elucidate the etiology of these race-related disparities and to improve outcomes for all patients., (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Glioblastoma (GBM) is the most common primary malignant brain tumor in adulthood. Despite multimodality treatments, including maximal safe resection followed by irradiation and chemotherapy, the median overall survival times range from 14 to 16 months. However, a small subset of GBM patients live beyond 5 years and are thus considered long-term survivors., Methods: A retrospective analysis of the clinical, radiographic, and molecular features of patients with newly diagnosed primary GBM who underwent treatment at The University of Texas MD Anderson Cancer Center was conducted. Eighty patients had sufficient quantity and quality of tissue available for next-generation sequencing and immunohistochemical analysis. Factors associated with survival time were identified using proportional odds ordinal regression. We constructed a survival-predictive nomogram using a forward stepwise model that we subsequently validated using The Cancer Genome Atlas., Results: Univariate analysis revealed 3 pivotal genetic alterations associated with GBM survival: both high tumor mutational burden ( P = .0055) and PTEN mutations ( P = .0235) negatively impacted survival, whereas IDH1 mutations positively impacted survival ( P < .0001). Clinical factors significantly associated with GBM survival included age ( P < .0001), preoperative Karnofsky Performance Scale score ( P = .0001), sex ( P = .0164), and clinical trial participation ( P < .0001). Higher preoperative T1-enhancing volume ( P = .0497) was associated with shorter survival. The ratio of TI-enhancing to nonenhancing disease (T1/T2 ratio) also significantly impacted survival ( P = .0022)., Conclusions: Our newly devised long-term survival - predictive nomogram based on clinical and genomic data can be used to advise patients regarding their potential outcomes and account for confounding factors in nonrandomized clinical trials., (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Resection is a critical component in the initial treatment of glioblastoma (GBM). Often GBMs are resected using an intralesional method. Circumferential perilesional resection of GBMs has been described, but with limited data., Objective: To conduct an observational retrospective analysis to test whether perilesional resection produced a greater extent of resection., Methods: We identified all patients with newly diagnosed GBM who underwent resection at our institution from June 1, 1993 to December 31, 2015. Demographics, presenting symptoms, intraoperative data, method of resection (perilesional or intralesional), volumetric imaging data, and postoperative outcomes were obtained. Complete resection (CR) was defined as 100% resection of all contrast-enhancing disease. Univariate analyses employed analysis of variance (ANOVA) and Fisher's exact test. Multivariate analyses used propensity score-weighted multivariate logistic regression., Results: Newly diagnosed GBMs were resected in 1204 patients, 436 tumors (36%) perilesionally and 766 (64%) intralesionally. Radiographic CR was achieved in 69% of cases. Multivariate analysis demonstrated that perilesional tumor resection was associated with a significantly higher rate of CR than intralesional resection (81% vs 62%, multivariate odds ratio = 2.5, 95% confidence interval: 1.8-3.4, P < .001). Among tumors in eloquent cortex, multivariate analysis showed that patients who underwent perilesional resection had a higher rate of CR (79% vs 58%, respectively, P < .001) and a lower rate of neurological complications (11% vs 20%, respectively, P = .018) than those who underwent intralesional resection., Conclusion: Circumferential perilesional resection of GBM is associated with significantly higher rates of CR and lower rates of neurological complications than intralesional resection, even for tumors arising in eloquent locations. Perilesional resection, when feasible, should be considered as a preferred option., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Background: Glioblastoma (GBM) is the most common and most malignant glioma. Nonglioblastoma (non-GBM) gliomas (WHO Grades II and III) are invasive and also often fatal. The goal of this study is to determine whether sex differences exist in glioma survival., Methods: Data were obtained from the National Cancer Database (NCDB) for years 2010 to 2014. GBM (WHO Grade IV; N = 2073) and non-GBM (WHO Grades II and III; N = 2963) were defined using the histology grouping of the Central Brain Tumor Registry of the United States. Non-GBM was divided into oligodendrogliomas/mixed gliomas and astrocytomas. Sex differences in survival were analyzed using Kaplan-Meier and multivariable Cox proportional hazards models adjusted for known prognostic variables., Results: There was a female survival advantage in patients with GBM both in the unadjusted ( P = .048) and adjusted ( P = .003) models. Unadjusted, median survival was 20.1 months (95% CI: 18.7-21.3 months) for women and 17.8 months (95% CI: 16.9-18.7 months) for men. Adjusted, median survival was 20.4 months (95% CI: 18.9-21.6 months) for women and 17.5 months (95% CI: 16.7-18.3 months) for men. When stratifying by age group (18-55 vs 56+ years at diagnosis), this female survival advantage appeared only in the older group, adjusting for covariates ( P = .017). Women (44.1%) had a higher proportion of methylated MGMT (O 6 -methylguanine-DNA methyltransferase) than men (38.4%). No sex differences were found for non-GBM., Conclusions: Using the NCDB data, there was a statistically significant female survival advantage in GBM, but not in non-GBM., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Spinal metastases from primary intracranial glioblastoma (GBM) are infrequently reported, and the disease has yet to be well characterized. A more accurate description of its clinical presentation and patient survival may improve understanding of this pathology, guide patient care, and advocate for increased inclusion in GBM research. The authors sought to describe the clinical presentation, treatment patterns, and survival in patients with drop metastases secondary to primary intracranial GBM., Methods: A systematic review was performed using the PRISMA guidelines. PubMed/MEDLINE, Scopus, Web of Science, and Cochrane databases were queried for abstracts that included patients with primary intracranial GBM and metastases to the spinal axis. Descriptive statistics were used to evaluate characteristics of the primary brain lesion, timing of spinal metastases, clinical symptoms, anatomical location of the metastases, and survival and treatment parameters. Kaplan-Meier analysis and log-rank analysis of the survival curves were performed for selected subgroups., Results: Of 1225 abstracts that resulted from the search, 51 articles were selected, yielding 86 subjects. The patients' mean age was 46.78 years and 59.74% were male. The most common symptom was lumbago or cervicalgia (90.24%), and this was followed by paraparesis (86.00%). The actuarial median survival after the detection of spinal metastases was 2.8 months and the mean survival was 2.72 months (95% CI 2.59-4.85), with a 1-year cumulative survival probability of 2.7% (95% CI 0.51%-8.33%). A diagnosis of leptomeningeal disease, present in 53.54% of the patients, was correlated, and significantly worse survival was on log-rank analysis in patients with leptomeningeal disease (p = 0.0046; median survival 2.5 months [95% CI 2-3] vs 4.0 months [95% CI 2-6])., Conclusions: This study established baseline characteristics of GBMs metastatic to the spinal axis. The prognosis is poor, though these results will provide patients and clinicians with more accurate survival estimates. The quality of studies reporting on this disease pathology is still limited. There is significant need for improved reporting methods for spinal metastases, either through enrollment of these patients in clinical trials or through increased granularity of coding for metastatic central nervous system diseases in cancer databases.

