Antiproliferative effects of D-allose associated with reduced cell division frequency in glioblastoma.

Recent studies have shown that D-allose, a rare sugar, elicits antitumor effects on different types of solid cancers, such as hepatocellular carcinoma, non-small-cell lung cancer, and squamous cell carcinoma of the head and neck. In this study, we examined the effects of D-allose on the proliferation of human glioblastoma (GBM) cell lines (i.e., U251MG and U87MG) in vitro and in vivo and the underlying mechanisms. D-allose treatment inhibited the proliferation of U251MG and U87MG cells in a dose-dependent manner (3-50 mM). However, D-allose treatment did not affect cell cycles or apoptosis in these cells but significantly decreased the cell division frequency in both GBM cell lines. In a subcutaneous U87MG cell xenograft model, intraperitoneal injection of D-allose (100 mg/kg/day) significantly reduced the tumor volume in 28 days. These data indicate that D-allose-induced reduction in cell proliferation is associated with a subsequent decrease in the number of cell divisions, independent of cell-cycle arrest and apoptosis. Thus, D-allose could be an attractive additive to therapeutic strategies for GBM.

Stone-event-free survival after ureteroscopic lithotripsy by age: comparison between young and older patients.

The aim of this study is to examine stone-event-free survival after ureteroscopic lithotripsy (URSL) and risk factors for stone events by age. We retrospectively collected data of all URSL cases at our institution from 2008 to 2021. A total of 1334 cases were included and divided into young (< 65 years, 792 cases), young-old (65-74 years, 316 cases), old-old (75-84 years, 172 cases), and oldest-old (≥ 85 years, 54 cases) groups. Patient characteristics, surgical outcomes, and postoperative stone events were evaluated. The stone-event-free survival and risk factors were compared between young and older groups. Overall, 214 (16.0%) cases developed stone events during a mean follow-up period of 763 days and the 2-year, 5-year, and 8-year stone-event-free survival rates were 84.5%, 72.2%, and 57.2%, respectively. The numbers of stone events in young, young-old, old-old, oldest-old groups were 133 (16.8%), 53 (16.8%), 21 (12.2%), and 7 (13.0%), respectively. No significant differences were found in stone-event-free survival between the young group and each of the older groups. Residual fragment > 4 mm and stone burden ≥ 15 mm were common risk factors in both young and older groups. Especially in older patients, preoperative stenting, which was most often performed to treat obstructive pyelonephritis, was the third risk factor. In conclusion, stone-event-free survival after URSL was comparable between young and older patients. Residual fragment > 4 mm and stone burden ≥ 15 mm were common risk factors in both groups. Preoperative stenting was an additional risk factor in older patients, suggesting that urinary tract infection may influence stone events.

Effects of a monoclonal antibody against (pro)renin receptor on gliomagenesis.

Glioblastoma is characterized by a strong self-renewal potential and poor differentiated state. We have reported previously that the (pro)renin receptor [(P)RR] is a potential target for glioma therapy by silencing the (P)RR gene. Here, we have examined the effects of a monoclonal antibody against (P)RR on gliomagenesis. Human glioma cell lines (U251MG and U87MG) and a glioma stem cell line (MGG23) were used for the in vitro study. The expressions of the Wnt/ß-catenin signaling pathway (Wnt signaling pathway) components and stemness markers were measured by Western blotting. The effects of the (P)RR antibody on cell proliferation, sphere formation, apoptosis and migration were also examined. Subcutaneous xenografts were also examined in nude mice. Treatment with the (P)RR antibody reduced expression of Wnt signaling pathway components and stemness markers. Furthermore, the (P)RR antibody reduced cell proliferation and decreased sphere formation significantly. The treatment also suppressed migration and induced apoptosis. In a subcutaneous xenograft model, systemic administration of the (P)RR antibody reduced tumor volume significantly. These data show that treatment with the (P)RR antibody is a potential therapeutic strategy for treating glioblastoma.

d-Allulose Supplementation Prevents Diet-Induced Hepatic Lipid Accumulation via miR-130-Mediated Regulation in C57BL/6 Mice.

