Comparison of transposition and interposition methods in microvascular decompression for hemifacial spasm: an analysis of 109 cases performed by a single surgeon in a single-center retrospective study.

BACKGROUND: Microvascular decompression (MVD), the standard surgical approach for hemifacial spasm (HFS), can be divided into the interposition and transposition methods. Although the risk of HFS recurrence following interposition has been reported, there is limited data comparing long-term outcomes between both methods performed by a single surgeon. This study aimed to investigate the efficacy of MVD techniques on HFS by comparing surgical outcomes performed by a single surgeon in a single-center setting. METHODS: A total of 109 patients who underwent MVD were analyzed and divided into the transposition (86 patients) and interposition (23 patients) groups. Postoperative outcomes at 1 month and 1 year were assessed and compared, including rates of spasm relief, complications, and recurrence. RESULTS: Outcome assessment revealed higher rates of early spasm relief in the interposition group (66.3% vs. 100%, transposition vs. interposition, respectively, p = 0.0004), although spasm relief at 1-year postoperatively was comparable between the two groups (84.9% vs. 95.7%, transposition vs. interposition, respectively, p = 0.2929). No significant differences were observed in complication and recurrence rates. Kaplan-Meier analysis demonstrated no significant differences in the duration of spasm resolution by MVD method (p = 0.4347, log-rank test). CONCLUSION: This study shows that both the transposition (Surgicel® and fibrin glue) and interposition (sponge) methods were excellent surgical techniques. The interposition method may achieve earlier spasm resolution compared to the transposition method.

Linagliptin decreased the tumor progression on glioblastoma model.

PURPOSE: Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral hypoglycemic drugs and are used for type II diabetes. Previous studies showed that DPP-4 expression is observed in several tumor types and DPP-4 inhibitors suppress the tumor progression on murine tumor models. In this study, we evaluated the role of DPP-4 and the antitumor effect of a DPP-4 inhibitor, linagliptin, on glioblastoma (GBM). METHODS: We analyzed DPP-4 expression in glioma patients by the public database. We also analyzed DPP-4 expression in GBM cells and the murine GBM model. Then, we evaluated the cell viability, cell proliferation, cell migration, and expression of some proteins on GBM cells with linagliptin. Furthermore, we evaluated the antitumor effect of linagliptin in the murine GBM model. RESULTS: The upregulation of DPP-4 expression were observed in human GBM tissue and murine GBM model. In addition, DPP-4 expression levels were found to positively correlate with the grade of glioma patients. Linagliptin suppressed cell viability, cell proliferation, and cell migration in GBM cells. Linagliptin changed the expression of phosphorylated NF-kB, cell cycle, and cell adhesion-related proteins. Furthermore, oral administration of linagliptin decreases the tumor progression in the murine GBM model. CONCLUSION: Inhibition of DPP-4 by linagliptin showed the antitumor effect on GBM cells and the murine GBM model. The antitumor effects of linagliptin is suggested to be based on the changes in the expression of several proteins related to cell cycle and cell adhesion via the regulation of phosphorylated NF-kB. This study suggested that DPP-4 inhibitors could be a new therapeutic strategy for GBM.

Optimal duration of dual antiplatelet therapy for stent-assisted coiling or flow diverter placement.

BACKGROUND: Dual antiplatelet therapy (DAPT) is necessary to prevent thromboembolic complications after stent-assisted coiling (SAC) or flow-diversion (FD) for cerebral aneurysms, but the optimal antiplatelet regimen remains unclear. OBJECTIVE: To determine the optimal DAPT duration in patients with SAC/FD. METHODS: This multicenter cohort study enrolled patients who received SAC/FD for cerebral aneurysms at seven Japanese institutions between January 2010 and December 2020. The primary outcome was the time from procedure to the occurrence of a composite of target vessel-related thromboembolic events, procedure-unrelated major bleeding events, or death. The cumulative event-free survival rates were analyzed using a Kaplan-Meier curve, and the differences in each outcome between the groups dichotomized by the duration of DAPT were analyzed using the log-rank test. RESULTS: Of 632 patients (median observational period, 646 days), primary outcome occurred in 63 patients (10.0%), most frequently within 30 days after the procedure. The cumulative event-free survival rates at 30 days, 1 year, and 2 years after the procedure were 93.3% (91.4 to 95.3%), 91.5% (89.3 to 93.7%), and 89.5% (87.0 to 92.0%), respectively. The cumulative event-free survival rates after switching to monotherapy were similar for the >91 and <90 days DAPT groups in the population limited to patients who were switched from DAPT to monotherapy without major clinical events. CONCLUSIONS: Thromboembolic events rarely occurred beyond 30 days after SAC/FD. The duration of DAPT may be shortened if patients have a periprocedural period without events. Further prospective studies are warranted to determine the optimal duration of antiplatelet therapy. TRIAL REGISTRATION NUMBER: UMIN000044122 :https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000050384.

