Management of Refractory Post-operative Osteomyelitis and Discitis: A Case Report.

Vertebral osteomyelitis/discitis is a relatively rare disease but is a known potential complication of spinal surgical intervention. In general, the first-line treatment for this condition is targeted antibiotic therapy with surgical intervention only utilized in refractory cases with evidence of extensive damage, structural instability, or abscess formation. However, surgical best practices have not been established for osteomyelitis, including indications for anterior lateral interbody fusion (ALIF), posterior lateral interbody fusion (PLIF), or direct lateral interbody fusion (DLIF). This case provides a discussion of the indications that led to a direct lateral approach in the setting of refractory osteomyelitis/discitis, supporting factors that led to its success, and the efficacy of utilizing intraoperative neuromonitoring in cases of infection.

Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects.

Cancer-associated fibroblasts (CAFs) were presumed absent in glioblastoma given the lack of brain fibroblasts. Serial trypsinization of glioblastoma specimens yielded cells with CAF morphology and single-cell transcriptomic profiles based on their lack of copy number variations (CNVs) and elevated individual cell CAF probability scores derived from the expression of 9 CAF markers and absence of 5 markers from non-CAF stromal cells sharing features with CAFs. Cells without CNVs and with high CAF probability scores were identified in single-cell RNA-Seq of 12 patient glioblastomas. Pseudotime reconstruction revealed that immature CAFs evolved into subtypes, with mature CAFs expressing actin alpha 2, smooth muscle (ACTA2). Spatial transcriptomics from 16 patient glioblastomas confirmed CAF proximity to mesenchymal glioblastoma stem cells (GSCs), endothelial cells, and M2 macrophages. CAFs were chemotactically attracted to GSCs, and CAFs enriched GSCs. We created a resource of inferred crosstalk by mapping expression of receptors to their cognate ligands, identifying PDGF and TGF-ß as mediators of GSC effects on CAFs and osteopontin and HGF as mediators of CAF-induced GSC enrichment. CAFs induced M2 macrophage polarization by producing the extra domain A (EDA) fibronectin variant that binds macrophage TLR4. Supplementing GSC-derived xenografts with CAFs enhanced in vivo tumor growth. These findings are among the first to identify glioblastoma CAFs and their GSC interactions, making them an intriguing target.

Glioblastoma induces the recruitment and differentiation of hybrid neutrophils from skull bone marrow.

Tumor-associated neutrophil (TAN) effects on glioblastoma biology remain under-characterized. We show here that 'hybrid' neutrophils with dendritic features - including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate MHCII-dependent T cell activation - accumulate intratumorally and suppress tumor growth in vivo . Trajectory analysis of patient TAN scRNA-seq identifies this phenotype as a polarization state which is distinct from canonical cytotoxic TANs and differentiates intratumorally from immature precursors absent in circulation. Rather, these hybrid-inducible immature neutrophils - which we identified in patient and murine glioblastomas - arise from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a potent contributor of antitumoral myeloid APCs, including hybrid TANs and dendritic cells, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow - such as intracalvarial AMD3100 whose survival prolonging-effect in GBM we demonstrate - present therapeutic potential.

Role of c-Met/ß1 integrin complex in the metastatic cascade in breast cancer.

Metastases cause 90% of human cancer deaths. The metastatic cascade involves local invasion, intravasation, extravasation, metastatic site colonization, and proliferation. Although individual mediators of these processes have been investigated, interactions between these mediators remain less well defined. We previously identified a complex between receptor tyrosine kinase c-Met and ß1 integrin in metastases. Using cell culture and in vivo assays, we found that c-Met/ß1 complex induction promoted intravasation and vessel wall adhesion in triple-negative breast cancer cells, but did not increase extravasation. These effects may have been driven by the ability of the c-Met/ß1 complex to increase mesenchymal and stem cell characteristics. Multiplex transcriptomic analysis revealed upregulated Wnt and hedgehog pathways after c-Met/ß1 complex induction. A ß1 integrin point mutation that prevented binding to c-Met reduced intravasation. OS2966, a therapeutic antibody disrupting c-Met/ß1 binding, decreased breast cancer cell invasion and mesenchymal gene expression. Bone-seeking breast cancer cells exhibited higher levels of c-Met/ß1 complex than parental controls and preferentially adhered to tissue-specific matrix. Patient bone metastases demonstrated higher c-Met/ß1 complex than brain metastases. Thus, the c-Met/ß1 complex drove intravasation of triple-negative breast cancer cells and preferential affinity for bone-specific matrix. Pharmacological targeting of the complex may have prevented metastases, particularly osseous metastases.

