Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort.

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ-associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ-associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ-associated HL and may be relevant in clinical practice.

Long-term outcome of cervical lymph node metastasis in superficial pharyngeal squamous cell carcinoma after endoscopic submucosal dissection.

BACKGROUND AND AIMS: Superficial pharyngeal squamous cell carcinoma (PSCC) has received increasing attention as a therapeutic target in the GI field with recent innovations in endoscopic submucosal dissection (ESD). However, there are currently no defined criteria for the application of ESD to superficial PSCC. One of the problems encountered during follow-up after ESD is cervical lymph node metastasis (LNM). Identifying the clinicopathologic predictors of cervical LNM can help to provide a basis for the refinement of therapeutic strategies for superficial PSCC. METHODS: The risk of cervical LNM was evaluated in 331 patients with superficial PSCC who underwent initial ESD between 2008 and 2021. Since tumor size, rather than depth, is the dominant factor in the current TNM classification for PSCC, the correlation between tumor size and thickness was investigated. RESULTS: The median follow-up period was 4.8 years. The cumulative 5-year cervical LNM rate was 6.1%. Multivariate Cox proportional hazards regression analysis identified tumor thickness ≥1000 µm and lymphatic invasion as significant independent predictors. Among 204 cases with subepithelial invasion, both factors were also revealed to be significant independent predictors, suggesting that tumor thickness was superior to tumor size in predicting cervical LNM. Despite the positive correlation between tumor thickness and size, there was noticeable variability in the values (R = .20), and the current staging was inadequate to identify groups at high risk for cervical LNM. CONCLUSIONS: Tumor thickness and lymphatic invasion are validated as significant independent predictors for cervical LNM and can be useful indicators to optimize the therapeutic strategies for superficial PSCC.

Successful cochlear implantation in a patient with Epstein syndrome during long-term follow-up.

Epstein syndrome is a rare disease characterized by macrothrombocytopenia, nephritis and progressive sensorineural hearing loss (SNHL). This syndrome is presently recognized as an autosomal dominant disease caused by mutations of non-muscle myosin heavy chain 9 (MYH9). Little information is available about the progress of SNHL, the efficacy of cochlear implants (CI) or the perioperative management of thrombocytopenia in patients with Epstein syndrome. We herein report a case of a patient with Epstein syndrome with the MYH9:c.2105G>A:p.R702H variant who underwent cochlear implantation after 27 years of follow-up for her progressive SNHL. The deterioration rates of hearing were 3.48 dB/year on the right ear and 2.46 dB/year on the left ear. The patient derived benefits from CI and had a speech recognition test result (for sentences) of 93% at 6-months postoperatively. Thrombocytopenia was successfully managed without any bleeding complications by using eltrombopag, an oral thrombopoietic agent, making transfusion of platelets unnecessary. The accurate diagnosis of Epstein syndrome was made only after long-term follow-up as the thrombocytopenia was initially diagnosed as idiopathic thrombocytopenic purpura. This case report highlights the perioperative management of thrombocytopenia, the progress of SNHL and the potential pitfalls of diagnosis.

Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

Development and validation of an iPad-based Japanese language monosyllable speech perception test (iCI2004 monosyllable).

BACKGROUND: Speech perception tests are commonly used as indices reflecting hearing ability in daily life. In Japan, the CI-2004 test, first developed in 2004, is widely used as standard, but it was not validated against a large number of normal hearing controls and hearing loss patients. AIMS/OBJECTIVES: The primary objective of the present study was to develop and validate iPad-based software for the Japanese monosyllable speech perception test, 'iCI2004'. MATERIAL AND METHODS: Seven universities and two medical centers participated in this study. The hearing threshold and Japanese monosyllable speech perception test results of 77 people with normal hearing and 459 people with hearing loss were collected. RESULTS: All participants with normal hearing achieved almost perfect perception results both in quiet and in noise. For cochlear implant users, the average monosyllable speech perception score was 55.1 ± 19.6% in quiet and 40.3 ± 19.2% in noise (SNR + 10dB). CONCLUSIONS AND SIGNIFICANCE: We developed iPad-based Japanese monosyllable speech perception test software and validated it by testing a large number of controls and hearing loss patients with cochlear implants or hearing aids. The developed monosyllable speech perception test has a sufficiently large dynamic range for assessing improvement in speech perception in Japanese cochlear implant users.

