Antitumor effects of minodronate, a third-generation nitrogen-containing bisphosphonate, in synergy with γδT cells in human glioblastoma in vitro and in vivo.

Nitrogen-containing bisphosphonates (N-BPs), which prevent bone resorption, exert direct and γδT cell (GDT)-mediated antitumor effects against several tumor cell types, including glioblastoma (GBM). However, limited information is available regarding the antitumor effects of N-BPs in GBM. Specifically, the antitumor effects of minodronate (MDA), a third-generation N-BP, in GBM are yet unclear. This study aimed to investigate the antitumor effects of MDA in GBM in vitro and in vivo. We performed growth inhibition and apoptosis detection assays using the GBM cell lines U87MG and U138MG. Apoptosis inhibition assays were also conducted. In vivo xenograft assays were performed in highly immunodeficient NOD.Cg-Prkdc(scid) Il2rg(tm1Sug)/Jic mice subcutaneously implanted with U87MG and U138MG cells. Growth inhibition and apoptosis detection assays demonstrated that MDA inhibited GBM cell growth via apoptosis, which was markedly enhanced by ex vivo expanded GDT. A pan-caspase inhibitor, z-VAD-fmk, inhibited MDA-induced U138MG apoptosis and MDA/GDT-induced U87MG and U138MG apoptosis. But z-VAD-fmk increased MDA-induced U87MG apoptosis. MDA/GDT-mediated apoptosis was blocked by the anti-T cell receptor (TCR) Vγ9, mevalonate pathway inhibitor, granzyme B inhibitor, and antitumor necrosis factor (TNF)-α. In vivo xenograft assays showed that combined intraperitoneal administration of MDA/GDT induced antitumor effects on unestablished U87MG-derived subcutaneous tumors. MDA exerted direct and GDT-mediated anti-GBM apoptotic effects in a caspase-dependent manner. GDT recognized MDA-exposed GBM cells via TCRVγ9 and induced apoptosis via granzyme B and TNF-α release. Because MDA elicited anti-GBM effects in synergy with GDT in vivo, a combination of MDA and ex vivo-generated GDT could be an effective treatment in patients with GBM.

Diagnostic Impact of Monitoring Visual Evoked Potentials to Prevent Visual Complications During Endovascular Treatment for Intracranial Aneurysm.

Introduction: The present study aimed to determine the incidence of intraprocedural visual-evoked potential (VEP) changes and to identify correlations with intraprocedural ischemic complications during endovascular treatment in patients with intracranial aneurysm related to visual function. Methods: This study analyzed data from 104 consecutive patients who underwent endovascular coil embolization to treat intracranial aneurysms related to visual function under VEP and transcranial motor evoked potential (MEP) monitoring. We analyzed associations between significant changes in MEP and VEP, defined as a >50% decrease in amplitude, and both intraprocedural complications and postoperative neurological deficits. Factors associated with postoperative neurological deficits were also assessed. Results: Treated aneurysms were predominantly located in the internal carotid artery (95%). Five (5%) were located in the posterior cerebral artery (PCA). Significant decreases in intraprocedural VEP occurred in four patients (4%), although one of those four patients did not show concomitant MEP decreases during procedures. Immediate salvage procedures avoided postoperative visual disturbances. All VEP decreases were transient and not associated with postoperative visual impairment. One of three cases who underwent intraoperative balloon occlusion test showed tolerance to balloon occlusion of the proximal PCA under VEP assessment; parent artery occlusion was performed without postoperative visual disturbance in that case. Conclusion: Although significant VEP decreases occurred 4% during neuro-endovascular aneurysm treatment related to visual function, intraprocedural VEP monitoring identifies ischemic changes associated with visual pathways and facilitates prompt initiation of salvage procedures.