Clinical trials using oncolytic viral therapy to treat adult glioblastoma: a progress report.

OBJECTIVE: Adult glioblastoma (GBM) has proven refractory to decades of innovation. Oncolytic viral therapy represents a novel therapy that uses viral vectors as both a delivery and therapeutic mechanism to target GBM cells. Despite the growing body of basic science data supporting the feasibility of viral therapy to treat GBM, the reporting of clinical trial results is heterogeneous. Correspondingly, the aim of this study was to present a contemporary summary of the progress all clinical trials have made to date. METHODS: The ClinicalTrials.gov database was reviewed in August 2020 for all possible interventional clinical trials involving viral vector-based therapy to treat adult GBM. These were then screened against selection criteria to identify pertinent clinical trials. RESULTS: A total of 29 oncolytic viral therapy trials treating adult GBM were identified. The median start and expected completion years were 2014 and 2020, respectively. At the time of this writing, 10 (35%) trials were reported to have completed recruitment, whereas 7 (24%) were actively recruiting. The median target enrollment number was 36 (range 13-108), with the majority of trials being phase I (n = 18, 62%), and involving secondary GBM among other malignant glioma (n = 19, 66%). A total of 10 unique viral vectors were used across all trials, with the most common being adenovirus (n = 16, 55%). Only 2 (7%) phase I trials to date have reported outcomes on the ClinicalTrials.gov portal. Results of 12 additional clinical trials were found in academic publications, with median progression-free and overall survival times of 3 and 15 months, respectively, after the first viral dose at recurrence. The coordination of the large majority of trials originated from the US (n = 21, 72%), and the median number of testing sites per trial was 1 (range 1-15), via industry funding (n = 18 trials, 62%). CONCLUSIONS: There are multiple early-stage oncolytic viral therapy clinical trials for adult GBM currently active. To date, limited results and outcomes are promising but scarce. The authors expect this to change in the near future because many trials are scheduled to have either nearly or actually reached their expected recruitment completion time. How exactly oncolytic viral therapy will fit into the current treatment paradigms for primary and secondary GBM remains to be seen, and will not be known until safety and toxicity profiles are established by these clinical trials.

Evaluating the Clinical Utility and Cost of Imaging Strategies in Adults with Newly Diagnosed Primary Intradural Spinal Tumors.

OBJECTIVE: In patients with new primary intradural spinal tumors, the best screening strategy for additional central nervous system (CNS) lesions is unclear. The goal of this study was to document the rate of additional CNS tumors in these patients. METHODS: Adults with primary intradural spinal tumors were retrospectively reviewed. Imaging strategy at diagnosis was classified as focused spine (cervical, thoracic, or lumbar), total spine, or complete neuraxis (brain and total spine). Tumor pathology, genetic syndromes, and presence of additional CNS lesions at diagnosis or follow-up were collected. RESULTS: The study comprised 319 patients with mean age of 51 years and mean follow-up of 41 months. In 151 patients with focused spine imaging, 3 (2.0%) were found to have new lesions with 2 (1.4%) requiring treatment. In 35 patients with total spine imaging, there were no additional lesions. In 133 patients with complete neuraxis imaging, 4 (3.0%) were found to have new lesions with 2 (1.5%) requiring treatment. There was no difference in the identification of new lesions (P = 0.542) or new lesions requiring treatment (P = 0.772) across imaging strategies. Among patients without genetic syndromes, rates of new lesions requiring treatment were 1.4% for focused spine, 0% for total spine, and 2.2% for complete neuraxis (P = 0.683). There were no cases of delayed identification causing risk to life or neurological function. Complete neuraxis imaging carried an increased charge of $4420 per patient. CONCLUSIONS: Among patients without an underlying genetic syndrome, the likelihood of identifying additional CNS lesions requiring treatment is low. In appropriate cases, focused spine imaging may be a more cost-effective strategy.