Purpose: Gliosarcoma is characterized by the World Health Organization as a Grade IV malignant neoplasm and a variant of glioblastoma. The association of race and ethnicity with survival has been established for numerous CNS malignancies, however, no epidemiological studies have reported these findings for patients with gliosarcoma. The aim of this study was to examine differences by race and ethnicity in overall survival, 30-day mortality, 90-day mortality, and 30-day readmission., Methods: Data were obtained by query of the National Cancer Database (NCDB) for years 2004-2014. Patients with gliosarcoma were identified by International Classification of Diseases for Oncology, Third Edition (ICD-O-3)-Oncology morphologic code 9442/3 and topographical codes C71.0-C71.9. Differences in survival by race/ethnicity were examined using univariable and multivariable Cox proportional hazards models. Readmission and mortality outcomes were examined with univariable and multivariable logistic regression., Results: A total of 1988 patients diagnosed with gliosarcoma were identified (White Non-Hispanic n = 1,682, Black Non-Hispanic n = 165, Asian n = 40, Hispanic n = 101). There were no differences in overall survival, 30- and 90-day mortality, or 30-day readmission between the races and ethnicities examined. Median survival was 10.4 months for White Non-Hispanics (95% CI 9.8, 11.2), 10.2 months for Black Non-Hispanics (95% CI 8.6, 13.1), 9.0 months for Asian Non-Hispanics (95% CI 5.1, 18.2), and 10.6 months for Hispanics (95% CI 8.3,16.2). 7.3% of all patients examined had an unplanned readmission within 30 days., Conclusion: Race/ethnicity are not associated with differences in overall survival, 30-day mortality, 90-day mortality, or 30-day readmission following surgical intervention for gliosarcoma.

Compounds targeting the sigma 2 receptor, which we recently cloned and showed to be identical with transmembrane protein 97 (σ2R/TMEM97), are broadly applicable therapeutic agents currently in clinical trials for imaging in breast cancer and for treatment of Alzheimer's disease and schizophrenia. These promising applications coupled with our previous observation that the σ2R/TMEM97 modulator SAS-0132 has neuroprotective attributes and improves cognition in wild-type mice suggests that modulating σ2R/TMEM97 may also have therapeutic benefits in other neurodegenerative conditions such as traumatic brain injury (TBI). Herein, we report that DKR-1677, a novel derivative of SAS-0132 with increased affinity and selectivity for σ2R/Tmem97 ( K i = 5.1 nM), is neuroprotective after blast-induced and controlled cortical impact (CCI) TBI in mice. Specifically, we discovered that treatment with DKR-1677 decreases axonal degeneration after blast-induced TBI and enhances survival of cortical neurons and oligodendrocytes after CCI injury. Furthermore, treatment with DKR-1677 preserves cognition in the Morris water maze after blast TBI. Our results support an increasingly broad role for σ2R/Tmem97 modulation in neuroprotection and suggest a new approach for treating patients suffering from TBI.

Son of sevenless homologue 1 (SOS1) is a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on RAS. In its active form, GTP-bound RAS is responsible for numerous critical cellular processes. Aberrant RAS activity is involved in ∼30% of all human cancers; hence, SOS1 is an attractive therapeutic target for its role in modulating RAS activation. Here, we describe a new series of benzimidazole-derived SOS1 agonists. Using structure-guided design, we discovered small molecules that increase nucleotide exchange on RAS in vitro at submicromolar concentrations, bind to SOS1 with low double-digit nanomolar affinity, rapidly enhance cellular RAS-GTP levels, and invoke biphasic signaling changes in phosphorylation of ERK 1/2. These compounds represent the most potent series of SOS1 agonists reported to date.