Canagliflozin Inhibits Glioblastoma Growth and Proliferation by Activating AMPK.

Sodium-glucose transporter 2 (SGLT2) inhibitors are antidiabetic drugs affecting SGLT2. Recent studies have shown various cancers expressing SGLT2, and SGLT2 inhibitors attenuating tumor proliferation. We evaluated the antitumor activities of canagliflozin, a SGLT2 inhibitor, on glioblastoma (GBM). Three GBM cell lines, U251MG (human), U87MG (human), and GL261 (murine), were used. We assessed the expression of SGLT2 of GBM through immunoblotting, specimen-use, cell viability assays, and glucose uptake assay with canagliflozin. Then, we assessed phosphorylation of AMP-activated protein kinase (AMPK), p70 S6 kinase, and S6 ribosomal protein by immunoblotting. Concentrations of 5, 10, 20, and 40 µM canagliflozin were used in these tests. We also evaluated cell viability and immunoblotting using U251MG with siRNA knockdown of SGLT2. Furthermore, we divided the mice into vehicle group and canagliflozin group. The canagliflozin group was administrated with 100 mg/kg of canagliflozin orally for 10 days starting from the third days post-GBM transplant. The brains were removed and the tumor volume was evaluated using sections. SGLT2 was expressed in GBM cell and GBM allograft mouse. Canagliflozin administration at 40 µM significantly inhibited cell proliferation and glucose uptake into the cell. Additionally, canagliflozin at 40 µM significantly increased the phosphorylation of AMPK and suppressed that of p70 S6 kinase and S6 ribosomal protein. Similar results of cell viability assays and immunoblotting were obtained using siRNA SGLT2. Furthermore, although less effective than in vitro, the canagliflozin group significantly suppressed tumor growth in GBM-transplanted mice. This suggests that canagliflozin can be used as a potential treatment for GBM.

NMDA receptor signaling induces the chemoresistance of temozolomide via upregulation of MGMT expression in glioblastoma cells.

PURPOSE: The alkylating agent temozolomide (TMZ) has a significant impact on the prognosis of glioblastoma (GBM) patients. Therefore, maximizing TMZ efficacy is important for GBM treatment. Many reports have shown that glutamate signaling promotes GBM progression via glutamate receptors, including N-methyl-D-aspartate receptors (NMDARs). Although NMDARs promote cell migration and invasion of GBM cells, their role in TMZ resistance remains unclear. Therefore, we focused on NMDAR signaling and investigated its effects on TMZ resistance. METHODS: We investigated the effect of NMDAR signaling on O6-methylguanine DNA methyltransferase (MGMT), a DNA repair enzyme that induces chemoresistance to TMZ, using quantitative real-time polymerase chain reaction and western blotting in human GBM T98G cells. In addition, we used memantine (MEM), an NMDAR antagonist, to investigate the cytotoxic effect of TMZ/MEM combination and its detailed mechanism. RESULTS: Activation of NMDAR by N-methyl-D-aspartate (NMDA) elevated MGMT expression and suppressed the effect of TMZ in T98G cells. In contrast, knockdown of NMDAR by NMDAR1 shRNA decreased MGMT expression and enhanced the effect of TMZ in T98G cells. The cytotoxic effect of TMZ was enhanced by MEM in T98G cells. Inhibition of NMDAR by MEM decreased MGMT expression and increased DNA alkylation by TMZ. CONCLUSION: NMDAR signaling induced chemoresistance of TMZ via the upregulation of MGMT expression in GBM cells. Furthermore, MEM inhibited TMZ-induced MGMT upregulation and increased the cytotoxic effect of TMZ on MGMT-positive cells. This study demonstrates that the combination of TMZ and MEM could be a new therapeutic strategy for MGMT-positive GBM. Overview of this study. NMDAR signaling controls the expression of MGMT and the cytotoxic effect of TMZ.

Platelet reactivity after clopidogrel loading in patients with acute ischemic stroke.