Implementation of Outpatient Minimally Invasive Lumbar Decompression at an Academic Medical Center without Ambulatory Surgery Centers: A Cost Analysis and Systematic Review.

BACKGROUND: Lumbar decompressions are increasingly performed at ambulatory surgery centers (ASCs). We sought to compare costs of open and minimally invasive (MIS) lumbar decompressions performed at a university without dedicated ASCs. METHODS: Lumbar decompressions performed at a tertiary academic hospital or satellite university hospital dedicated to outpatient surgery were retrospectively reviewed. Care pathways were same-day, overnight observation, or inpatient admission. Patient demographics, American Society of Anesthesiologists classification, Charlson Comorbidity Index, surgical characteristics, 30-day readmission, and costs were collected. A systematic review of lumbar decompression cost literature was performed. RESULTS: A total of 354 patients, mean age 55 years with 128 women (36.2%), were reviewed. There was no significant difference in age, gender, body mass index, American Society of Anesthesiologists classification, or Charlson Comorbidity Index between patients treated with open and minimally invasive surgery. Open decompression was associated with higher total cost ($21,280 vs. $14,407; P < 0.001); however, this was driven by care pathway and length of stay. When stratifying by care pathway, there was no difference in total cost between open versus minimally invasive surgery among same-day ($10,609 vs. $11,074; P = 0.556), overnight observation ($14,097 vs. $13,992; P = 0.918), or inpatient admissions ($24,507 vs. $27,929; P = 0.311). CONCLUSIONS: When accounting for care pathway, the cost of open and MIS decompression were no different. Transition from a tertiary academic hospital to a university hospital specializing in outpatient surgery was not associated with lower costs. Academic departments may consider transitioning lumbar decompressions to a dedicated ASC to maximize cost savings; however, additional studies are needed.

Cost Analysis of Outpatient Anterior Cervical Discectomy and Fusion at an Academic Medical Center without Dedicated Ambulatory Surgery Centers.

BACKGROUND: Anterior cervical discectomy and fusion (ACDF) are increasingly performed at ambulatory surgical centers (ASCs). Academic centers lacking dedicated ASCs must perform these at large university hospitals, which pose unique challenges to cost savings and efficiency. OBJECTIVE: To describe the safety and cost of outpatient ACDF at a major academic medical center without a dedicated ASC. METHODS: ACDFs performed from 2015 to 2018 were retrospectively reviewed. Cases were performed at the major tertiary university hospital or a satellite university hospital dedicated to outpatient surgery. Patient demographics, surgical characteristics, perioperative complications, fusion at 12 months, and cost were collected. RESULTS: A total of 470 patients were included. The mean age was 56 years, with 255 women (54.3%). When comparing same-day discharge, overnight observation, or inpatient admission, there were no differences in age, gender, or number of levels fused. Same-day and overnight observation cases were associated with shorter procedure duration and less estimated blood loss. There were no differences in perioperative complications, 30-day readmissions, or fusion at 12 months. Direct and total costs were lowest for same-day cases, followed by overnight observation and inpatient admissions (P < 0.001). CONCLUSION: Academic centers without dedicated ASCs can safely perform ACDF as a same-day or overnight observation procedure with significant reductions in cost. The lack of a dedicated ASC should not preclude academic centers from allocating appropriately selected patients into same-day or overnight observation care pathways. This strategy can improve resource utilization and preserve precious hospital resources for the most critically ill patients while also allowing these centers to build viable outpatient spine practices.

The contribution of ketone bodies to glycolytic inhibition for the treatment of adult and pediatric glioblastoma.