Introduction: Medulloblastoma is an aggressive but potentially curable central nervous system tumor that remains a treatment challenge. Analysis of therapeutic targets can provide opportunities for the selection of agents., Methods: Using multiplatform analysis, 36 medulloblastomas were extensively profiled from 2009 to 2015. Immunohistochemistry, next generation sequencing, chromogenic in situ hybridization, and fluorescence in situ hybridization were used to identify overexpressed proteins, immune checkpoint expression, mutations, tumor mutational load, and gene amplifications., Results: High expression of MRP1 (89%, 8/9 tumors), TUBB3 (86%, 18/21 tumors), PTEN (85%, 28/33 tumors), TOP2A (84%, 26/31 tumors), thymidylate synthase (TS; 80%, 24/30 tumors), RRM1 (71%, 15/21 tumors), and TOP1 (63%, 19/30 tumors) were found in medulloblastoma. TOP1 was found to be enriched in metastatic tumors (90%; 9/10) relative to posterior fossa cases (50%; 10/20) (p = 0.0485, Fisher exact test), and there was a positive correlation between TOP2A and TOP1 expression (p = 0.0472). PD-1 + T cell tumor infiltration was rare, PD-L1 tumor expression was uncommon, and TML was low, indicating that immune checkpoint inhibitors as a monotherapy should not necessarily be prioritized for therapeutic consideration based on biomarker expression. Gene amplifications such as those of Her2 or EGFR were not found. Several unique mutations were identified, but their rarity indicates large-scale screening efforts would be necessary to identify sufficient patients for clinical trial inclusion., Conclusions: Therapeutics are available for several of the frequently expressed targets, providing a justification for their consideration in the setting of medulloblastoma.

Introduction: Surgery and radiation therapy are the standard treatment options for meningiomas, but these treatments are not always feasible. Expression profiling was performed to determine the presence of therapeutic actionable biomarkers for prioritization and selection of agents., Methods: Meningiomas (n = 115) were profiled using a variety of strategies including next-generation sequencing (592-gene panel: n = 14; 47-gene panel: n = 94), immunohistochemistry (n = 8-110), and fluorescent and chromogenic in situ hybridization (n = 5-70) to determine mutational and expression status., Results: The median age of patients in the cohort was 60 years, with a range spanning 6-90 years; 52% were female. The most frequently expressed protein markers were EGFR (93%; n = 44), followed by PTEN (77%; n = 110), BCRP (75%; n = 8), MRP1 (65%, n = 23), PGP (62%; n = 84), and MGMT (55%; n = 97). The most frequent mutation among all meningioma grades occurred in the NF2 gene at 85% (11/13). Recurring mutations in SMO and AKT1 were also occasionally detected. PD-L1 was expressed in 25% of grade III cases (2/8) but not in grade I or II tumors. PD-1 + T cells were present in 46% (24/52) of meningiomas. TOP2A and thymidylate synthase expression increased with grade (I = 5%, II = 22%, III = 62% and I = 5%, II = 23%, III = 47%, respectively), whereas progesterone receptor expression decreased with grade (I = 79%, II = 41%, III = 29%)., Conclusion: If predicated on tumor expression, our data suggest that therapeutics directed toward NF2 and TOP2A could be considered for most meningioma patients.

Circulating metabolomics profiling holds prognostic potential. However, such efforts have not been extensively carried out in glioblastoma. In this study, two-step (training and testing) metabolomics profiling was conducted from the plasma samples of 159 glioblastoma patients. Metabolomics profiling was tested for correlation with 2-year overall and disease-free survivals. Arginine, methionine, and kynurenate levels were significantly associated with 2-year overall survival in both the training and testing sets. In the combined sets, elevated levels of arginine and methionine were associated with a 34% and 37% increased probability whereas kynurenate was associated with a 55% decreased probability of 2-year overall survival. These three metabolites were also significantly associated with 2-year disease-free survival. Risk scores were generated using the linear combination of levels of these significant metabolites. Glioblastoma patients with a high-risk score exhibited a 2.41-fold decreased probability of 2-year overall survival (hazard ratio (HR) = 2.41; 95% Confidence Interval (CI) = 1.20-4.93) and a 3.17-fold decreased probability of 2-year disease free survival (HR = 3.17, 95%CI = 1.42-7.54) relative to those with a low-risk score. In conclusion, we identified a unique plasma metabolite profile that is predictive of glioblastoma prognosis., (© 2018 Wiley Periodicals, Inc.)

Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol. However, whether the sigma-2 receptor, recently cloned and identified as transmembrane protein 97 (σ2R/TMEM97), plays a role in alcohol-related behaviors is currently unknown. Using a Caenorhabditis elegans model, we identified two novel, selective σ2R/Tmem97 modulators that reduce alcohol withdrawal behavior via an ortholog of σ2R/TMEM97. We then show that one of these compounds blunted withdrawal-induced excessive alcohol drinking in a well-established rodent model of alcohol dependence. These discoveries provide the first evidence that σ2R/TMEM97 is involved in alcohol withdrawal behaviors and that this receptor is a potential new target for treating alcohol use disorder.