SCOPE: d-allulose is a low-calorie rare sugar. It has been reported that d-allulose supplementation significantly inhibits diet-induced hepatic fat accumulation. However, the underlying molecular mechanisms remain unclear. This study elucidates the mechanism underlying the suppressive effect of d-allulose on hepatic fat accumulation in terms of miRNA regulation. METHODS AND RESULTS: Male C57BL/6 mice are divided into three experimental groups-normal diet and distilled water (CC group), high-fat diet (HFD) and distilled water (HC group), and HFD and 5% d-allulose solution (HA group)-and fed the respective diets for 8 weeks. Weight gain is significantly lower in the HA group than that in the HC group, although the caloric intake is the same in both. Histological analysis of liver tissues reveals excessive lipid accumulation in the HC group; this is greatly attenuated in the HA group. Real-time PCR and western blot analyses demonstrate that, compared to the HC group, the HA group exhibits decreased hepatic PPARγ and CD36 expression. Hepatic miR-130 expression levels are higher in the HA group than those in the CC and HC groups. CONCLUSIONS: These results indicate that miRNA changes associated with PPARγ may underlie the suppression of hepatic lipid accumulation induced by d-allulose intake.

A novel catheter interaction simulating method for virtual reality interventional training systems.

Endovascular robotic systems have been applied in robot-assisted interventional surgery to improve surgical safety and reduce radiation to surgeons. However, this surgery requires surgeons to be highly skilled at operating vascular interventional surgical robot. Virtual reality (VR) interventional training systems for robot-assisted interventional surgical training have many advantages over traditional training methods. For virtual interventional radiology, simulation of the behaviors of surgical tools (here mainly refers to catheter and guidewire) is a challenging work. In this paper, we developed a novel virtual reality interventional training system. This system is an extension of the endovascular robotic system. Because the master side of this system can be used for both the endovascular robotic system and the VR interventional training system, the proposed system improves training and reduces the cost of education. Moreover, we proposed a novel method to solve catheterization modeling during the interventional simulation. Our method discretizes the catheter by the collision points. The catheter between two adjacent collision points is treated as thin torsion-free elastic rods. The deformation of the rod is mainly affected by the force applied at the collision points. Meanwhile, the virtual contact force is determined by the collision points. This simplification makes the model more stable and reduces the computational complexity, and the behavior of the surgical tools can be approximated. Therefore, we realized the catheter interaction simulation and virtual force feedback for the proposed VR interventional training system. The performance of our method is experimentally validated.

Perioperative Clinical Course Variables Associated with Length of Hospital Stay after Primary Intracranial Meningioma Resection.

The relationship between perioperative clinical course variables and postoperative length of hospital stay (LOS) in patients undergoing primary intracranial meningioma resection has not been fully elucidated. We therefore aimed to identify the perioperative clinical course variables that predict postoperative LOS in such patients. We retrospectively collected data concerning demographics, tumor characteristics, and perioperative clinical course variables in 76 patients who underwent primary intracranial meningioma resection between January 2010 and December 2019, and tested for associations with postoperative LOS. Univariate analyses showed that younger age, fewer days to postoperative initiation of standing/walking, preoperative independence in activities of daily living (ADL), and ADL independence one week after surgery were associated with shorter postoperative LOS. Multiple regression analyses with these factors identified that days to stand/walk initiation and ADL independence one week after surgery were associated with postoperative LOS. Based on these results, we conclude that rehabilitation programs that promote early mobilization and the early acquisition of independence may reduce postoperative LOS in patients who undergo primary intracranial meningioma resection.

Different failure rates of insertion of 10/12-Fr ureteral access sheaths during retrograde intrarenal surgery in patients with and without stones.

PURPOSE: The aim of this study was to compare the failure rates of insertion of a 10/12-Fr ureteral access sheath (UAS) during retrograde intrarenal surgery (RIRS) in cases with and without stones and to analyze the risk factors for UAS insertion failure. MATERIALS AND METHODS: A total of 640 RIRS cases (538 with and 102 without stones) were evaluated. The primary outcome of interest was the failure rate of insertion of a 10/12-Fr UAS. Associated risk factors were assessed using univariate and multivariate logistic regression analyses. Propensity score (PS) matching and inverse probability of treatment weighting (IPTW) were used to ensure the robustness of the results. RESULTS: The overall failure rate of 10/12-Fr UAS insertion in the cases without stones was significantly higher than that in the cases with stones (39.2% vs. 7.2%; p<0.001), and was approximately 2.5 to 4 times higher after PS matching and IPTW. Multivariate logistic analyses showed that being in the group without stones and younger age were independent significant risk factors for insertion failure in both the PS-matched cohort (odds ratio [OR], 5.43; 95% confidence interval [CI], 2.16-13.6; and OR, 1.04; 95% CI, 1.01-1.07) and the IPTW-adjusted cohort (OR, 1.82; 95% CI, 1.14-2.90; and OR, 1.03; 95% CI, 1.01-1.04). CONCLUSIONS: The incidence of 10/12-Fr UAS insertion failure during RIRS was higher in cases without stones than in those with stones. These results provide valuable information for surgeons to use during informed consent discussions with patients undergoing RIRS, especially patients without stones.

