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Abstract Introduction The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. Methods The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. Results GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. Conclusion ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.

ObjectiveCavernous sinus (CS) invasion is frequently encountered in the management of skull base tumors. Surgical treatment of tumors in the CS is technically demanding, and selection of an optimal surgical approach is critical for maximal tumor removal and patient safety. We aimed to evaluate the feasibility of an endoscopic transorbital approach (ETOA) to the CS based on a cadaveric study.MethodsFive cadaveric heads were used for dissection under the ETOA in the comparison with the endoscopic endonasal approach (EEA) and the microscopic transcranial approach (TCA). The CS was exposed, accessed, and explored, first using the ETOA, followed by the EEA and TCA. A dedicated endoscopic system aided by neuronavigation guidance was used for the procedures. During the ETOA, neurovascular structures inside the CS were approached through different surgical triangles.ResultsAfter completing the ETOA with interdural dissection, the lateral wall of the CS was fully exposed. The lateral and posterior compartments of the CS, of which accessibility is greatly limited under the EEA, were effectively approached and explored under the ETOA. The anteromedial triangle was the largest window via which most of the lateral compartment was freely approached. The internal carotid artery and abducens nerve were also observed through the anteromedial triangle and just behind V1. During the ETOA, the approaching view through the supratrochlear and infratrochlear triangles was more directed towards the posterior compartment. After validation of the feasibility and safety based on the cadaveric study, ETOA was successfully performed in a patient with a pituitary adenoma with extensive CS invasion.ConclusionsBased on the cadaveric study, we demonstrated that the lateral CS wall was reliably accessed under the ETOA. The lateral and posterior compartments of the CS were effectively explored via surgical triangles under the ETOA. ETOA provides a unique and valuable surgical route to the CS with a promising synergy when used with EEA and TCA. Our experience with a clinical case convinces us of the efficacy of the ETOA during surgical management of skull base tumors with CS-invasion.