Deregulated RAS activity, often the result of mutation, is implicated in approximately 30% of all human cancers. Despite this statistic, no clinically successful treatment for RAS-driven tumors has yet been developed. One approach for modulating RAS activity is to target and affect the activity of proteins that interact with RAS, such as the guanine nucleotide exchange factor (GEF) son of sevenless homologue 1 (SOS1). Here, we report on structure-activity relationships (SAR) in an indole series of compounds. Using structure-based design, we systematically explored substitution patterns on the indole nucleus, the pendant amino acid moiety, and the linker unit that connects these two fragments. Best-in-class compounds activate the nucleotide exchange process at submicromolar concentrations in vitro, increase levels of active RAS-GTP in HeLa cells, and elicit signaling changes in the mitogen-activated protein kinase-extracellular regulated kinase (MAPK-ERK) pathway, resulting in a decrease in pERK1/2 T202/Y204 protein levels at higher compound concentrations.

The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently, we developed a single-copy model of amyloid precursor protein (SC&#95;APP) induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons. Our previous work with this model suggests that small molecule ligands of the sigma 2 receptor (σ2R), which was recently cloned and identified as transmembrane protein 97 (TMEM97), are neuroprotective. To determine structure-activity relationships for unexplored chemical space in our σ2R/Tmem97 ligand collection, we developed an in vivo high-content screening (HCS) assay to identify potential drug leads. The HCS assay uses our recently developed large-scale microfluidic immobilization chip and automated imaging platform. We discovered norbenzomorphans that reduced neurodegeneration in our C. elegans model, including two compounds that demonstrated significant neuroprotective activity at multiple doses. These findings provide further evidence that σ2R/Tmem97-binding norbenzomorphans may represent a new drug class for treating neurodegenerative diseases.

Circulating long non-coding RNAs (lncRNAs) are a new class of cancer biomarkers. However, their significance in predicting outcomes in glioblastoma patients is unclear. We measured the levels of six known oncogenic lncRNAs-CRNDE, GAS5, H19, HOTAIR, MALAT1, and TUG1 in serum samples from 106 patients with primary glioblastoma and analyzed their association with outcomes. High levels of HOTAIR were associated with decreased probability of 2-year overall survival (adjusted hazard ratio [HR] = 2.04; 95% confidence interval [CI] = 1.08-9.76), and disease-free survival (adjusted HR = 1.82; 95% CI = 1.04-6.17). High levels of GAS5 were associated with increased probability of 2-year overall survival (adjusted HR = 0.44; 95% CI = 0.18-0.99), and disease-free survival (adjusted HR = 0.46; 95% CI = 0.16-0.98). HOTAIR and GAS5 levels could serve as reciprocal prognostic predictors of survival and disease progression in patients with glioblastoma., (© 2017 Wiley Periodicals, Inc.)

Background: Despite a multiplicity of clinical trials testing immune checkpoint inhibitors, the frequency of expression of potential predictive biomarkers is unknown in glioma., Methods: In this study, we profiled the frequency of shared biomarker phenotypes. To clarify the relationships among tumor mutational load (TML), mismatch repair (MMR), and immune checkpoint expression, we profiled patients with glioma (n = 327), including glioblastoma (GBM) (n = 198), whose samples had been submitted for analysis from 2009 to 2016. The calculation algorithm for TML included nonsynonymous mutation counts per tumor, with germline mutations filtered out. Immunohistochemical analysis and next-generation sequencing were used to determine tumor-infiltrating lymphocyte expression positive for programmed cell death protein 1 (PD-1), PD ligand 1 (PD-L1) expression on tumor cells, MMR (MLH1, MSH2, MSH6, and PMS2) protein expression and mutations, and DNA polymerase epsilon (POLE) mutations., Results: High TML was only found in 3.5% of GBM patients (7 of 198) and was associated with the absence of protein expression of mutL homolog 1 (MLH1) (P = .0345), mutS homolog 2 (MSH2) (P = .0099), MSH6 (P = .0022), and postmeiotic segregation increased 2 (PMS2) (P = .0345) and the presence of DNA MMR mutations. High and moderate TML GBMs did not have an enriched influx of CD8+ T cells, PD-1+ T cells, or tumor-expressed PD-L1. IDH1 mutant gliomas were not enriched for high TML, PD-1+ T cells, or PD-L1 expression., Conclusions: To clarify the relationships among TML, MMR, and immune checkpoint expression, we profiled the frequency of shared biomarker phenotypes. On the basis of a variety of potential biomarkers of response to immune checkpoints, only small subsets of glioma patients are likely to benefit from monotherapy immune checkpoint inhibition., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

A unique approach to gliocladin C and related alkaloids was developed that features an unprecedented nucleophilic addition of a diketopiperazine to an isatin derivative followed by a Friedel-Crafts alkylation of the resultant tertiary alcohol with indole to set the key quaternary center. Chemoselective oxindole reduction and cyclization delivered a pivotal hexahydropyrrolo[2,3-b]indole diketopiperazine intermediate that was readily converted into (±)-gliocladin C, (±)-T988C, and (±)-gliocladine C, culminating in the shortest approach to these alkaloids reported to date.

