Comparison of vestibular function in hereditary hearing loss patients with GJB2, CDH23, and SLC26A4 variants.

To investigate the association between hereditary hearing loss and vestibular function, we compared vestibular function and symptoms among patients with GJB2, SLC26A4, and CDH23 variants. Thirty-nine patients with sensory neural hearing loss (11 males and 28 females) with biallelic pathogenic variants in either GJB2, SLC26A4, or CDH23 were included in this study (13 GJB2, 15 SLC26A4, and 11 CDH23). The patients were examined using caloric testing and cervical and ocular vestibular-evoked myogenic potentials (cVEMP and oVEMP). We also compared vestibular function and symptoms between patients with these gene variants and 78 normal-hearing ears without vestibular symptoms as controls. The frequency of semicircular canal hypofunction in caloric testing was higher in patients with SLC26A4 variants (47%) than in those with GJB2 (0%) and CDH23 variants (27%). According to the cVEMP results, 69% of patients with GJB2 variants had saccular hypofunction, a significantly higher proportion than in those carrying other variants (SLC26A4, 20%; CDH23, 18%). In oVEMP, which reflects utricular function, no difference was observed in the frequency of hypofunction among the three genes (GJB2, 15%; SLC26A4, 40%; and CDH23, 36%). Hence, discernable trends indicate vestibular dysfunction associated with each gene.

Factors Affecting Nivolumab Therapy Outcome in Patients with Head and Neck Cancer: A Single-Center Analysis.

BACKGROUND: Nivolumab, a programmed death-1 antibody, is an immune checkpoint inhibitor approved in Japan in March 2017 for the treatment of recurrent or metastatic head and neck cancers (RM-HNCs) after platinum drug administration. This study aimed to evaluate the effectiveness and safety of nivolumab and to determine the prognostic factors affecting the treatment outcome, in a real-world setting in Japanese RM-HNCs. METHODS: Forty-six patients with RM-HNCs treated with nivolumab between April 2017 and April 2021 at Shinshu University Hospital were retrospectively assessed in this cohort study. RESULTS: The overall response rate was 17.4%, and the disease control rate was 41.3%. The median first and second progression-free survival (PFS1 and PFS2) were 2.6 and 10.3 months, respectively. The median overall survival (OS) was 14.8 months. Multivariate analysis showed that performance status (PS) (p = 0.003) and a decrease in neutrophil-lymphocyte ratio (NLR) (p = 0.02) were significantly associated with a better OS, and a decrease in NLR (p = 0.035) was associated with a better PFS2. CONCLUSIONS: This study is the first report of PFS2 in RM-HNCs treated with nivolumab; the long PFS2 may contribute to prolonged OS. We propose that the PS and a decrease in NLR could be useful clinical prognostic markers of nivolumab therapy, which can easily be evaluated in the clinical setting.

Vestibular nerve deficiency and vestibular function in children with unilateral hearing loss caused by cochlear nerve deficiency.

BACKGROUND: High-resolution MR imaging enables the visualization of individual nerves in the internal auditory canal (IAC). Cochlear nerve deficiency (CND) is recognized as one of the major causes of sensory neural hearing loss (SNHL), especially in cases of unilateral hearing loss in childhood. Some patients with CND are thought to have accompanying vestibular nerve deficiency (VND). However, there have been few reports focusing on VND and vestibular function in these children. AIMS: The aim of this study was to evaluate the frequency of VND and vestibular dysfunction in children with unilateral SNHL caused by CND. MATERIAL AND METHODS: Thirty-eight children with unilateral SNHL, who were diagnosed with CND by 3 T-MRI, were evaluated for VND and underwent caloric testing and cervical vestibular evoked potential (cVEMP). RESULTS: Fourteen of 38 patients (37%) had VND, and eleven (29%) of the patients [ten of the patients (71%) with VND] had at least one vestibular dysfunction. The patients with VND had significantly worse hearing and an IAC of smaller diameter than did patients without VND. CONCLUSIONS AND SIGNIFICANCE: We should pay attention to VND as well as vestibular dysfunction in hearing loss patients with CND.

Vestibular Preservation After Cochlear Implantation Using the Round Window Approach.

