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Purpose: To examine the occurrence of glioma-related preoperative seizures (GPS) and post-operative seizure control (PSC) with respect to patients characteristics including five commonly tested tumor molecular markers (TMMs)., Methods: A single-center retrospective cohort study of patients with glioma evaluated at the Mayo Clinic, Florida between 2016 and 2018., Results: 68 adult patients (mean age = 51-years, 45-males) were included. 46 patients had GPS. 57 patients underwent intra-operative electrocorticography during awake craniotomy-assisted glioma resection. All patients underwent glioma resection (53, gross-total resection) with histologies of pilocytic astrocytoma (n = 2), diffuse astrocytoma (n = 4), oligodendroglioma (n = 14), anaplastic astrocytoma (n = 16), anaplastic oligodendroglioma (n = 1), and glioblastoma (n = 31). 31 (67%) patients had PSC (median follow-up = 14.5 months; IQR = 7-16.5 months). IDH1 mutation (IDH1 mut ) was present in 32, ARTX retention in 53, MGMT gene promotor methylation in 15, 1p/19q co-deletion in 15, and over-expression of p53 in 19 patients. Patients with IDH1 mut were more likely to have GPS (p = 0.037) and PSC (p = 0.035) compared to patients with IDH1 wild-type. Patients with MGMT gene promoter methylation were also likely to have PSC (p = 0.032). GPS or PSC did not differ by age, sex, extent of surgery, glioma grade, location, and histopathological subtype, p53 expression, ARTX retention, or 1p/19q co-deletion status., Conclusions: GPS and PSC may be associated with IDH1 mutation and MGMT gene promoter methylation status but not other glioma characteristics including tumor grade, location, or histopathology. Prospective studies with larger sample size are needed to clarify the exact mechanisms of GPS and PSC by the various TMMs to identify new treatment targets., (Published by Elsevier Ltd.)

Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression. Lentiviral knockdown of PAR1 inhibited the expansion and self-renewal of human GBM-derived A2B5(+) TPCs in vitro, while pharmacological inhibition of PAR 1 similarly slowed both the growth and migration of A2B5(+) TPCs in culture. In addition, PAR1 silencing potently suppressed tumor expansion in vivo, and significantly prolonged the survival of mice following intracranial transplantation of human TPCs. These data strongly suggest the importance of PAR1 to the self-renewal and tumorigenicity of A2B5-defined glioma TPCs; as such, the abrogation of PAR1-dependent signaling pathways may prove a promising strategy for gliomas.

Introduction: Glioblastoma is the most common primary malignant brain tumor, and is refractory to surgical resection, radiation, and chemotherapy. Human mesenchymal stem cells (hMSC) may be harvested from bone marrow (BMSC) and adipose (AMSC) tissue. These cells are a promising avenue of investigation for the delivery of adjuvant therapies. Despite extensive research into putative mechanisms for the tumor tropism of MSCs, there remains no direct comparison of the efficacy and specificity of AMSC and BMSC tropism towards glioma., Methods: Under an IRB-approved protocol, intraoperative human Adipose MSCs (hAMSCs) were established and characterized for cell surface markers of mesenchymal stem cell origin in conjunction with the potential for tri-lineage differentiation (adipogenic, chondrogenic, and osteogenic). Validated experimental hAMSCs were compared to commercially derived hBMSCs (Lonza) and hAMSCs (Invitrogen) for growth responsiveness and glioma tropism in response to glioma conditioned media obtained from primary glioma neurosphere cultures., Results: Commercial and primary culture AMSCs and commercial BMSCs demonstrated no statistically significant difference in their migration towards glioma conditioned media in vitro. There was statistically significant difference in the proliferation rate of both commercial AMSCs and BMSCs as compared to primary culture AMSCs, suggesting primary cultures have a slower growth rate than commercially available cell lines., Conclusions: Adipose- and bone marrow-derived mesenchymal stem cells have similar in vitro glioma tropism. Given the well-documented ability to harvest larger numbers of AMSCs under local anesthesia, adipose tissue may provide a more efficient source of MSCs for research and clinical applications, while minimizing patient morbidity during cell harvesting.

Glioblastoma (GB) is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na(+)-K(+)-Cl(-) cotransporter 1 (NKCC1) can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF), which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1) through the regulation of focal adhesion dynamics and cell contractility and (2) through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms., Competing Interests: The authors have declared that no competing interests exist.