Clinical relevance of endoscopic treatment for superficial pharyngeal cancer: feasibility of techniques corresponding to each location and long-term outcomes.

BACKGROUND AND AIMS: Superficial pharyngeal cancers are being detected and treated using endoscopy in many medical facilities with increasing frequency. However, the reports focus on the hypopharynx. We identified reliable treatments by adapting the method for each region of the pharynx. Here, we introduce our methods for treating various pharyngeal regions and show their long-term results. METHODS: Of 308 consecutive patients who underwent pharyngeal endoscopic submucosal dissection between February 2007 and December 2018 at our institution, we selected 293 patients who were diagnosed histologically with squamous cell carcinoma. The patients were divided into 4 groups based on the specific location of superficial pharyngeal lesions and the short- and long-term outcomes, such as technical success, adverse events, overall survival, and case-specific survival, were evaluated. RESULTS: The procedure time was 51 minutes at location A where cancer develops most commonly. The rate of en bloc resection was 99.4%, and the R0 resection rate was 82.6%. With regard to adverse events, there were 2 cases of postoperative hemorrhage, both treated with endoscopic hemostasis. The average observation period was 61.2 months overall, with 14 cases of recurrent lymph node metastasis. The 5-year survival rate was 84.1%, and cause-specific survival was 100%. CONCLUSIONS: Adaptation of the treatment method according to the location of the lesion led to good results. Endoscopic treatment of superficial pharyngeal cancer is both feasible and beneficial.

Novel ACTG1 mutations in patients identified by massively parallel DNA sequencing cause progressive hearing loss.

Human ACTG1 mutations are associated with high-frequency hearing loss, and patients with mutations in this gene are good candidates for electric acoustic stimulation. To better understand the genetic etiology of hearing loss cases, massively parallel DNA sequencing was performed on 7,048 unrelated Japanese hearing loss probands. Among 1,336 autosomal dominant hearing loss patients, we identified 15 probands (1.1%) with 13 potentially pathogenic ACTG1 variants. Six variants were novel and seven were previously reported. We collected and analyzed the detailed clinical features of these patients. The average progression rate of hearing deterioration in pure-tone average for four frequencies was 1.7 dB/year from 0 to 50 years age, and all individuals over 60 years of age had severe hearing loss. To better understand the underlying disease-causing mechanism, intracellular localization of wild-type and mutant gamma-actins were examined using the NIH/3T3 fibroblast cell line. ACTG1 mutants p.I34M p.M82I, p.K118M and p.I165V formed small aggregates while p.R37H, p.G48R, p.E241K and p.H275Y mutant gamma-actins were distributed in a similar manner to the WT. From these results, we believe that some part of the pathogenesis of ACTG1 mutations may be driven by the inability of defective gamma-actin to be polymerized into F-actin.

Utility of Valsalva maneuver in the endoscopic pharyngeal observation.

BACKGROUND: Metachronous cancer rate in the pharynx is high before and after the treatment of esophageal cancer. Endoscopic observation is difficult in the pharynx especially in the postcricoid area. Pharyngeal cancer in the postcricoid area has been often found in advanced stage. Valsalva maneuver has been reported to improve the visibility. METHODS: From May 2017 we introduced a dedicated mouthpiece to conduct Valsalva maneuver. One hundred consecutive patients who had been observed throughout the pharynx by one endoscopist were enrolled. A total of 200 image files before and after introduction were made and reviewed by three endoscopists. We retrospectively evaluated the utility and safety of Valsalva maneuver. RESULTS: The visibility before introduction was Good in three cases, Moderate in 12 cases and Poor in 85 cases. Meanwhile, the visibility after introduction was Good in 58 cases, Moderate in 23 cases, and Poor in 19 cases (P < 0.05). Nine lesions including hypopharyngeal cancer were found and adverse events were not observed in this study. CONCLUSION: The Valsalva maneuver was considered to be a safe and effective method in endoscopic observation of the pharynx.

