Fluoxetine enhances the antitumor effect of olfactory ensheathing cell-thymidine kinase/ganciclovir gene therapy in human glioblastoma multiforme cells through upregulation of Connexin43 levels.

Glioblastoma multiforme (GBM) is the most invasive form of primary brain astrocytoma, resulting in poor clinical outcomes. Herpes simplex virus thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy is considered a promising strategy for GBM treatment. Since Connexin43 (Cx43) expression is reduced in GBM cells, increasing Cx43 levels could enhance the effectiveness of gene therapy. The present study aims to examine the impact of fluoxetine on HSV-TK/GCV gene therapy in human GBM cells using human olfactory ensheathing cells (OECs) as vectors. The effect of fluoxetine on Cx43 levels was assessed using the western blot technique. GBM-derived astrocytes and OECs-TK were Cocultured, and the effect of fluoxetine on the Antitumor effect of OEC-TK/GCV gene therapy was evaluated using MTT assay and flow cytometry. Our results showed that fluoxetine increased Cx43 levels in OECs and GBM cells and augmented the killing effect of OECs-TK on GBM cells. Western blot data revealed that fluoxetine enhanced the Bax/Bcl2 ratio and the levels of cleaved caspase-3 in the coculture of OECs-TK and GBM cells. Moreover, flow cytometry data indicated that fluoxetine increased the percentage of apoptotic cells in the coculture system. This study suggests that fluoxetine, by upregulating Cx43 levels, could strengthen the Antitumor effect of OEC-TK/GCV gene therapy on GBM cells.

Evaluation of Diffusion Tensor Imaging-Based Tractography of the Corticospinal Tract: A Correlative Study With Intraoperative Magnetic Resonance Imaging and Direct Electrical Subcortical Stimulation.

Background: The accuracy of intraoperative diffusion tensor imaging (DTI)­based tractography of the corticospinal tract (CST) is crucial for its use in neurosurgical planning and its implementation in image-guided surgery. To the best of our knowledge, this is the largest prospective correlative study of the intraoperative DTI tractography of the CST and intraoperative direct electrical subcortical stimulation (DESS) of the CST, with application of intraoperative magnetic resonance imaging (iMR). Objective: To evaluate intraoperatively acquired DTI-based tractography of the CST in correlation with DESS. Methods: Twenty patients with gliomas (grades II-IV) adjacent to the CST were included in this prospective study. Bilateral DTI tractography of the CST was performed pre- and intraoperatively with application of 1.5-T iMRI and the results correlated and compared with the prevailing gold standard of DESS. Sensitivity, specificity, positive predictive value, and negative predictive value were considered to quantify the correlation of DTI tractography with DESS. The intensity of DESS was correlated with the distance from the CST. Moreover, the tissue quality of stimulation points at the wall of the resection cavity was evaluated with 5-aminolevulinic acid. The clinical and volumetric outcomes at postoperative and follow-up periods were also analyzed. Results: The mean ± SD age of the patients was 54.9 ± 12 years. A total of 40 CSTs were reconstructed and 36 stimulations were included at 20 pathological CSTs, resulting in 18 true-positive, 5 false-positive, and 13 true-negative responses. The sensitivity, specificity, positive predictive value, and negative predictive value of DTI tractography to localize the CST were 100%, 72%, 78%, and 100%, respectively. DTI-based tractography correlated well at 86% of DESSs, and a linear correlation was detected between the intensity of DESS and the distance. All of the patients improved clinically, and the mean extent of resection was 97.2%. 5-Aminolevulinic acid was valuable in visualizing tumor infiltration in the false-positive cases, suggesting an infiltration of the CST at stimulation points. Conclusion: CST visualization in the iMRI setting appears to have a high sensitivity in accurately localizing the area of the CST adjacent to the resection cavity in glioma surgery. More prospective studies with a large sample size are needed to further support the results.