Background: The development of less traumatic surgical techniques, such as the round window approach (RWA), as well as the use of flexible electrodes and post-operative steroid administration have enabled the preservation of residual hearing after cochlear implantation (CI) surgery. However, consideration must still be given to the complications that can accompany CI. One such potential complication is the impairment of vestibular function with resulting vertigo symptoms. The aim of our current study was to examine the changes in vestibular function after implantation in patients who received CI using less traumatic surgery, particularly the RWA technique. Methods: Sixty-six patients who received CI in our center were examined by caloric testing, cervical vestibular evoked myogenic potential (cVEMP) and ocular VEMP (oVEMP) before or after implantation, or both, to obtain data on semicircular canal, saccular and utricular function, respectively. Less traumatic CI surgery was performed by the use of the RWA and insertion of flexible electrodes such as MED-EL FLEX soft, FLEX 28, and FLEX 24 (Innsbruck, Austria). Results: Caloric response and the asymmetry ratio of cVEMP and oVEMP were examined before and after implantation using less traumatic surgical techniques. Compared with before implantation, 93.9, 82.4, and 92.5% of the patients showed preserved vestibular function after implantation based on caloric testing, cVEMP and oVEMP results, respectively. We also examined the results for vestibular function by a comparison of the 66 patients using the RWA and flexible electrodes, and 17 patients who underwent cochleostomy and insertion of conventional or hard electrodes. We measured responses using caloric testing, cVEMP and oVEMP in patients after CI. There were no differences in the frequencies of abnormal caloric and oVEMP results in the implanted ears between the RWA and cochleostomy. On the other hand, the frequency of abnormal cVEMP responses in the implanted ears in the patients who received implantation by cochleostomy was significantly higher than that in the patients undergoing surgery using the RWA. Conclusion: Patients receiving CI using less traumatic surgical techniques such as RWA and flexible electrodes have reduced risk of damage to vestibular function.

Preoperative Arterial Embolization to Avoid Intraoperative Bleeding during Endoscopic Sinus Surgery for Organized Hematoma of the Maxillary Sinus: A Case Series and Literature Review.

Purpose: This study aimed to evaluate the safety and efficacy of preoperative arterial embolization of organized hematoma of the maxillary sinus. Material and Methods: Seven patients who were pathologically diagnosed with an organized hematoma of the maxillary sinus and who underwent endoscopic sinus surgery following preoperative arterial embolization for the same from July 2013 to April 2020 at our hospital were included. A literature review of the PubMed database was performed to identify 13 cases on organized hematomas of the maxillary sinuses. The embolization and nonembolization groups comprised patients who underwent preoperative embolization (n = 10, seven from this study and three from literature) and those who did not undergo preoperative embolization (n = 10, from literature), respectively. Outcomes of embolization including embolization-related complications and postoperative bleeding were assessed, and volumes of intraoperative blood loss and duration of surgery were compared between the groups. Results: No preoperative embolization-related complications were observed in our cases. The volume of surgical blood loss in the seven cases varied from 0 to 100 mL with a median of 30 mL, and the duration of surgery ranged from 45 to 166 minutes with a median of 112 minutes. The volume of blood loss was significantly lower for the embolization group than that for the nonembolization group (p = 0.0031). There was no statistically significant difference regarding duration of surgery between the groups (p > 0.10). Conclusions: Preoperative embolization of an organized hematoma of the maxillary sinus is a safe and effective method that helps prevent serious intraoperative hemorrhage.

A Rare Distant Metastasis of Papillary Cystadenocarcinoma Arising from Maxillary Gingiva.

Papillary cystadenocarcinoma is an uncommon disease with low-grade histological and clinical features. Although the tumor has the potential to produce regional lymph node metastasis, there have been no reports of cases with distant metastasis. We describe a case of papillary cystadenocarcinoma arising from the maxilla that developed pulmonary metastasis 3 years after radical surgery of the primary tumor and regional lymph node. The histological findings were confirmed on resected specimens of the pulmonary nodule and a pathological diagnosis of a metastatic lesion derived from papillary cystadenocarcinoma was made. To our knowledge, this is the first report of the development of pulmonary metastasis in a patient with papillary cystadenocarcinoma. The present case suggests that papillary cystadenocarcinoma has the potential to produce lung metastasis in the clinical course. Based on our experience, we emphasize that long-term follow-up and/or careful examination are necessary in patients with cystadenocarcinoma, especially in patients with lymph node metastasis during the initial surgical therapy.