Comprehensive analysis of syndromic hearing loss patients in Japan.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.

OTOF mutation analysis with massively parallel DNA sequencing in 2,265 Japanese sensorineural hearing loss patients.

The OTOF gene (Locus: DFNB9), encoding otoferlin, is reported to be one of the major causes of non-syndromic recessive sensorineural hearing loss, and is also reported to be the most common cause of non-syndromic recessive auditory neuropathy spectrum disorder (ANSD). In the present study, we performed OTOF mutation analysis using massively parallel DNA sequencing (MPS). The purpose of this study was to reveal the frequency and precise genetic and clinical background of OTOF-related hearing loss in a large hearing loss population. A total of 2,265 Japanese sensorineural hearing loss (SNHL) patients compatible with autosomal recessive inheritance (including sporadic cases) from 53 otorhinolaryngology departments nationwide participated in this study. The mutation analysis of 68 genes, including the OTOF gene, reported to cause non-syndromic hearing loss was performed using MPS. Thirty-nine out of the 2,265 patients (1.72%) carried homozygous or compound heterozygous mutations in the OTOF gene. It is assumed that the frequency of hearing loss associated with OTOF mutations is about 1.72% of autosomal recessive or sporadic SNHL cases. Hearing level information was available for 32 of 39 patients with biallelic OTOF mutations; 24 of them (75.0%) showed profound hearing loss, 7 (21.9%) showed severe hearing loss and 1 (3.1%) showed mild hearing loss. The hearing level of patients with biallelic OTOF mutations in this study was mostly severe to profound, which is consistent with the results of past reports. Eleven of the 39 patients with biallelic OTOF mutations had been diagnosed with ANSD. The genetic diagnosis of OTOF mutations has significant benefits in terms of clinical decision-making. Patients with OTOF mutations would be good candidates for cochlear implantation; therefore, the detection of OTOF mutations is quite beneficial for patients, especially for those with ANSD.

Sensorineural hearing loss and mild cardiac phenotype caused by an EYA4 mutation.

EYA4 is a member of the vertebrate eya gene family of transcriptional activators and plays several roles in both embryonic and inner ear development. The majority of EYA4 gene mutations are associated with autosomal dominant non-syndromic hearing loss (DFNA10). In addition, some mutations in this gene cause autosomal dominant syndromic hearing loss with dilated cardiomyopathy. EYA4 is a rare cause of sensorineural hearing loss, and only a limited number of papers regarding mutations in this gene have been published. Thus, detailed clinical features remain unclear. We conducted next-generation sequencing of a Japanese individual with progressive sensorineural hearing loss and identified an EYA4 pathogenic variant. Pure-tone audiometry revealed bilateral, nearly symmetric, moderate sensorineural hearing loss in the low and middle frequencies. Minor abnormalities were observed on the patient's electrocardiogram and echocardiography without any apparent symptoms. Next-generation sequencing is effective in elucidating the etiology of hearing loss, and the present findings suggested the possible phenotypic expansion of deafness caused by EYA4 gene mutations.

Relationships among drinking and smoking habits, history of diseases, body mass index and idiopathic sudden sensorineural hearing loss in Japanese patients.

OBJECTIVES: To present the cardiovascular risk factors in idiopathic sudden sensorineural hearing loss (SSNHL) patients enrolled in a nationwide epidemiological survey of hearing disorders in Japan. MATERIALS AND METHODS: We compiled the cardiovascular risk factors in 3073 idiopathic SSNHL subjects (1621 men and 1452 women) and compared their proportions with controls as part of the National Health and Nutrition Survey in Japan, 2014. The cardiovascular risk factors consisted of drinking and smoking habits, a history of five conditions related to cardiovascular disease and body mass index. RESULTS: The proportion of current smokers was significantly higher among men aged 50-59, 60-69 and 70+ and among women aged 30-39, 40-49 and 60-69. The proportion of patients with a history of diabetes mellitus was significantly higher among men aged 50-59, 60-69 and 70+, but not in women. In addition, male and female SSNHL subjects aged 60-69 showed lower proportions of current drinking; and female SSNHL subjects aged 60-69 showed higher proportions of overweight (BMI ≥25 kg/m2). CONCLUSIONS: The present cross-sectional study revealed showed significantly higher proportions of current smokers among both men and women as well as those with a history of diabetes mellitus among men across many age groups in patients with idiopathic SSNHL compared with the controls.