Some norbenzomorphans exhibit high affinity for sigma 1 and sigma 2 receptors, and varying the position of substituents on the aromatic ring of this scaffold has a significant effect on subtype selectivity. In particular, compounds bearing several different substituents at C7 of the norbenzomorphan ring system exhibit a general preference for the sigma 1 receptor, whereas the corresponding C8-substituted analogues preferentially bind at the sigma 2 receptor. These findings suggest that the norbenzomorphan scaffold may be a unique chemical template that can be easily tuned to prepare small molecules for use as tool compounds to study the specific biological effects arising from preferential binding at either sigma receptor subtype. In the absence of structural characterization data for the sigma 2 receptor, such compounds will be useful toward refining the pharmacophore model of its binding site.

Immunotherapy for glioblastoma (GBM) provides a unique opportunity for targeted therapies for each patient, addressing individual variability in genes, tumor biomarkers and clinical profile. As immunotherapy has the potential to specifically target tumor cells with minimal risk to normal tissue, several immunotherapeutic strategies are currently being evaluated in clinical trials in GBM. With the Precision Medicine Initiative being announced in the President's State of the Union Address in 2016, GBM immunotherapy provides a useful platform for changing the landscape in treating patients with difficult disease., Competing Interests: Financial & competing interests disclosure The Dr Marnie Rose Foundation, the Ben and Catherine Ivy Foundation, The University of Texas MD Anderson Cancer Center GBM Moonshot Program, and the NIH grants CA1208113, P50 CA127001 and P30 CA016672. AB Heimberger has received research grants from Merck, has been a paid consultant for Bristol Myers Squibb, and receives licensing and royalty fees from Celldex Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Background: Tumor-based molecular biomarkers have redefined in the classification gliomas. However, the association of systemic metabolomics with glioma phenotype has not been explored yet., Methods: In this study, we conducted two-step (discovery and validation) metabolomic profiling in plasma samples from 87 glioma patients. The metabolomics data were tested for correlation with glioma grade (high vs low), glioblastoma (GBM) versus malignant gliomas, and IDH mutation status., Results: Five metabolites, namely uracil, arginine, lactate, cystamine, and ornithine, significantly differed between high- and low-grade glioma patients in both the discovery and validation cohorts. When the discovery and validation cohorts were combined, we identified 29 significant metabolites with 18 remaining significant after adjusting for multiple comparisons. Those 18 significant metabolites separated high- from low-grade glioma patients with 91.1% accuracy. In the pathway analysis, a total of 18 significantly metabolic pathways were identified. Similarly, we identified 2 and 6 metabolites that significantly differed between GBM and non-GBM, and IDH mutation positive and negative patients after multiple comparison adjusting. Those 6 significant metabolites separated IDH1 mutation positive from negative glioma patients with 94.4% accuracy. Three pathways were identified to be associated with IDH mutation status. Within arginine and proline metabolism, levels of intermediate metabolites in creatine pathway were all significantly lower in IDH mutation positive than in negative patients, suggesting an increased activity of creatine pathway in IDH mutation positive tumors., Conclusion: Our findings identified metabolites and metabolic pathways that differentiated tumor phenotypes. These may be useful as host biomarker candidates to further help glioma molecular classification.

A novel structural class with high affinity and subtype selectivity for the sigma 2 receptor has been discovered. Preliminary structure-affinity relationship data are presented showing that 8-substituted 1,3,4,5-tetrahydro-1,5-methanobenzazepine (norbenzomorphan) derivatives elicit modest to high selectivity for the sigma 2 over the sigma 1 receptor subtype. Indeed, piperazine analogue 8-(4-(3-ethoxy-3-oxopropyl)piperazin-1-yl)-1,3,4,5-tetrahydro-1,5-methanobenzazepine-2-carboxylate (SAS-1121) is 574-fold selective for the sigma 2 over the sigma 1 receptor, thereby establishing it as one of the more subtype-selective sigma 2 binding ligands reported to date. Emerging evidence has implicated the sigma 2 receptor in multiple health disorders, so the drug-like characteristics of many of the selective sigma 2 receptor ligands disclosed herein, coupled with their structural similarity to frameworks found in known drugs, suggest that norbenzomorphan analogues may be promising candidates for further development into drug leads., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Emerging immunotherapeutic strategies for the treatment of glioblastoma (GBM) such as dendritic cell (DC) vaccines, heat shock proteins, peptide vaccines, and adoptive T-cell therapeutics, to name a few, have transitioned from the bench to clinical trials. With upcoming strategies and developing therapeutics, it is challenging to critically evaluate the practical, clinical potential of individual approaches and to advise patients on the most promising clinical trials., Methods: The authors propose a system to prioritize such therapies in an organized and data-driven fashion. This schema is based on four categories of factors: antigenic target robustness, immune-activation and -effector responses, preclinical vetting, and early evidence of clinical response. Each of these categories is subdivided to focus on the most salient elements for developing a successful immunotherapeutic approach for GBM, and a numerical score is generated., Results: The Score Card reveals therapeutics that have the most robust data to support their use, provides a reference prioritization score, and can be applied in a reiterative fashion with emerging data., Conclusions: The authors hope that this schema will give physicians an evidence-based and rational framework to make the best referral decisions to better guide and serve this patient population.