Detailed MR imaging assessment of endolymphatic hydrops in patients with SLC26A4 mutations.

OBJECTIVE: Mutations in SLC26A4 represent the second most common mutations in deafness patients. The majority of patients with SLC26A4 mutations have a large vestibular aqueduct (LVA). Recently, some reports showed the presence of endolymphatic hydrops (ELH) in patients with LVA on the basis of high-resolution enhanced 3T-MRI. However, detailed evaluation has not been performed. We provide the first report on ELH in LVA patients with biallelic SLC26A4 mutations. In this study, we focused on 1) the findings of ELH in LVA patients with biallelic SLC26A4 mutations, and 2) the findings of the endolymphatic duct (ED) and endolymphatic sac (ES) by using two different gadodimide (Gd) enhancement methods. SUBJECTS AND METHODS: Five patients with SLC26A4 mutations underwent enhanced 3T-MRI using the intratympanic (IT) or intravenous (IV) injection of Gd for the diagnosis ELH. RESULTS: All of the patients had ELH in at least one ear. ELH was identified in the vestibule (8/10 ears) as well as in the cochlea (7/10 ears). With regard to the ED and ES, all ears for which MRI was performed with an IT injection of Gd had black areas in the ES or VA or both; however, all of the ears receiving an IV injection had no black areas and were well enhanced. CONCLUSIONS: A majority of the patients had severe ELH in the cochleo-vestibular endolymph, with two different patterns observed in the MRI findings of the ED and ES.

A phase I/IIa double blind single institute trial of low dose sirolimus for Pendred syndrome/DFNB4.

INTRODUCTION: Pendred syndrome (PDS)/DFNB 4 is a disorder with fluctuating and progressive hearing loss, vertigo, and thyroid goiter. We identified pathophysiology of a neurodegenerative disorder in PDS patient derived cochlear cells that were induced via induced pluripotent stem cells and found sirolimus, an mTOR inhibitor, as an inhibitor of cell death with the minimum effective concentration less than 1/10 of the approved dose for other diseases. Given that there is no rational standard therapy for PDS, we planned a study to examine effects of low dose oral administration of sirolimus for the fluctuating and progressive hearing loss, and the balance disorder of PDS by daily monitor of their audio-vestibular symptoms. METHODS AND ANALYSIS: This is a phase I/IIa double blind parallel-group single institute trial in patient with PDS/DFNB4. Sixteen of outpatients with fluctuating hearing diagnosed as PDS in SLC26A4 genetic testing aged in between 7 and 50 years old at the time of consent are given either placebo or sirolimus tablet (NPC-12T). In NPC-12T placebo arm, placebo will be given for 36 weeks; in active substance arm, placebo will be given for 12 weeks and the NPC-12T for 24 weeks. Primary endpoints are safety and tolerability. The number of occurrences and types of adverse events and of side effects will be sorted by clinical symptoms and by abnormal change of clinical test results. A 2-sided 95% confidence interval of the incidence rate by respective dosing arms will be calculated using the Clopper-Pearson method. Clinical effects on audio-vestibular tests performed daily and precise physiological test at each visit will also be examined as secondary and expiratory endpoints. TRIAL REGISTRATION NUMBER: JMA-IIA00361; Pre-results.

Endoscopic Endonasal Odontoidectomy in the Hybrid Operating Room.

BACKGROUND: The endoscopic endonasal approach for the craniovertebral junction (CVJ), instead of the microscopic transoral approach, has been widely adopted and accepted, especially in resection of the odontoid process for basilar invagination. However, there is concern regarding insufficient resection of odontoid and surgical complications, including vessel injuries, because this is a historically immature procedure. Here, we report a surgical case of endoscopic endonasal odontoidectomy (EEO) in the hybrid operating room (hOR) for improvement of its safety and reliability. CASE DESCRIPTION: A 70-year-old man presented with a 2-month history of myelopathic gait disturbance and swallowing disturbance. Neuroimaging analysis indicated medulla oblongata compression associated with basilar invagination. The patient underwent EEO in the hOR after posterior instrumented fixation. With the hOR, the extent of bone resection and anatomic orientation were confirmed intraoperatively. Postoperative course was uneventful, and symptoms were improved after surgery. CONCLUSIONS: The application of the hOR may make the EEO safe and precise for anterior decompression of the CVJ. To our knowledge, this is the first case report describing clinical experience of EEO in the hOR.