A Home-based Tele-rehabilitation System With Enhanced Therapist-patient Remote Interaction: A Feasibility Study.

As a promising alternative to hospital-based manual therapy, robot-assisted tele-rehabilitation therapy has shown significant benefits in reducing the therapist's workload and accelerating the patient's recovery process. However, existing telerobotic systems for rehabilitation face barriers to implementing appropriate therapy treatment due to the lack of effective therapist-patient interactive capabilities. In this paper, we develop a home-based tele-rehabilitation system that implements two alternative training methods, including a haptic-enabled guided training that allows the therapist to adjust the intensity of therapeutic movements provided by the rehabilitation device and a surface electromyography (sEMG)-based supervised training that explores remote assessment of the patient's kinesthetic awareness. Preliminary experiments were conducted to demonstrate the feasibility of the proposed alternative training methods and evaluate the functionality of the developed tele-rehabilitation system. Results showed that the proposed tele-rehabilitation system enabled therapist-in-the-loop to dynamically adjust the rehabilitation intensity and provided more interactivity in therapist-patient remote interaction.

Validity of identification algorithms combining diagnostic codes with other measures for acute ischemic stroke in MID-NET®.

PURPOSE: We aimed to develop a reliable identification algorithm combining diagnostic codes with several treatment factors for inpatients with acute ischemic stroke (AIS) to conduct pharmacoepidemiological studies using the administrative database MID-NET® in Japan. METHODS: We validated 11 identification algorithms based on 56 different diagnostic codes (International Classification of Diseases, Tenth Revision; ICD-10) using Diagnosis Procedure Combination (DPC) data combined with information on AIS therapeutic procedures added as "AND" condition or "OR" condition. The target population for this study was 366 randomly selected hospitalized patients with possible cases of AIS, defined as relevant ICD-10 codes and diagnostic imaging and prescription or surgical procedure, in three institutions between April 1, 2015 and March 31, 2017. We determined the positive predictive values (PPVs) of these identification algorithms based on comparisons with a gold standard consisting of chart reviews by experienced specialist physicians. Additionally, the sensitivities of them among 166 patients with the possible cases of AIS at a single institution were evaluated. RESULTS: The PPVs were 0.618 (95% confidence interval [CI]: 0.566-0.667) to 0.909 (95% CI: 0.708-0.989) and progressively increased with adding or limiting information on AIS therapeutic procedures as "AND" condition in the identification algorithms. The PPVs for identification algorithms based on diagnostic codes I63.x were >0.8. However, the sensitivities progressively decreased to a maximum of ~0.2 after adding information on AIS therapeutic procedures as "AND" condition. CONCLUSIONS: The identification algorithms based on the combination of appropriate ICD-10 diagnostic codes in DPC data and other AIS treatment factors may be useful to studies for AIS at a national level using MID-NET®.

Risk factors and predictive model for incidence of difficult ureter during retrograde ureteroscopic lithotripsy.

OBJECTIVE: Difficult ureter can be a challenge for accessing upper urinary tract during lithotripsy. In this study, we evaluated the risk factors for the incidence of difficult ureter in retrograde ureteroscopic lithotripsy. Moreover, we aimed to develop a predictive model for the incidence of difficult ureter. METHODS: We retrospectively reviewed consecutive retrograde ureteroscopic lithotripsies performed at our institution between 2009 and 2021. A total of 1010 renal units were evaluated: 449 units with renal stones only and 561 units with ureteral stones, with or without renal stones. RESULTS: The overall incidence of difficult ureter was 5.9%, with a higher incidence in the renal alone stone group than in the ureteral stone group (7.8% vs 4.5%, P = 0.026). Multivariate regression analysis revealed three risk factors for the incidence of difficult ureter: absence of stone history (odds ratio 5.67, 95% confidence interval 2.40-13.4, and P < 0.001), age ≤45 years (odds ratio 3.61, 95% confidence interval 2.05-6.37, and P < 0.001), and renal stone only (odds ratio 2.11, 95% confidence interval 1.22-3.64, and P = 0.008). A simple model using these three risks enabled the stratification of the incidence rate of difficult ureter, with the incidence of high-risk cases being 12.7%. CONCLUSIONS: The greatest risk factor for the incidence of difficult ureter was the absence of stone history, followed by age 45 years or younger, and having only renal stones. In high-risk cases of difficult ureter, the possibility of secondary lithotripsy should be explained to the patients.