Background: Surgical outcomes for intramedullary spinal cord tumors are affected by many variables including tumor histology and preoperative neurological function., Objective: To analyze the impact of tumor histology on neurological outcome in primary intramedullary spinal cord tumors., Methods: A retrospective review of 102 consecutive patients with intramedullary spinal cord tumors treated at a single institution between January 1998 and March 2009., Results: Ependymomas were the most common tumors with 55 (53.9%), followed by 21 astrocytomas (20.6%), 12 hemangioblastomas (11.8%), and 14 miscellaneous tumors (13.7%). Gross total resection was achieved in 50 ependymomas (90.9%), 3 astrocytomas (14.3%), 11 hemangioblastomas (91.7%), and 12 miscellaneous tumors (85.7%). At a mean follow-up of 41.8 months (range, 1-132 months), we observed recurrences in 4 ependymoma cases (7.3%), 10 astrocytoma cases (47.6%), 1 miscellaneous tumor case (7.1%), and no recurrence in hemangioblastoma cases. When analyzed by tumor location, there was no difference in neurological outcomes (P = .66). At the time of their last follow-up visit, 11 patients (20%) with an ependymoma improved, 38 (69%) remained the same, and 6 (10.9%) worsened. In patients with an astrocytoma, 1 (4.8%) improved, 10 (47.6%) remained the same, and 10 (47.6%) worsened. One patient (8.3%) with a hemangioblastoma improved and 11 (91.7%) remained the same. No patient with a hemangioblastoma worsened. In the miscellaneous tumor group, 2 (14.3%) improved, 10 (71.4%) remained the same, and 2 (14.3%) worsened. Preoperative neurological status (P = .02), tumor histology (P = .005), and extent of resection (P < .0001) were all predictive of functional neurological outcomes., Conclusion: Tumor histology is the most important predictor of neurological outcome after surgical resection because it predicts resectability and recurrence.

Study Design: Systematic review., Objective: To provide a systematic review of published literature on the impact of subsidence on clinical outcomes and radiographic fusion rates after anterior cervical discectomy and fusion with plates or without plates., Background: Subsidence of interbody implants is common after anterior cervical spine fusions. The impact of subsidence on fusion rates and clinical outcomes is unknown., Methods: Systematic literature review on published articles on anterior cervical discectomy and fusion, which objectively measured graft subsidence, radiographic fusion rates, and clinical outcomes between April 1966 and December 2010., Results: A total of 35 articles that measured subsidence and provided fusion rates and/or clinical outcomes were selected for inclusion. The mean subsidence rate ranged from 19.3% to 42.5%. The rate of subsidence based on the type of implant ranged from 22.8% to 35.9%. The incidence of subsidence was not impacted by the type of implant (P=0.98). The overall fusion rate of the combined studies was 92.8% and was not impacted by subsidence irrespective of subsidence definition or the measurement technique used (P=0.19). Clinical outcomes were evaluated in 27 of 35 studies with all studies reporting an improvement in patient outcomes postoperatively., Conclusions: Subsidence irrespective of the measurement technique or definition does not appear to have an impact on successful fusion and/or clinical outcomes. A validated definition and standard measurement technique for subsidence is needed to determine the actual incidence of subsidence and its impact on radiographic and clinical outcomes.

While advanced surgical techniques, radiation therapy and chemotherapeutic regimens provide a tangible benefit for patients with glioblastoma (GBM), the average survival from the time of diagnosis remains less than 15 months. Current therapy for GBM is limited by the nonspecific nature of treatment, prohibiting therapy that is aggressive and prolonged enough to eliminate all malignant cells. As an alternative, bispecific antibodies can redirect the immune system to eliminate malignant cells with exquisite potency and specificity. We have recently developed an EGF receptor variant III (EGFRvIII)-targeted bispecific antibody that redirects T cells to eliminate EGFRvIII-expressing GBM. The absolute tumor specificity of EGFRvIII and the lack of immunologic crossreactivity with healthy cells allow this therapeutic to overcome limitations associated with the nonspecific nature of the current standard of care for GBM. Evidence indicates that the molecule can exert therapeutically significant effects in the CNS following systemic administration. Additional advantages in terms of ease-of-production and off-the-shelf availability further the clinical utility of this class of therapeutics.

Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.

Background and Importance: Paragangliomas are rare tumors of neuroendocrine origin that arise from paraganglionic tissue of the extrachromaffin cell system. These lesions may be seen at various sites along the neuraxis. Primary thoracic paragangliomas have rarely been reported in the literature, with secretory thoracic lesions being exceedingly rare as only 3 previous cases have been cited., Clinical Presentation: A 49-year-old woman presented with episodes of hypertension, palpitations, and diaphoresis. Workup revealed positive urine catecholamines and a thoracic spine mass extending into the thoracic apex. Preoperative α-blockade with phenoxybenzamine was used followed by posterior decompression and tumor resection. Arthrodesis from C5 to T4 was subsequently performed, and the patient received postoperative radiation., Conclusion: Two years postoperatively, the patient has continued to have regression of her symptoms. We report a rare case of a catecholamine-secreting primary thoracic paraganglioma in a 49-year-old woman. These tumors should be treated carefully by the neurosurgeon with preoperative assistance from endocrinology for α-blockade, followed by gross total resection and postoperative radiation if residual tumor remains.