Bilateral delayed endolymphatic hydrops evaluated by bilateral intratympanic injection of gadodiamide with 3T-MRI.

The purpose of this study was to assess the diagnostic performance of 3T MRI after intratympanic injection of gadodiamide for delayed endolymphatic hydrops (DEH), and assess the relationship between endolymphatic hydrops (ELH) and vestibular function in patients diagnosed with DEH and confirmed by 3T MRI. Nineteen patients clinically diagnosed with DEH (11 ipsilateral DEH, 8 contralateral DEH) participated in this study. Diluted gadodiamide was administered to the bilateral tympanic cavity by injection through the tympanic membrane. At 24 hours post-injection, the ELH was evaluated by MRI. Patient vestibular functions were evaluated by caloric testing and cVEMP. ELH was observed in all patients (19/19: positive rate 100%). The distribution patterns of ELH varied between the cochlear or vestibular region. Vestibular ELH was observed in the affected ear in all ipsilateral DEH patients. In the contralateral DEH patients, however, there were individual differences in the distribution patterns of ELH. Six patients (1 ipsilateral DEH, 5 contralateral DEH) had bilateral ELH. No obvious relationships were observed between ELH and vestibular function. ELH distribution was complicated, particularly in the contralateral DEH cases. It was difficult to identify the existence of ELH by vestibular functional testing alone; therefore, 3T MRI is thought to be useful for identifying the affected ear. A significant number of cases had "bilateral" DEH, particularly among the contralateral DEH cases, indicating that we should pay careful attention to this pathology when treating DEH.

Feasibility of hearing preservation for residual hearing with longer cochlear implant electrodes.

BACKGROUND: Hearing preservation is thought to be achievable following atraumatic surgery with thin cochlear implant electrodes; therefore, the surgical approach and implant electrode design are crucial considerations. OBJECTIVE: To assess the feasibility of hearing preservation with long electrodes for patients meeting the criteria for conventional cochlear implantation. METHODS: One hundred and two patients (132 ears) who underwent cochlear implant surgery were analyzed. Inclusion criteria included measurable residual hearing in the low frequency before implantation and not meeting the criteria for electric acoustic stimulation (EAS). RESULTS: Of the 18 patients with residual hearing in the low frequency enrolled, 17 subjects (94.4%) retained low frequency hearing. A younger age at surgery tended to contribute to better hearing preservation than that observed in older patients. There was no clear trend regarding the influence of insertion depth angle of the electrode on hearing preservation. CONCLUSION: It is possible to achieve hearing preservation in the lower frequency by the use of longer electrodes. This study underscores the importance of atraumatic surgery, even for patients with only limited residual hearing, and longer electrodes should be adopted for EAS.

Long-term results of hearing preservation cochlear implant surgery in patients with residual low frequency hearing.

CONCLUSION: Differences were found between patients with stable hearing and those with progressive hearing loss in the lower frequencies with respect to the rate of progression in the contralateral ear. It is suggested that the electric acoustic stimulation (EAS) can provide improvement in hearing ability over the long-term if residual hearing might be lost to some extent. OBJECTIVE: To evaluate the long-term threshold changes in the low frequency hearing of the implanted ear as compared with the non-implanted ear, and the hearing abilities with EAS along with the extent of residual hearing. METHODS: Seventeen individuals were enrolled and received the EAS implant with a 24-mm FLEXeas electrode array. Hearing thresholds and speech perception were measured pre- and post-operatively for 1-5 years. Post-operative hearing preservation (HP) rates were calculated using the preservation numerical scale. RESULTS: The average linear regression coefficient for the decline in hearing preservation score was -6.9 for the implanted ear and the patients were subsequently categorized into two groups: those with better than average, stable hearing; and those with worse than average, progressive hearing loss. EAS showed better results than electric stimulation alone, in spite of an absence of speech perception with acoustic stimulation.

Ethnic-specific spectrum of GJB2 and SLC26A4 mutations: their origin and a literature review.