Endovascular Treatment for Posterior Communicating Artery Aneurysms with Oculomotor Nerve Palsy.

Objective: Coil embolization for the treatment of internal carotid artery-posterior communicating artery aneurysms (PComAAn) associated with oculomotor nerve palsy (ONP) remains controversial in terms of the therapeutic effect to improve ONP. Patients with PComAAn treated in our hospital were retrospectively analyzed to evaluate the effectiveness of coil embolization on ONP. Methods: Twenty-three patients who had coil embolization for PComAAn with ONP were included in the analysis. In the evaluation of postoperative outcome of ONP, complete resolution of all symptoms was considered as a total recovery. ONP with a few residual symptoms that are stable and not disabling was considered as a subtotal recovery and that with only a slight improvement as a partial recovery. Results: Preoperative ONP was complete palsy in 14 and partial palsy in nine cases. The mean maximum diameter of the aneurysms was 9.1 ± 3.5 mm (3-17 mm), and the mean time from the onset to treatment was 46.3 ± 98.4 days (0-300 days). The embolization state immediately after the procedure was complete occlusion in seven, neck remnant in eight, and body filling (BF) in eight cases. Total recovery was observed in nine, subtotal recovery in 11, and partial recovery in three cases. The mean time to any improvement in ONP was 6.0 ± 6.0 months (0.5-25 months). Comparing 20 cases with total plus subtotal recovery and three cases with partial recovery, five (25.0%) and three (100%) cases showed BF immediately after the procedure, respectively, which was statistically significant (P = 0.015). Conclusion: The analysis indicated that coil embolization for the treatment of PComAAn with ONP resulted in satisfactory recovery of ONP in 87% of the cases and the outcome of aneurysm embolization was related to improvement in ONP.

Case Series of Endovascular Therapy for Blood Blister-Like Aneurysm in Acute Phase.

Objective: Blood blister-like aneurysms (BBAs) of the internal carotid artery are highly challenging to treat due to their variable morphology and tendency for rupture and regrowth. Here, we report a single-institution experience of endovascular therapy (EVT) for BBA treatment. Methods: We retrospectively reviewed patients with ruptured BBA from 2006 to 2019. All patients in whom BBA was treated with EVT were included. Patients' aneurysmal characteristics, progression status, aneurysm occlusion on follow-up angiography, and modified Rankin Scale (mRS) score were recorded. Results: A total of 11 patients (5 women and 6 men) with the mean age of 46 ± 10 years were included in this study. As initial treatment, 9 patients were treated with stent-assisted coiling (SAC). Immediate angiographic results showed that 2 cases were body filling, 4 were neck remnant, and 3 were complete obliteration. Perioperative ischemic complications were not observed. On postoperative day 1, 2 patients suffered from rerupture, and their prognoses were poor. Retreatments were performed in 5 patients. Parent artery occlusion (PAO) was performed in 6 patients including 2 initial treatments and 4 retreatments. Symptomatic infarction developed in 2 patients. In 3 patients, bypass in combination with PAO was performed. Clinical data revealed discharge mRS scores of 0-2 and 3-6 in 4 and 7 patients, respectively. Conclusion: SAC is effective for the management of BBA. Careful follow-up and response are necessary after treatment with SAC.

[Points to Note about Neuropsychological Impairment in the Acute Management of Traumatic Brain Injury].