PURPOSE: Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Targeting tumor metabolism has emerged as a promising-targeted therapeutic strategy for GBM and characteristically resistant GBM stem-like cells (GSCs). METHODS: Gene expression data was obtained from the online patient-histology database, GlioVis. GSC mitochondria morphology was examined by TEM. Cell viability and effect on GSC self-renewal was determined via MTS assay and neurosphere assay, respectively. Proteins were evaluated by Western Blot. RESULTS: Enzymes necessary for ketone catabolism (BDH1, OXCT1 and ACAT1) are significantly downregulated in adult and pediatric GBM. GSC mitochondrial ultrastructure suggested defects in oxidative phosphorylation. Treatment of both GBM and GSC cell lines resulted in dose-dependent decreases in viability in response to glycolytic inhibitor 2-deoxy-D-glucose (2-DG), and ketone body Acetoacetate (AA), but not ß-hydroxybutyrate (ßHB). AA induced apoptosis was confirmed by western blot analysis, indicating robust caspase activation and PARP cleavage. AA reduced neurosphere formation at concentrations as low as 1 mM. Combined treatment of low dose 2-DG (50 µM) with AA resulted in more cell death than either treatment alone. The effect was greater than additive at low concentrations of AA, reducing viability approximately 50% at 1 mM AA. AA was found to directly upregulate mitochondrial uncoupling protein 2 (UCP2), which may explain this potential drug synergism via multi-faceted inhibition of the glycolytic pathway. CONCLUSION: Targeting the metabolic pathway of GBM via glycolytic inhibition in conjunction with ketogenic diet or exogenous ketone body supplementation warrants further investigation as a promising adjunctive treatment to conventional therapy.

Clonal ZEB1-Driven Mesenchymal Transition Promotes Targetable Oncologic Antiangiogenic Therapy Resistance.

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.

Multimodal Management of Carotid-Cavernous Fistulas.

BACKGROUND: Techniques for endovascular management of carotid-cavernous fistulas (CCFs) have evolved over the years. Current strategies include transarterial or transvenous approaches and direct puncture or exposure of the cavernous sinus. Rarely, complex CCFs may require multiple approaches or procedures. We describe our experience managing CCFs, reporting on outcomes and technical nuances. METHODS: A retrospective review of institutional records was conducted to identify consecutive cases of CCF treated between July 2005 and July 2016. Pertinent technical details and outcomes were recorded. RESULTS: In 44 patients, 51 procedures were performed. There were 13 direct CCFs and 31 indirect CCFs: 13 (30%) type A, 3 (7%) type B, 5 (11%) type C, and 23 (52%) type D. A transarterial approach was selected in 39% of cases (n = 20), resulting in a long-term successful embolization rate of 60% (n = 12). Transvenous methods via the inferior petrosal sinus or superior ophthalmic vein were used in 49% of cases (n = 25), resulting in a long-term obliteration rate of 88% (n = 22). Multimodal management was required in 5 patients, including 1 patient in whom a craniotomy was performed to facilitate coil embolization of the cavernous sinus under direct vision. A 7% complication rate (n = 3) was observed, with significant morbidity in 1 patient. CONCLUSIONS: CCFs are complex vascular lesions that require facility with various endovascular and surgical approaches. High-flow, direct-type fistulas may harbor a significant risk of recurrence after transarterial embolization. Partial or unsuccessful embolization may necessitate an open surgical approach to the superior ophthalmic vein or cavernous sinus.

Use of Vycor Tubular Retractors in the Management of Deep Brain Lesions: A Review of Current Studies.