OBJECTIVE: The mutation spectrum of the GJB2 and SLC26A4 genes, the 2 most common genes causing deafness, are known to be ethnic specific. In this study, the spectrum of the reported GJB2 and SLC26A4 mutations in different populations are reviewed and considered from a human migration perspective. METHODS: Fifty-two and 17 articles on GJB2 and SLC26A4 mutations, respectively, were reviewed through the PubMed database from April 1996 to September 2014. The 4 most prevalent mutations were selected and compared. A cluster analysis was subsequently performed for these selected mutations. RESULTS: The present review of frequent mutations shows the ethnic-specific GJB2 and SLC26A4 gene mutation spectrum. A cluster analysis of the GJB2 and SLC26A4 genes revealed similarities between ethnic populations. CONCLUSION: The mutation spectrum reviewed in this study clearly indicated that the frequent mutations in the GJB2 and SLC26A4 genes are consistent with the founder mutation hypothesis. A comparison with the Y-chromosome phylogenetic tree indicated that these mutations may have occurred during human migration.

Vestibular functions of hereditary hearing loss patients with GJB2 mutations.

OBJECTIVES: Mutations in the GJB2 gene have been of particular interest as it is the most common causative gene for congenital deafness in all populations. Detailed audiological features, including genotype-phenotype correlations, have been well documented. However, in spite of abundant gene as well as protein expression in the vestibular end organs, neither vestibular symptoms nor vestibular functions have yet been elucidated. In the present study, vestibular functions were evaluated in patients diagnosed with GJB2-related deafness. SUBJECTS AND METHODS: Vestibular functions were evaluated by caloric test and cervical vestibular evoked myogenic potential (cVEMP) testing in 24 patients with biallelic GJB2 mutations. RESULTS AND DISCUSSION: Twenty-one of 23 patients (91.3%) had normal caloric responses and significantly lower cVEMP amplitudes than the control subjects. In the patients who were able to undergo vestibular testing, the mostly normal reactions to caloric testing indicated that the lateral semicircular canal was intact. However, the majority of GJB2 patients showed low cVEMP reactions, indicating a saccular defect.

Gene expression profiles of the cochlea and vestibular endorgans: localization and function of genes causing deafness.

OBJECTIVES: We sought to elucidate the gene expression profiles of the causative genes as well as the localization of the encoded proteins involved in hereditary hearing loss. METHODS: Relevant articles (as of September 2014) were searched in PubMed databases, and the gene symbols of the genes reported to be associated with deafness were located on the Hereditary Hearing Loss Homepage using localization, expression, and distribution as keywords. RESULTS: Our review of the literature allowed us to systematize the gene expression profiles for genetic deafness in the inner ear, clarifying the unique functions and specific expression patterns of these genes in the cochlea and vestibular endorgans. CONCLUSIONS: The coordinated actions of various encoded molecules are essential for the normal development and maintenance of auditory and vestibular function.

Detailed hearing and vestibular profiles in the patients with COCH mutations.

OBJECTIVES: To evaluate the clinical features of Japanese DFNA9 families with mutations of the COCH gene. METHODS: Mutation screening was performed using targeted next-generation sequencing (NGS) for 63 previously reported deafness genes. The progression of hearing loss and vestibular dysfunction were evaluated by pure-tone audiometry, caloric testing, cVEMP, and computed dynamic posturography. RESULTS: We detected 1 reported mutation of p.G88E and 2 novel mutations of p.I372T and p.C542R. The patients with the novel mutations of p.I372T and p.C542R within the vWFA2 domain showed early onset progressive hearing loss, and the patients with the p.G88E mutation showed late onset hearing loss and acute hearing deterioration over a short period. Vestibular symptoms were reported in the patients with p.G88E and p.C542R. Vestibular testing was performed for the family with the p.G88E mutation. Severe vestibular dysfunction was observed in the proband, and the proband's son showed unilateral semicircular canal dysfunction with mild hearing loss. CONCLUSIONS: Targeted exon resequencing of selected genes using NGS successfully identified mutations in the relatively rare deafness gene, COCH, in the Japanese population. The phenotype is compatible with that described in previous reports. Additional supporting evidence concerning progressive hearing loss and deterioration of vestibular function was obtained from our study.

