Malignant gliomas (MG) are highly infiltrative tumours with a poor prognosis. Nuclear factor I (NFI) is a family of 4 transcription factors (NFIA, B, C and X) implicated in the regulation of genes involved in MG cell migration and infiltration, particularly the neural stem cell marker, brain fatty acid binding protein (B-FABP). NFI activity is regulated by its phosphorylation status, with hypophosphorylated NFI being the active form. Our results indicate that the phosphatase calcineurin is able to dephosphorylate NFI. In turn, calcineurin is cleaved and activated by calpain proteases. We have identified CAST, a gene that encodes calpain inhibitor, calpastatin, as a putative target of NFI based on chromatin immunoprecipitation. Putative NFI binding elements are located in intron 3 of the CAST gene. To determine whether there is a bona fide alternative promoter within intron 3 of CAST, we carried out gel shifts as well as luciferase reporter gene assays using both the canonical and alternative promoters of CAST. These assays confirmed CAST alternative promoter usage in MG cells. Knockdown of individual NFIs revealed a role for NFIC and NFIX in the repression of CAST gene expression, specifically in cells expressing the hypophosphorylated (active) form of NFI. NFI depletion also altered the subcellular localization of both calpain and calineurin protein. Our results suggest a feedback loop for the NFI –calcineurin – calpain – calpastatin pathway in MG cells which may regulate cell migration.

Background: We aimed to identify preoperative predictors of survival in Metastatic Epidural Spinal Cord Compression (MESCC) patients surgically treated, examine how these predictors relate to eight prognostic models, and to perform the first full external validation of these models in accordance with the TRIPOD statement. Methods: 142 surgically treated MESCC patients were enrolled in a prospective, multicenter cohort study and followed for 12 months or until death. Cox proportional hazards (PH) regressions were used. Non-collinear predictors with <10% missing data, ≥10 events per stratum and p<0.05 in univariable analysis were tested through a backward stepwise selection. For the original and revised Tokuhashi, Tomita, modified Bauer, van der Linden, Bartels, OSRI, Bartels and Bollen, we examined calibration and discrimination; survival stratified by risk groups with the Kaplan-Meier method and log-rank test. Results: Primary tumor, organ metastasis and SF-36v2 PC were associated with survival in multivariable analysis; corrected discrimination was 0.68. These three predictors were common to most current prognostic models. However, calibration was poor overall while discrimation was possibly helpful. Conclusions: Primary tumor type (breast, prostate and thyroid), absence of organ metastasis, and a lower degree of physical disability are preoperative predictors of longer survival in surgical MESCC patients. Clinicians should use these 8 prognostic models with caution.

Glioblastoma is inherently resistant to radiation and drug treatments. This is mediated by the most common forms of cell death are often actively inhibited. Identifying and exploiting alternative cell death pathways are essential to overcoming or bypassing drug resistance. Ferroptosis, a newly described, morphologically and biochemically distinct, cell death mechanism is characterized by iron-dependent cellular accumulation of reactive oxygen species. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor (TKI), synergistically induced death in glioma cancer cells. This cell death had characteristics of ferroptosis: it was blocked by the ferroptosis inhibitor ferrostatin-1 and the iron chelator deferoxamine. In addition, the amount of ROS and lipid peroxidation were increased in glioma cells. Iron transport protein remained unchanged but reactive iron levels increased. One target for kinase inhibitors is protein bisulfate isomerase (PDI). Knockdown of PDI in combination with siramesine increased cell death that was blocked by ferrostatin-1. Taken together, drug combinations that alter reactive iron and ROS levels might induce ferroptosis and overcome drug resistance in glioma cells.