Objective: It remains unclear when sufficient antiplatelet effect is achieved after administration of a loading dose of clopidogrel in patients with acute ischemic stroke (AIS). This study aimed to evaluate the clopidogrel response in patients with AIS identified by the platelet function test (PFT). Methods: P2Y12 reaction unit (PRU) values measured using VerifyNow at baseline and at 6, 24, and 72 h after administration of a loading dose (300 mg) of clopidogrel were compared between patients with AIS and those of other cerebrovascular diseases (CVD). The prevalence of clopidogrel abnormal response and its associated factors were examined. Results: The PRU value was significantly reduced with time in the other CVD group (p < 0.0001), and also in the AIS group (p = 0.0073). The PRU values were significantly higher in the AIS group than in the other CVD group (p < 0.0001 between the groups, baseline: 314 ± 53 vs. 284 ± 62, p = 0.35; 6 h: 290 ± 66 vs. 214 ± 71, p = 0.016; 24 h: 270 ± 75 vs. 190 ± 70, p < 0.0001; and 72 h: 231 ± 76 vs. 163 ± 93, p = 0.105). The prevalence of clopidogrel hypo-responder (PRU > 240 at 24 h after administration) was higher in the AIS group (79 vs. 33%, p < 0.0001) and associated with the baseline PRU value but not with the cytochrome P450 2C19 genotype or clinical ischemic events. Conclusions: Residual platelet reactivity at 24 h after clopidogrel loading was substantially higher in patients with AIS than in patients with other CVD. In addition, most patients with AIS were judged to be hypo-responders on PFT. This should be carefully interpreted in patients with AIS because of poor specificity for predicting clinical ischemic events.

Long-term complications after stent assist coiling dependent on clopidogrel response.

BACKGROUND: Dual antiplatelet therapy (DAPT) is necessary for stent assisted coiling. However, long term use of DAPT has a potential risk of hemorrhagic events. We aimed to examine the relationship between clopidogrel reactivity and complications. METHODS: Patients who underwent stent assisted coiling for unruptured aneurysms or previously treated aneurysms and received periprocedural DAPT in our institution between August 2011 to March 2020 were included. Platelet reactivity for clopidogrel was measured by VerifyNow assay system, and we defined the cut off value of P2Y12 Reaction Units (PRU) at 208 and classified patients as hypo-responders (PRU≧208) or responders (PRU<208). The rates of hemorrhagic and thrombotic events within 30 days (acute phase) and 30 days after the procedure (delayed phase) were compared between the two groups. Furthermore, changes in hemoglobin levels were measured before and after the procedure and at chronic stages (1 to 6 months thereafter). RESULTS: From 61 patients included in this study, 36 patients were hypo-responders and 25 patients were responders. Hemorrhagic events occurred 8.0% only in responders in the acute phase (p = 0.16), and 2.78% in hypo-responders and 20.0% in responders in the delayed phase (p = 0.037). Changes in hemoglobin levels before and after the procedure were 1.22 g/dl in hypo-responders and 1.74 g/dl in responders (p = 0.032) while before the procedure and chronic stages they were 0.39 g/dl in hypo-responders and 1.39 g/dl in responders (p <  0.01). Thrombotic events were not significantly different between the two groups. CONCLUSION: Long term use of DAPT after stent assisted coiling is related to hemorrhagic events in the delayed phase. Preventing for hemorrhagic events, the duration of DAPT should be carefully considered in clopidogrel responders.

Endoscopic third ventriculostomy for hydrocephalus in a patient with achondroplasia: a case report and literature review.

Hydrocephalus, a complication of achondroplasia, requires treatment when it is symptomatic. Hydrocephalus associated with achondroplasia is often treated with ventriculoperitoneal shunting, and endoscopic third ventriculostomy (ETV) is rarely performed in these patients. Here, we report the case of an 18-month-old boy with achondroplasia and progressive hydrocephalus who underwent ETV. He had a family history of achondroplasia and was diagnosed with achondroplasia at birth. Magnetic resonance imaging (MRI) at the age of 1 month showed no hydrocephalus. At the age of 15 months, he was admitted to our hospital due to increased head circumference. He had developmental delays, and MRI showed hydrocephalus with ballooning of the third ventricle. The ETV success score was 80 points; therefore, we performed ETV. Postoperatively, the progression of head circumference increase was controlled. The ventricular size remained unchanged on MRI at 13 months after surgery. Recently, an association between non-communicating hydrocephalus and achondroplasia has been reported. Depending on age and imaging findings, ETV may be effective in some patients with achondroplasia with hydrocephalus.