Idiopathic sudden sensorineural hearing loss and acute low-tone sensorineural hearing loss: a comparison of the results of a nationwide epidemiological survey in Japan.

OBJECTIVES: The aim of this study was to investigate the differences between idiopathic sudden sensorineural hearing loss (SSNHL), and acute low-tone sensorineural hearing loss (ALHL) using the results of a nationwide survey database in Japan and to analyze the variables associated with their clinical features and the severity of hearing impairment, treatment, and prognosis. METHODS: Participants were patients registered between April 2014 and March 2016 in a multicenter epidemiological survey database involving 30 university hospitals and medical centers across Japan. Statistical analysis was performed to clarify the factors associated with their clinical characteristics and the severity of hearing impairment, treatment, and prognosis. RESULTS: Idiopathic SSNHL and ALHL differed significantly in terms of male-to-female ratio, age distribution, and time from onset to start of treatment. The treatment methods and hearing prognosis also differed markedly between the two diseases. A majority (92%) of idiopathic SSNHL patients were administered some type of corticosteroid, while half of the ALHL patients received corticosteroids and a diuretic agent. CONCLUSION: The results suggested that idiopathic SSNHL and ALHL belonged to different categories of inner ear disease.

The effect of initial treatment on hearing prognosis in idiopathic sudden sensorineural hearing loss: a nationwide survey in Japan.

OBJECTIVE: To investigate the hearing prognosis of idiopathic sudden sensorineural hearing loss (SSNHL) treated with different initial therapies. METHODS: Subjects consisted of patients diagnosed with idiopathic SSNHL within 7 days from onset and showing severe hearing loss (≥60 dB), who were registered in a Japanese multicenter database between April 2014 and March 2016. Subjects were divided into four groups according to initial therapy: (1) steroids, (2) steroids + Prostaglandins (PGs), (3) intratympanic steroids (ITS), and (4) no steroids. Hearing outcomes were compared among the groups. RESULTS: In total, 1305 patients were enrolled. The final hearing level and hearing gain of patients treated with steroids + PGs were significantly higher than those of patients treated with steroids alone or no steroids. The ratio of good prognosis (complete recovery or marked improvement) in patients treated with steroids + PGs was higher than that in patients treated with steroids alone or no steroids. There was no difference in the prognosis of patients treated with steroids alone or no steroids. CONCLUSION: A large number of patients with idiopathic SSNHL were registered in a multicenter database. PG use in combination with steroid administration was associated with a good hearing prognosis in patients with severe hearing loss.

Nationwide epidemiological survey of idiopathic sudden sensorineural hearing loss in Japan.

OBJECTIVES: Using a large-scale nationwide survey database, we investigated the epidemiological characteristics for idiopathic SSNHL in Japan. METHODS: The subjects for this analysis were patients registered in a Japanese multicentre database between April 2014 and March 2016. A total of 3419 idiopathic SSNHL patients were registered in the database, and the clinical characteristics of the idiopathic SSNHL patients were obtained. Several factors associated with the severity of hearing impairment and prognosis were then investigated. Statistical analysis was performed to clarify the factors associated with the severity of hearing impairment and prognosis. RESULTS: There were significant correlations between the severity of hearing loss and diabetes mellitus, kidney disease, past history of brain infarction, heart disease, age (under 16 years/elderly), and symptoms of vertigo/dizziness. We also analyzed the prognostic factors for idiopathic SSNHL, and found that the severity of hearing loss (Grade 3 or 4), heart disease, aged 65 years or over, time from onset to treatment (over 7 days), and symptoms of vertigo/dizziness were all significantly related to poor prognosis. CONCLUSION: The present large-scale clinical survey revealed current epidemiological trends for idiopathic sudden sensorineural hearing loss (SSNHL) and various factors associated with the severity of hearing impairment and prognosis.