BACKGROUND: Traditional manual retraction to access deep-seated brain lesions has been associated with complications related to vascular compromise of cerebral tissue. Various techniques have been developed over time to minimize injury, such as self-sustaining retractors, neuronavigation, and endoscopic approaches. Recently, tubular retractors, such as the ViewSite Brain Access System (VBAS), have been developed to reduce mechanical damage from retraction by dispersing the force of the retractor radially over the parenchyma. Therefore, we sought to review the current literature to accurately assess the indications, benefits, and complications associated with use of VBAS retractors. METHODS: A literature search for English articles published between 2005 and 2019 was performed using the MEDLINE database archive with the search terminology "Vycor OR ViewSite OR Brain-Access-System NOT glass." The VBAS website was also examined. Only articles detailing neurosurgical procedures using the VBAS tubular retractor system alone, or in combination with other retractors, were included. Postoperative morbidity and mortality were analyzed to estimate complications linked to using the retractor. RESULTS: Twelve publications (106 patients) met the inclusion criteria. The VBAS retractor was used for tumor resections, hematoma evacuations, cyst removal, foreign body extractions, and lesion resection in toxoplasmosis and multiple sclerosis. These cases were subdivided into groups based on lesion location, size, and resection volume for further analysis. Gross total resection was achieved in 63% of tumor excisions, and subtotal resection was achieved in 37%. Hematoma evacuation was successful in all cases. There were 3 short-term postoperative complications linked to the retractor, with an overall complication rate of 2.8%. CONCLUSIONS: This report is the first formal assessment of the VBAS, highlighting technical considerations of the retractor from the surgeon's perspective, patient outcomes, and complications. The retractor is a safe and efficacious tubular retraction system that can be used for tumor biopsy and resection, colloid cyst removal, hematoma evacuation, and removal of foreign bodies. However, further randomized controlled trials are indicated to accurately assess complication rates and outcomes.

The Role of Single-Nucleotide Polymorphisms in Pituitary Adenomas Tumorigenesis.

Pituitary adenomas (PAs) are among the most common intracranial neoplasms, but despite their histologically benign nature, these tumors sometimes grow large enough to cause symptoms of mass effect such as vision loss, headaches, or hypopituitarism. When they get this large, surgery will unfortunately not be curative and, other than prolactinomas, medical options are limited, and radiation has variable efficacy in controlling growth. Understanding the genetic perturbations, such as single nucleotide polymorphisms (SNPs), that promote the formation or growth of functional and nonfunctional PAs is important because such genetic insights could improve the diagnosis and subsequent classification of PAs as well as unlock potential therapeutic targets outside contemporary standard of care. While there have been great strides in the research of SNPs as drivers of PA formation and maintenance, a comprehensive discussion of these genetic mutations has not been undertaken. In the present article, and with the goal of providing scientists and clinicians a central review, we sought to summarize the current literature on SNPs and their relationship to PA formation. Across multiple tumor types, such as nonfunctioning PAs, prolactinomas, corticotroph adenomas, somatotroph adenomas, thyrotropic adenomas, and gonadotroph adenomas, SNPs in cell surface receptors implicated in proliferation can be appreciated. Polymorphisms found in tumor suppressors and cell cycle regulators have also been identified, such as p53 SNPs in nonfunctioning PAs or cyclin D1 in prolactinomas. While the translational relevance of SNPs in the formation of PAs is still in the early stages, the use of wide-scale genomic analysis to identify patients at risk for developing PAs could yield therapeutic benefit in the future.

The neurosurgery applicant's "arms race": analysis of medical student publication in the Neurosurgery Residency Match.