Inflammatory pseudotumor (IP) is a benign process that most commonly occurs in the lung and orbit. Extension into the central nervous system is extremely rare, and primary intraventricular lesions of the lateral ventricles are even more infrequent with only 2 cases reported in pediatric patients to date. Here, the authors present an unusual case of IP occurring in a 16-year-old female presenting with a 2-week history of progressive headaches and vomiting, without focal neurological deficits or radiographic evidence of hydrocephalus. The patient underwent left parietal craniotomy and complete resection of the tumor, with no signs of recurrence at 3-month follow-up. Although the rarity of intraventricular IP in pediatric patients can make its initial identification difficult, IP should be considered as a potential diagnosis in this population wherein good outcomes may be achieved following surgical resection., (Copyright © 2013 S. Karger AG, Basel.)

Background and Importance: To report a rare case of spinal intradural extraosseous Ewing sarcoma in an adult and review current literature. Although Ewing sarcoma belongs to the family, the treatment modalities are different, and thus the correct diagnosis is very important despite its rare occurrence., Clinical Presentation: A 56-year-old woman presented with nocturnal bilateral buttock and leg pain. Magnetic resonance imaging (MRI) showed an enhancing intradural extramedullary extraosseous tumor at L1., Intervention: A T12-L2 laminectomy was performed to resect the tumor. Immunohistochemical analysis confirmed the diagnosis of Ewing sarcoma. A thorough diagnostic workup did not reveal any bony origin of the tumor. Primary intradural central nervous system Ewing sarcoma is infrequently encountered and shares imaging and histopathological features with central primitive neuroectodermal tumors. Establishment of the right diagnosis is crucial because it mandates a distinct workup and treatment modality different from that for central primitive neuroectodermal tumor. Although osseous Ewing sarcoma predominantly occurs in children and young adults, extraosseous central nervous system Ewing sarcoma is not uncommon in adults and should therefore be considered in the differential diagnosis of extraosseous small blue cell tumors in adult patients.

Background and Importance: Calcifying pseudoneoplasms are rare tumors of the neuraxis. To our knowledge, this is only the second reported case in the literature of calcifying pseudoneoplasm of the cerebellopontine angle. The etiology and natural history of these neoplasms are not well understood. This case report provides a thorough review of the histology and potential origins of calcifying pseudoneoplasm., Clinical Presentation: A 34-year-old previously healthy man presented with a 6-month history of progressive worsening headaches, fatigue, tinnitus, dizziness, and blurry vision. Neurological examination was notable for tongue deviation, tongue atrophy, and left uvula deviation. Computed tomography (CT) scanning showed a 3.3 × 3.5 cm densely calcified posterior fossa mass appearing to arise from the occipital bone. Magnetic resonance imaging (MRI) revealed a 4.3 × 2.9 × 2.9 cm left posterior fossa enhancing mass with the margin tip from the left occipital condyle. A transcondylar approach was used to resect the lesion. The mass was found to have eroded through the bone into the foramen magnum. Histopathological examination confirmed the diagnosis of calcifying pseudoneoplasm of the cerebellopontine angle., Conclusion: Calcifying pseudoneoplasms should be considered in the differential diagnosis of calcified cerebellopontine angle tumors. Histopathologic diagnosis is extremely important in the characterization of these lesions in order to direct the course of appropriate management. An inaccurate diagnosis of a malignant tumor can result in potentially harmful and unnecessary therapies, as prognosis for these lesions is generally favorable.

Study Design: Retrospective review of prospective collected data on 22 patients., Objective: To describe our initial clinical experience and outcomes with the extreme lateral interbody fusion (XLIF) approach for spinal diseases requiring access to the thoracic cavity., Summary of Background Data: Minimally invasive anterior approaches to the thoracic spine have traditionally consisted of thoracoscopic and mini-open thoracotomy techniques. We present our initial experience with employing the XLIF technique to treat thoracic spine diseases., Methods: Clinical, radiographic, operative, postoperative, and functional outcomes were analyzed., Results: A total of 22 patients (15 females, 7 males, average age 64.6 y) with isolated thoracic and thoracolumbar spine diseases were treated between 2005 and 2009. The indications for surgery included degenerative scoliosis (11), pathological fractures from tumors (2), adjacent level disease from prior fusions (5), thoracic disc herniations (3), and discitis/osteomyelitis (1). A total of 47 levels were treated. In the subset of patients treated for degenerative scoliosis, the mean preoperative and postoperative coronal Cobb angles were 22 and 14, respectively. The mean preoperative and postoperative sagittal angles were 39 and 44, respectively. The average estimated blood loss and length of stay were 227.5 mL and 4.8 d, respectively. Three complications consisting of wound infection, subsidence, and adjacent level disease requiring additional procedures were encountered. There were no neural, vascular, visceral injuries, or death. At a mean follow-up of 16.4 months (range, 3-50), we observed a 95.5% substantial clinical benefit. All patients who had reached a minimum of 6 months (95.5%) demonstrated radiographic evidence of fusion., Conclusions: The XLIF technique can be expanded to treat diseases in the thoracic spine. Although the magnitude of deformity correction achieved is less than that of the traditional open approaches, the lesser invasiveness of this technique may be tolerable for the elderly and in patients with significant medical comorbidities.