Neuropsychological impairment after traumatic brain injury(TBI)is occasionally difficult to diagnose and called "invisible or hidden impairment," especially when physical impairment is mild. Patients and their family do not recognize the impairment during hospitalization and even after discharge. However, they manifest many problems when they return to real life and society. Here, we have presented the characteristics and tips to diagnose neuropsychological impairment after TBI that are important for clinical neurosurgeons working at acute care hospitals. They are as follows: 1)In the emergency room, accurate evaluation of the consciousness state is the first step. 2)In the acute phase after TBI, do not mix up acute symptomatic seizure and post-traumatic epilepsy. 3)Soon after stabilization of the general condition, detailed radiological examinations should be performed to detect organic brain damages with MRI including DWI, FLAIR, T2*, and SWI. 4)At discharge, it is necessary to provide information about neuropsychological impairment to the patients and their family members. Neurosurgeons should diagnose and treat the patients with accurate understanding of neuropsychological impairment in the acute management of TBI.

Long-term Multidisciplinary Rehabilitation Efficacy in Older Patients After Traumatic Brain Injury: Assessed by the Functional Independence Measure.

Instances of traumatic brain injury (TBI) in the elderly have been increasing along with the aging of popula-tions. In the present study, we examined the effect of aging on long-term multidisciplinary in-patient rehabili-tation efficacy after TBI. Sixty-three patients with physical and cognitive impairments after TBI were enrolled in this study. Patients were divided into 4 age groups (≤ 24, 25-44, 45-64, ≥ 65 years) and the clinical charac-teristics and rehabilitation efficacy of each age group were determined. Functional disability was evaluated using motor and cognitive Functional Independence Measure (FIM) scores. Rehabilitation efficacy was assessed by FIM gains during rehabilitation and compared among the groups. There were no statistically significant dif-ferences in motor and cognitive FIM gains among the age groups. However, cognitive FIM gain was limited in a subset of ≥ 65 patients, and initial cognitive measures could not predict cognitive FIM improvement. These results indicate that chronological age is insufficient to accurately predict rehabilitation efficacy in older TBI patients, and that such patients should be considered candidates for intensive rehabilitation programs based on these results. Accurate prognostication of rehabilitation efficacy with continuing data collection is important when using rehabilitation resources for older TBI patients.

Hypoxia and glucose metabolism assessed by FMISO and FDG PET for predicting IDH1 mutation and 1p/19q codeletion status in newly diagnosed malignant gliomas.

BACKGROUND: Tumor hypoxia and glycolysis have been recognized as determinant factors characterizing tumor aggressiveness in malignant gliomas. To clarify in vivo hypoxia and glucose metabolism in relation to isocitrate dehydrogenase (IDH) mutation and chromosome 1p and 19q (1p/19q) codeletion status, we retrospectively analyzed hypoxia as assessed by positron emission tomography (PET) with [18F]-fluoromisonidazole (FMISO) and glucose metabolism as assessed by PET with [18F]-fluoro-2-deoxy-D-glucose (FDG) in newly diagnosed malignant gliomas. METHODS: In total, 87 patients with newly diagnosed supratentorial malignant (WHO grade III and IV) gliomas were enrolled in this study. They underwent PET studies with FMISO and FDG before surgery. The molecular features and histopathological diagnoses based on the 2016 WHO classification were determined using surgical specimens. Maximal tumor-to-normal ratio (TNR) was calculated for FDG PET, and maximal tumor-to-blood SUV ratio (TBR) was calculated for FMISO PET. The PET uptake values in relation to IDH mutation and 1p/19q codeletion status were statistically analyzed. RESULTS: In all tumors and malignant astrocytomas, the median FMISO TBR in IDH-wildtype tumors was significantly higher than that in IDH-mutant tumors (P < 0.001 and P < 0.01, respectively). In receiver operating characteristic (ROC) analysis, the area under the curve showed that the sensitivity for the discrimination was moderate (0.7-0.8) and the specificity was low (0.65-0.68). In the same population, the median FDG TNR in IDH-wildtype tumors tended to be higher than that in IDH-mutant tumors, but the difference was not statistically significant. In WHO grade III anaplastic astrocytomas, there were no significant differences in median FMISO TBR or FDG TNR between IDH-mutant and IDH-wildtype tumors. In IDH-mutant WHO grade III anaplastic gliomas, there were no significant differences in median FMISO TBR or FDG TNR between anaplastic astrocytomas and anaplastic oligodendrogliomas. CONCLUSIONS: Tumor hypoxia as assessed by FMISO PET was informative for prediction of the IDH mutation status in newly diagnosed malignant gliomas. However, the accuracy of the discrimination was not satisfactory for clinical application. On the other hand, glucose metabolism as assessed by FDG PET could not differentiate the IDH-mutant status. Moreover, PET studies using FMISO and FDG could not predict IDH mutation and 1p/19q codeletion status in WHO grade III tumors.