OBJECTIVE: Neurosurgery is consistently one of the most competitive specialties for resident applicants. The emphasis on research in neurosurgery has led to an increasing number of publications by applicants seeking a successful residency match. The authors sought to produce a comprehensive analysis of research produced by neurosurgical applicants and to establish baseline data of neurosurgery applicant research productivity given the increased emphasis on research output for successful residency match. METHODS: A retrospective review of publication volume for all neurosurgery interns in 2009, 2011, 2014, 2016, and 2018 was performed using PubMed and Google Scholar. Missing data rates were 11% (2009), 9% (2011), and < 5% (all others). The National Resident Matching Program report "Charting Outcomes in the Match" (ChOM) was interrogated for total research products (i.e., abstracts, presentations, and publications). The publication rates of interns at top 40 programs, students from top 20 medical schools, MD/PhD applicants, and applicants based on location of residency program and medical school were compared statistically against all others. RESULTS: Total publications per neurosurgery intern (mean ± SD) based on PubMed and Google Scholar were 5.5 ± 0.6 in 2018 (1.7 ± 0.3, 2009; 2.1 ± 0.3, 2011; 2.6 ± 0.4, 2014; 3.8 ± 0.4, 2016), compared to 18.3 research products based on ChOM. In 2018, the mean numbers of publications were as follows: neurosurgery-specific publications per intern, 4.3 ± 0.6; first/last author publications, 2.1 ± 0.3; neurosurgical first/last author publications, 1.6 ± 0.2; basic science publications, 1.5 ± 0.2; and clinical research publications, 4.0 ± 0.5. Mean publication numbers among interns at top 40 programs were significantly higher than those of all other programs in every category (p < 0.001). Except for mean number of basic science publications (p = 0.1), the mean number of publications was higher for interns who attended a top 20 medical school than for those who did not (p < 0.05). Applicants with PhD degrees produced statistically more research in all categories (p < 0.05) except neurosurgery-specific (p = 0.07) and clinical research (p = 0.3). While there was no statistical difference in publication volume based on the geographical location of the residency program, students from medical schools in the Western US produced more research than all other regions (p < 0.01). Finally, research productivity did not correlate with likelihood of medical students staying at their home institution for residency. CONCLUSIONS: The authors found that the temporal trend toward increased total research products over time in neurosurgery applicants was driven mostly by increased nonindexed research (abstracts, presentations, chapters) rather than by increased peer-reviewed publications. While we also identified applicant-specific factors (MD/PhDs and applicants from the Western US) and an outcome (matching at research-focused institutions) associated with increased applicant publications, further work will be needed to determine the emphasis that programs and applicants will need to place on these publications.

Stratifying nonfunctional pituitary adenomas into two groups distinguished by macrophage subtypes.

Tumor-associated macrophages (TAMs) polarize to M1 and M2 subtypes exerting anti-tumoral and pro-tumoral effects, respectively. To date, little is known about TAMs, their subtypes, and their roles in non-functional pituitary adenomas (NFPAs). We performed flow cytometry on single cell suspensions from 16 NFPAs, revealing that CD11b+ myeloid cells comprise an average of 7.3% of cells in NFPAs (range = 0.5%-27.1%), with qPCR revealing most CD11b+ cells to be monocyte-derived TAMs rather than native microglia. The most CD11b-enriched NFPAs (10-27% CD11b+) were the most expansile (size>3.5 cm or MIB1>3%). Increasing CD11b+ fraction was associated with decreased M2 TAMs and increased M1 TAMs. All NFPAs with cavernous sinus invasion had M2/M1 gene expression ratios above one, while 80% of NFPAs without cavernous sinus invasion had M2/M1<1 (P = 0.02). Cultured M2 macrophages promoted greater invasion (P < 10-5) and proliferation (P = 0.03) of primary NFPA cultures than M1 macrophages in a manner inhibited by siRNA targeting S100A9 and EZH2, respectively. Primary NFPA cultures were of two types: some recruited more monocytes in an MCP-1-dependent manner and polarized these to M2 TAMs, while others recruited fewer monocytes and polarized them to M1 TAMS in a GM-CSF-dependent manner. These findings suggest that TAM recruitment and polarization into the pro-tumoral M2 subtype drives NFPA proliferation and invasion. Robust M2 TAM infiltrate may occur during an NFPA growth phase before self-regulating into a slower growth phase with fewer overall TAMs and M1 polarization. Analyses like these could generate immunomodulatory therapies for NFPAs.

Targeting Glioblastoma Stem Cells with 2-Deoxy-D-Glucose (2-DG) Potentiates Radiation-Induced Unfolded Protein Response (UPR).