The patients associated with TMPRSS3 mutations are good candidates for electric acoustic stimulation.

OBJECTIVES: To clarify the frequency of TMPRSS3 mutations in the hearing loss population, genetic analysis was performed, and detailed clinical characteristics were collected. Optical intervention for patients with TMPRSS3 mutations was also discussed. METHODS: Massively parallel DNA sequencing (MPS) was applied for the target exon-sequencing of 63 deafness genes in a population of 1120 Japanese hearing loss patients. RESULTS: Hearing loss in 5 patients was found to be caused by compound heterozygous TMPRSS3 mutations, and their detailed clinical features were collected and analyzed. Typically, all of the patients showed ski slope type audiograms and progressive hearing loss. Three of the 5 patients received electric acoustic stimulation (EAS), which showed good results. Further, the onset age was found to vary, and there were some correlations between genotype and phenotype (onset age). CONCLUSIONS: MPS is a powerful tool for the identification of rare causative deafness genes, such as TMPRSS3. The present clinical characteristics not only confirmed the findings from previous studies but also provided clinical evidence that EAS is beneficial for patients possessing TMPRSS3 mutations.

The advantages of sound localization and speech perception of bilateral electric acoustic stimulation.

CONCLUSION: Bilateral electric acoustic stimulation (EAS) effectively improved speech perception in noise and sound localization in patients with high-frequency hearing loss. OBJECTIVE: To evaluate bilateral EAS efficacy of sound localization detection and speech perception in noise in two cases of high-frequency hearing loss. METHODS: Two female patients, aged 38 and 45 years, respectively, received bilateral EAS sequentially. Pure-tone audiometry was performed preoperatively and postoperatively to evaluate the hearing preservation in the lower frequencies. Speech perception outcomes in quiet and noise and sound localization were assessed with unilateral and bilateral EAS. RESULTS: Residual hearing in the lower frequencies was well preserved after insertion of a FLEX(24) electrode (24 mm) using the round window approach. After bilateral EAS, speech perception improved in quiet and even more so in noise. In addition, the sound localization ability of both cases with bilateral EAS improved remarkably.

A clinical experience of 'STAMP' plate-guided Bonebridge implantation.

CONCLUSION: The surface template-assisted marker positioning (STAMP) method is useful for successful Bonebridge™ (BB) implantation on a planned site while avoiding dangerous positions. OBJECTIVES: To confirm the usefulness of the STAMP method for the safe operation of BB. METHODS: From a patient's temporal bone CT data, a guide plate and confirmation plate were generated by the STAMP method. The guide plate is used to mark the correct place for implantation, while the confirmation plate lets us know the correct angle and depth of the hole. RESULTS: With the guide plate, the correct place for BB implantation was easily found. The hole was made to be an appropriate size with the confirmation plate while exposing only a small part of sigmoid sinus as simulated. Finally, the BB implant was successfully placed exactly at the planned site.

Hearing preservation and clinical outcome of 32 consecutive electric acoustic stimulation (EAS) surgeries.

CONCLUSIONS: Our results indicated that electric acoustic stimulation (EAS) is beneficial for Japanese-speaking patients, including those with less residual hearing at lower frequencies. Comparable outcomes for the patients with less residual hearing indicated that current audiological criteria for EAS could be expanded. Successful hearing preservation results, together with the progressive nature of loss of residual hearing in these patients, mean that minimally invasive full insertion of medium/long electrodes in cochlear implantation (CI) surgery is a desirable solution. The minimally invasive concepts that have been obtained through EAS surgery are, in fact, crucial for all CI patients. OBJECTIVES: This study was conducted to evaluate hearing preservation results and speech discrimination outcomes of hearing preservation surgeries using medium/long electrodes. METHODS: A total of 32 consecutive minimally invasive hearing preservation CIs (using a round window approach with deep insertion of a flexible electrode) were performed in 30 Japanese patients (two were bilateral cases), including patients with less residual hearing. Hearing preservation rates as well as speech discrimination/perception scores were investigated on a multicenter basis. RESULTS: Postoperative evaluation after full insertion of the flexible electrodes (24 mm, 31.5 mm) showed that residual hearing was well preserved in all 32 ears. In all patients, speech discrimination and perception scores were improved postoperatively.