Gastrointestinal Endoscopy-Assisted Minimally Invasive Surgery for Superficial Cancer of the Uvula.

Previous studies reported that endoscopic resection is effective for the treatment of superficial pharyngeal cancers, as for digestive tract cancers. However, the optimal treatment for superficial cancer of the uvula has not been established because of the rarity of this condition. We present two male patients in their 70s with superficial cancer of the uvula, detected with upper gastrointestinal endoscopy. Both patients underwent surgical resection of the uvula under general anesthesia. The extent of the lesions was determined by means of gastrointestinal endoscopy by using magnifying observation with narrow-band imaging, enabling the performance of minimally invasive surgery. Endoscopic submucosal dissection was performed to achieve en bloc resection of the intramucosal carcinoma that had infiltrated the area adjacent to the uvula. Gastrointestinal endoscopists should carefully examine the laryngopharynx to avoid missing superficial cancers. Our minimally invasive treatment for superficial cancer of the uvula had favorable postoperative outcomes, and prevented postoperative loss of breathing, swallowing, and articulation functions.

Utility of magnifying endoscopy with narrow band imaging in determining the invasion depth of superficial pharyngeal cancer.

BACKGROUND: Magnifying endoscopy with narrow band imaging (ME-NBI) is useful to diagnose invasion depth of superficial esophageal cancer. The purpose of this study was to evaluate the utility of ME-NBI of superficial pharyngeal cancer. METHODS: Between April 2008 and June 2012, 146 lesions in 104 patients who underwent ME-NBI and en bloc resection were retrospectively analyzed. Based on magnifying endoscopic classification, proposed by the Japan Esophageal Society, microvasculature type was classified into B1, B2, and B3. RESULTS: B1 alone, B2, and B3 were observed in 128, 14, and 4 lesions, respectively. The frequency of subepithelial cancer were 20.3% (26 of 128), 78.6% (11 of 14), and 100% (4 of 4), respectively (p < .05). Mean invasion distance were 650 µm, 720.0 µm, and 2256.5 µm. Positive and negative predictive value for diagnosing subepithelial cancer based on the presence of B2 or B3 was 83.3% (15 of 18) and 79.7% (102 of 128). CONCLUSION: ME-NBI is useful to determining invasion depth of superficial pharyngeal cancer.

A new technique for pharyngeal endoscopic submucosal dissection: peroral countertraction (with video).

BACKGROUND: Endoscopic submucosal dissection (ESD) can be used to perform resections en bloc for early-stage GI tumors. Pharyngeal ESD is less invasive, but technically difficult. Therefore, innovations to safely and easily perform this procedure are needed. OBJECTIVE: The aim of this study was to evaluate ESD under peroral countertraction, a new traction system for improving subepithelial cutting line visualization, compared with conventional ESD. DESIGN: Retrospective study. SETTING: Toranomon Hospital, Tokyo, Japan. PATIENTS: A total of 93 patients (140 lesions) with superficial pharyngeal cancers treated with ESD were enrolled. INTERVENTIONS: ESD under peroral countertraction or conventional ESD. MAIN OUTCOME MEASUREMENTS: En bloc resection rate, size of the tumor, and procedure time. RESULTS: All lesions were resected en bloc by using this technique. The mean longest lesion size was 23.4 mm in the peroral countertraction group and 18.1 mm in the conventional group (P = .038). The mean procedure time did not differ between the 2 groups. Subcutaneous emphysema as an adverse event was observed in the conventional ESD group. No treatment-related adverse events occurred in the peroral countertraction group. LIMITATIONS: Retrospective comparison. CONCLUSIONS: ESD under peroral countertraction is easier and appears to be safer for completely removing superficial mesopharyngeal and hypopharyngeal cancers.