Background: The number of spine operations performed in the elderly population is rising., Objective: To identify and describe perioperative and postoperative complications in patients 70 years and older who have undergone minimally invasive lumbar interbody spine fusion., Methods: A retrospective analysis was performed on 66 consecutive patients aged 70 years or older who underwent a minimally invasive interbody lumbar fusion. Electronic medical records were analyzed for patient demographics, procedures, and perioperative and postoperative complications., Results: Between 2000 and 2009, 66 patients with an average age of 74.9 years (range, 70-86 years) underwent 68 lumbar interbody fusions procedures. The mean follow-up was 14.7 months (range, 1.5-50 months). The minimally invasive approaches included 41 cases of extreme lateral interbody fusion and 27 minimally invasive transforaminal lumbar interbody fusions. We observed 5 major (7.4%) and 17 minor (25%) complications. The 5 major complications consisted of 4 cases of interbody graft subsidence and 1 adjacent level disease. There were no intraoperative medical complications. There were no myocardial infarctions, pulmonary embolisms, hardware complications requiring removal, wound infections, major visceral, vascular, neural injuries, or death in the study period., Conclusion: Minimally invasive interbody fusions can be performed in the elderly (ages 70 years and older) with an overall low rate of major complications. Graft subsidence in this population when not supplemented with posterior instrumentation is a concern. Age should not be a deterrent to performing complex minimally invasive interbody fusions in the elderly.

Background: Surgical outcomes for intramedullary spinal cord tumors are affected by many variables including tumor histology and preoperative neurological function., Objective: To analyze the impact of tumor histology on neurological outcome in primary intramedullary spinal cord tumors., Methods: A retrospective review of 102 consecutive patients with intramedullary spinal cord tumors treated at a single institution between January 1998 and March 2009., Results: Ependymomas were the most common tumors with 55 (53.9%), followed by 21 astrocytomas (20.6%), 12 hemangioblastomas (11.8%), and 14 miscellaneous tumors (13.7%). Gross total resection was achieved in 50 ependymomas (90.9%), 3 astrocytomas (14.3%), 11 hemangioblastomas (91.7%), and 12 miscellaneous tumors (85.7%). At a mean follow-up of 41.8 months (range, 1-132 months), we observed recurrences in 4 ependymoma cases (7.3%), 10 astrocytoma cases (47.6%), 1 miscellaneous tumor case (7.1%), and no recurrence in hemangioblastoma cases. When analyzed by tumor location, there was no difference in neurological outcomes (P = .66). At the time of their last follow-up visit, 11 patients (20%) with an ependymoma improved, 38 (69%) remained the same, and 6 (10.9%) worsened. In patients with an astrocytoma, 1 (4.8%) improved, 10 (47.6%) remained the same, and 10 (47.6%) worsened. One patient (8.3%) with a hemangioblastoma improved and 11 (91.7%) remained the same. No patient with a hemangioblastoma worsened. In the miscellaneous tumor group, 2 (14.3%) improved, 10 (71.4%) remained the same, and 2 (14.3%) worsened. Preoperative neurological status (P = .02), tumor histology (P = .005), and extent of resection (P < .0001) were all predictive of functional neurological outcomes., Conclusion: Tumor histology is the most important predictor of neurological outcome after surgical resection because it predicts resectability and recurrence.

Fas-associated factor 1 or FAF1 is a Fas-binding protein implicated in apoptosis. FAF1 is the product of a gene at PARK 10 locus on chromosome 1p32, a locus associated with late-onset PD [Hicks, A.A., Petursson, H., Jonsson, T., Stefansson, H., Johannsdottir, H.S., Sainz, J., Frigge, M.L.et al., 2002. A susceptibility gene for late-onset idiopathic Parkinson's disease. Ann Neurol. 52, 549-555.]. In the present study we investigated the role of FAF1 in cell death and in Parkinson's disease (PD) pathogenesis. FAF1 levels were significantly increased in frontal cortex of PD as well as in PD cases with Alzheimer's disease (AD) pathology compared to control cases. Changes in FAF1 expression were specific to PD-related alpha-synuclein pathology and nigral cell loss. In addition, PD-related insults including, mitochondrial complex I inhibition, oxidative stress, and increased alpha-synuclein expression specifically increased endogenous FAF1 expression in vitro. Increased FAF1 levels induced cell death and significantly potentiated toxic effects of PD-related stressors including, oxidative stress, mitochondrial complex I inhibition and proteasomal inhibition. These studies, together with previous genetic linkage studies, highlight the potential significance of FAF1 in pathogenesis of idiopathic PD.