A Magnetorheological Fluids-Based Robot-Assisted Catheter/Guidewire Surgery System for Endovascular Catheterization.

A teleoperated robotic catheter operating system is a solution to avoid occupational hazards caused by repeated exposure radiation of the surgeon to X-ray during the endovascular procedures. However, inadequate force feedback and collision detection while teleoperating surgical tools elevate the risk of endovascular procedures. Moreover, surgeons cannot control the force of the catheter/guidewire within a proper range, and thus the risk of blood vessel damage will increase. In this paper, a magnetorheological fluid (MR)-based robot-assisted catheter/guidewire surgery system has been developed, which uses the surgeon's natural manipulation skills acquired through experience and uses haptic cues to generate collision detection to ensure surgical safety. We present tests for the performance evaluation regarding the teleoperation, the force measurement, and the collision detection with haptic cues. Results show that the system can track the desired position of the surgical tool and detect the relevant force event at the catheter. In addition, this method can more readily enable surgeons to distinguish whether the proximal force exceeds or meets the safety threshold of blood vessels.

Multiple positron emission tomography tracers for use in the classification of gliomas according to the 2016 World Health Organization criteria.

BACKGROUND: The molecular diagnosis of gliomas such as isocitrate dehydrogenase (IDH) status (wild-type [wt] or mutation [mut]) is especially important in the 2016 World Health Organization (WHO) classification. Positron emission tomography (PET) has afforded molecular and metabolic diagnostic imaging. The present study aimed to define the interrelationship between the 2016 WHO classification of gliomas and the integrated data from PET images using multiple tracers, including 18F-fluorodeoxyglucose (18F-FDG), 11C-methionine (11C-MET), 18F-fluorothymidine (18F-FLT), and 18F-fluoromisonidazole (18F-FMISO). METHODS: This retrospective, single-center study comprised 113 patients with newly diagnosed glioma based on the 2016 WHO criteria. Patients were divided into 4 glioma subtypes (Mut, Codel, Wt, and glioblastoma multiforme [GBM]). Tumor standardized uptake value (SUV) divided by mean normal cortical SUV (tumor-normal tissue ratio [TNR]) was calculated for 18F-FDG, 11C-MET, and 18F-FLT. Tumor-blood SUV ratio (TBR) was calculated for 18F-FMISO. To assess the diagnostic accuracy of PET tracers in distinguishing glioma subtypes, a comparative analysis of TNRs and TBR as well as the metabolic tumor volume (MTV) were calculated by Scheffe's multiple comparison procedure for each PET tracer following the Kruskal-Wallis test. RESULTS: The differences in mean 18F-FLT TNR and 18F-FMISO TBR were significant between GBM and other glioma subtypes (P < .001). Regarding the comparison between Gd-T1WI volumes and 18F-FLT MTVs or 18F-FMISO MTVs, we identified significant differences between Wt and Mut or Codel (P < .01). CONCLUSION: Combined administration of 4 PET tracers might aid in the preoperative differential diagnosis of gliomas according to the 2016 WHO criteria.

Rationale and Design of BeatNF2 Trial: A Clinical Trial to Assess the Efficacy and Safety of Bevacizumab in Patients with Neurofibromatosis Type 2 Related Vestibular Schwannoma.

Neurofibromatosis type 2 (NF2) causes bilateral vestibular schwannomas (VSs), leading to deafness. VS is treated by surgery or radiation, but neither treatments prevent hearing loss. Bevacizumab was found to be effective in suppressing the tumor's growth and may help to improve hearing. We are conducting a randomized, double-blind, multicenter clinical trial to verify the efficacy and safety of bevacizumab in NF2-related VS. The primary objective is to evaluate the efficacy of bevacizumab in improving hearing in the affected ear. One of the secondary objectives is to evaluate bevacizumab's efficacy in rechallenge treatment in relapsed cases. Sixty patients will randomly receive either bevacizumab or a placebo and will be clinically observed for 48 weeks in the initial intervention phase. In the first half (24 weeks), they will receive either 5 mg/kg of bevacizumab or a placebo drug. In the second half, all patients will receive 5 mg/kg of bevacizumab. If hearing function deteriorated in a patient who had shown improvement during the first phase, a rechallenge dose with bevacizumab would be offered.