Background: There remains an important role for consolidating evidence on the utility of image guidance (IG) in neurosurgery. In 1963, Ayub Ommaya proposed a surgical technique for the -placement of a subcutaneous reservoir and pump to allow access to intraventricular cerebrospinal fluid. In this study, we sought to compile evidence from the literature about surgical outcome in ORI with and without IG. Methods: A systematic review was conducted in accordance with PRISMA guidelines. Overall surgical complication rate was considered a primary outcome and further classified into specific complication categories. Results: 40 studies were identified, including our own series, for a total of 1947 independent ORI procedures. Pooled rates of outcome for IG compared to non-IG were 6.0% versus 13.6% for overall complications; 2.0% versus 2.8% for catheter malfunction; 1.9% versus 2.3% for catheter malposition; 0.5% versus 4.0% for early infection; 4.3% versus 9.4% for any infection; and 0.4% versus 1.4% for mortality. Conclusions: We observed that IG ORI resulted in improved accuracy and decreased complications compared to non-IG. To our knowledge, this study comprises the largest observational analysis of operative outcomes demonstrating evidence for the utility of IG.

Estimation of tumor recurrence in meningioma patients is one of the important clinical challenges. The prognostic impact of immune modulatorymolecule PD-L1 in several malignancies has been demonstrated. We studied the association of PD-L1 expression in meningioma with tumor recurrence and the underlying mechanism of its activation. Immunohistochemical staining(IHC) was performed for detection of PD-L1and NFKB2 on whole sections of meningiomas diagnosed between1998-2016 at TorontoWesternHospital. The biologic role of hypoxia in activation of PD-L1 in meningioma was investigated using gene set enrichment analysis(GSEA)-based on RNAseq data in validation cohorts. We analyzed a total of 93 meningioma cases: F/M ratio58/35;WHOgrade I(41),II(43),III(9),42(47%)cases with tumor recurrence and median follow up was 6.97yrs. PD-L1 expression on tumor cells(PD-L1TC) in 33(35%) cases was identified with distinctive patchy distribution. Univariate analysis indicated expression of PD-L1TC as a prognostic factor for tumor recurrence(p<0.0001). Multivariate analysis showed that PD-L1TC expression is an independent prognostic factor for tumor recurrence after adjusting for extent of resection(EOR),WHO grade and maximum tumor diameter(p<0.0001). Analysis of RNAseq data of two GEOmeningioma studies demonstrated prominent expression of NFKB activation associated with PD-L1expression. IHC analysis confirmed increased expression of NFKB2 protein in 26(30%)cases,which correlated with PD-L1TC expression(p=0.02). Furthermore,GSEAon a RNAseq data of 88 sporadic meningiomas using Hypoxia gene signature of HUVEC cells we found that the hypoxic sporadic meningiomas have significantly elevated PD-L1 expression(p<0.001). Our data strongly suggest that PD-L1TCexpression serves as a significant prognostic marker for tumor recurrence and. We found that hypoxia andNFKB2 activation are potential underlying mechanisms. These results also provide a rationale for potential adjuvant therapeutic role for PD-L1 inhibitors in meningioma.

Background: Although surgery is the mainstay of treatment for most pituitary adenomas, post-operative radiotherapy has been shown to be of benefit in improving tumor control and recurrence-free survival. To understand potential side effects of radiotherapy we performed a systematic review and meta-analysis to determine the efficacy and safety of post-operative radiotherapy for pituitary adenoma. Methods: A systematic review was performed according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. We searched PubMed, MEDLINE and Cochrane databases with no language or publication date restrictions. Outcomes included 5- and 10-year progression-free survival and adverse events rates. Results: A total of 48 studies from 1986-2016 met the inclusion criteria, with 7551 cumulative patients. The cumulative 5- and 10-year s progression-free survival rates were 90.8% (95% CI 86-94%) and 88.6% (95% CI 81-93%), respectively. The overall adverse events rate was 8% (95% CI 5-12%). All outcomes were associated with significant heterogeneity (I2 ≥ 70%). No differences in survival rates or adverse events in relation to study date, tumor pathology, radiosurgery system used or dose of radiation. Conclusions: Post-operative radiotherapy for pituitary adenomas is effective and safe. Because of the significant heterogeneity and lack of matched controls in the literature, optimum timing and dosage are still unclear. Further prospective studies are needed.