Utility of minimally invasive endoscopic skull base approaches for the treatment of drug-resistant mesial temporal lobe epilepsy: a review of current techniques and trends.

Mesial temporal lobe epilepsy (mTLE) is an important cause of drug-resistant epilepsy (DRE) in adults and children. Traditionally, the surgical option of choice for mTLE includes a frontotemporal craniotomy and open resection of the anterior temporal cortex and mesial temporal structures. Although this technique is effective and durable, the neuropsychological morbidity resulting from temporal neocortical resections has resulted in the investigation of alternative approaches to resect the mesial temporal structures to achieve seizure freedom while minimizing postoperative cognitive deficits. Outcomes supporting the use of selective temporal resections have resulted in alternative approaches to directly access the mesial temporal structures via endoscopic approaches whose direct trajectory to the epileptogenic zone minimizes retraction, resection, and manipulation of surrounding cortex. The authors reviewed the utility of the endoscopic transmaxillary, endoscopic endonasal, endoscopic transorbital, and endoscopic supracerebellar transtentorial approaches for the treatment of drug-resistant mesial temporal lobe epilepsy. First, a review of the literature demonstrated the anatomical feasibility of each approach, including the limits of exposure provided by each trajectory. Next, clinical data assessing the safety and effectiveness of these techniques in the treatment of DRE were analyzed. An outline of the surgical techniques is provided to highlight the technical nuances of each approach. The direct access to mesial temporal structures and avoidance of lateral temporal manipulation makes endoscopic approaches promising alternatives to traditional methods for the treatment of DRE arising from the temporal pole and mesial temporal lobe. A dearth of literature outlining clinical outcomes, a need for qualified cosurgeons, and a lack of experience with endoscopic approaches remain major barriers to widespread application of the aforementioned techniques. Future studies are warranted to define the utility of these approaches moving forward.

Targeting mitochondrial energetics reverses panobinostat- and marizomib-induced resistance in pediatric and adult high-grade gliomas.

In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high-grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain-penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug-naïve cells. The levels of adenosine 5'-triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat- and marizomib-resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.