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, and despite optimized treatment options, median survival remains dismal. Contemporary evidence suggests disease recurrence results from expansion of a robustly radioresistant subset of GBM progenitor cells, termed GBM stem cells (GSCs). In this study, we utilized transmission electron microscopy to uncover ultrastructural effects on patient-derived GSC lines exposed to supratherapeutic radiotherapy levels. Elevated autophagosome formation and increased endoplasmic reticulum (ER) internal diameter, a surrogate for ER stress and activation of unfolded protein response (UPR), was uncovered. These observations were confirmed via protein expression through Western blot. Upon interrogating genomic data from an open-access GBM patient database, overexpression of UPR-related chaperone protein genes was inversely correlated with patient survival. This indicated controlled UPR may play a role in promoting radioresistance. To determine if potentiating UPR further can induce apoptosis, we exposed GSCs to radiation with an ER stress-inducing drug, 2-deoxy-D-glucose (2-DG), and found dose-dependent decreases in viability and increased apoptotic marker expression. Taken together, our results indicate GSC radioresistance is, in part, achieved by overexpression and overactivation of ER stress-related pathways, and this effect can be overcome via potentiation of UPR, leading to loss of GSC viability.

Transradial Approach for Complex Anterior and Posterior Circulation Interventions: Technical Nuances and Feasibility of Using Current Devices.

BACKGROUND: Despite several studies analyzing the safety of transradial access (TRA) for neurointervention compared to transfemoral approach (TFA), neurointerventionalists are apprehensive about implementing TRA. From our positive institutional experience, we now utilize TRA first line for a majority of our cases. Here, we present our single-institution experience. OBJECTIVE: To determine safety and feasibility of TRA for neurointervention. METHODS: Through retrospective review of patients receiving TRA for anterior and posterior circulation cerebrovascular interventions at our institution between December 2015 and January 2018, we present our experience regarding this transition, while focusing on technique, complications, feasibility, indications, and limitations. RESULTS: One hundred five procedures were performed on 92 patients (anterior circulation: 77%; posterior circulation: 23%). Radial artery access was achieved in all patients. Twenty-nine cases constituted mechanical thrombectomy, 33 cases represented intracranial aneurysms treatments, and 33 cases included interventions like angioplasty, balloon test occlusion, chemotherapy delivery, and thrombolysis. TRA was used as second-line access to TFA in 5 instances due to aortic arch anomalies and atherosclerotic disease. Minor access-site complications were seen in 2.85% of patients. Ten procedures (9.0%) could not be completed with TRA, with crossover to TFA occurring in 7 cases. CONCLUSION: TRA is safe and feasible for the majority of neurointerventional procedures and provides decreased risk of major access-site complications compared to TFA. Perceived limitations of TRA can likely be eliminated via operator experience and engineering ingenuity; thus, there is a role for TRA for neurointervention, especially in patients with increased risk of access-site complications from TFA.

Epidemiology and etiology of secondary piriformis syndrome: A single-institution retrospective study.

Piriformis syndrome (PS) is a rare etiology of extra-spinal sciatica in which pathologies associated with or around the piriformis muscle (PM) irritate the adjacent sciatic nerve (SN), however, there is scarcity in the literature regarding its exact etiologies, thus, we performed a retrospective study to elucidate the epidemiology of PS and assess various causes of the syndrome. Our study included patients assessed at our institution who presented with sciatica of non-spinal origin between May 2014 and December 2015. Radiology reports of all patients who received pelvic MRI were examined for positive findings involving PM and SN. Of the 143 patients recognized with sciatica and negative lumbar pathology, 24 patients (17%) exhibited positive PM and SN findings. Average patient age was 50.0 ±â€¯15.1 years (range: 21-75), and 17 were female. Seven patients (5%; 4M/3F) presented with tumor, seven patients (5%) had chronic inflammatory changes, one patient had SN adhesions to obturator muscle, three patients (2%, 3F) had aberrant anatomy, and the remaining patients had positive MRI findings, such as nerve atrophy or PM hypertrophy without identifiable cause. Seven patients received steroid injections in the peri-sciatic fossa, and four displayed poor response. Our findings suggested possible trends in extra-spinal sciatica. Affected males appeared more likely to present with tumor, while affected females were more likely to present younger, but with aberrant anatomy. Steroid injections appeared to be suboptimal in most cases. Pelvic MRI is helpful in patients with sciatica and negative spine imaging to rule out neoplastic involvement.