Published papers

Hearing impairments are the most common symptom of congenital defects, and they generally remain intractable to treatment. Pendred syndrome, the most frequent syndromic form of hereditary hearing loss, is associated with mutations in the anion exchanger pendrin. Loss of pendrin function as an anion exchanger is thought to be causative, but rodent models do not exhibit progressive deafness. Here, we report a degenerative phenotype exhibiting mutant pendrin aggregates and increased susceptibility to cellular stresses in cochlear epithelial cells induced from patient-derived induced pluripotent stem cells (iPSCs). These degenerative phenotypes were rescued by site-specific gene corrections. Moreover, low-dose rapamycin and metformin reduced aggregation and cell death. Our results provide an unexpected, comprehensive understanding of deafness due to “degenerative cochlear disease” and may contribute to rational therapeutic development. This iPSC-based disease model provides an approach to the study of pathogenesis and therapeutic development for hereditary hearing loss.

Objectives/Hypothesis: This study was designed to assess the feasibility of the submucosal infusion technique combined with microflap dissection as a radical therapeutic and diagnostic option for precancerous laryngeal leukoplakia. Study Design: Retrospective study. Methods: Severe dysplasia or carcinoma in situ was diagnosed after phonomicrosurgical dissections in 25 patients with unilateral laryngeal leukoplakia. Of these, 15 patients preferred no additional surgery (observation group), whereas 10 patients underwent further laser subligamental cordectomy (additional surgery group). The relationship between the initial surgical margin and histopathological characteristics of additionally excised tissues was assessed to evaluate diagnostic reliability. Disease control was assessed to determine the oncologic efficacy of the therapeutic procedure. Comparative multidimensional vocal assessments were performed in both groups to evaluate functional advantages of one-stage excision. Results: After the initial phonomicrosurgical resection, three patients had residual dysplastic lesions near the vocal process and anterior commissure, whereas three other patients had lesions suspicious for recurrence. No postoperative malignant transformation was observed in any patient. Although well-preserved vocal function was observed in the observation group, vocal quality deteriorated shortly after laser surgery in the additional surgery group. Regarding acoustics, aerodynamics, and quality-of-life evaluations, statistically equivalent scores were observed between the observation and control groups, whereas scores were inferior in the additional surgery group than in the control group. Conclusions: Phonomicrosurgical resection may be a therapeutic option with oncologic efficacy against precancerous laryngeal leukoplakia. This radical management might achieve more satisfactory postoperative vocal function. Level of Evidence: NA Laryngoscope, 127:153–158, 2017.

Globus sensation is a common symptom seen daily in ear-nose-throat (ENT) clinics. Globus is affected by multiple factors, and of these, gastroesophageal reflux disease (GERD), has been recognized as a relatively more manageable cause of globus than the other causes. However, we still commonly encounter globus patients with unclear backgrounds who require multiple diagnostic and therapeutic modalities. To provide an appropriate treatment approach and create favorable situations for these patients, we developed and applied an intramural algorithm to manage globus considering GERD, laryngeal allergy, and psychological problems as major factors of this pathology. Twenty-six patients with globus sensation who visited our voice clinic from June 2012 to March 2015 were enrolled in this study. All these patients had undergone general ENT examinations, including naso-pharyngo-laryngeal endoscopies and cervicothoracic computed tomographic scans. Upper gastrointestinal endoscopy revealed 2 cancers. Further study classified 23 patients into the GERD group and 1 patient into the allergy group. Proton pump inhibitor (PPI) therapy was successful in 11 patients of the GERD group (response rate, 47.2%). Improvement in subjective symptoms of globus were measured by the scores of questionnaires, including the F scale and Reflux Symptom Index. Significant improvement in these scores were observed 1 month after PPI prescription in the PPI-responder group in this study. Further assessment of medical history as well as the scores of questionnaires to measure the severity levels of depression (Self-rating Depression Scale) and anxiety (State-Trait Anxiety Inventory-Form JYZ, STAI) proved that relatively longer lasting symptoms (≥4 months) or relatively higher anxiety scores (STAIS50 points) were predictive of PPI resistance. Our study results suggested that the pathology of globus is affected by multiple factors and that a multidisciplinary team approach is required for better management of this disease.

Objectives/Hypothesis: Recurrent respiratory papillomatosis (RRP) is a benign epithelial tumor that exhibits a high frequency of recurrence. This study assesses the vocal function after laser treatment for RRP, particularly in relation to the frequency of surgery. Study Design: Retrospective study. Methods: Thirty RRP patients who underwent laser surgery that controlled the tumor were included. Preoperative and postoperative Grade, Roughness, Breathiness, Asthenia, and Strain Scale, videostroboscopic findings, aerodynamic and acoustic parameters, and self-assessment questionnaires were measured and compared with an age- and sex-matched control group. Subsequently, to evaluate the association between postoperative voice quality and the number of surgeries, the patients were divided into three groups (group 1: single surgery, group 2: 2-5 surgeries, group3: >6 surgeries), and comparative multidimensional vocal assessments were performed. Results: The mean number of surgeries was 3.4 (range, 1-8). Although all patients exhibited poorer vocal function than the control group preoperatively, they showed improvement in postoperative subjective and objective parameters. However, four patients who underwent one surgery with relatively aggressive ablation exhibited vocal cord scarring and deteriorated objective parameters. All remaining patients showed voice quality that was on par with the control group. Subgroup analysis proved no association between post-therapeutic voice quality and the patient characteristics, including preoperative staging and the number of surgical treatments performed. Conclusions: RRP patients can achieve a close to normal voice with high satisfaction even after recurrent surgical treatment when ablation of a subepithelial lesion using sufficient laser energy is adequate.

Objectives/Hypothesis: To determine the frequency of the incomplete partition type III anomaly and the genetic and clinical features associated with POU3F4 mutations in children with hearing loss. Study Design: Retrospective case series from 2000 to 2014 at the National Hospital Organization Tokyo Medical Center and collaborating hospitals. Methods: A total of 1,004 patients (from 938 families) who had hearing loss by 10 years of age and had undergone computed tomography scanning of their temporal bones were enrolled in this genetic, clinical, and radiological study. Results: The incomplete partition type III anomaly was identified in six patients (0.6%), each of whom had an enlargement of the vestibular aqueduct at the end close to the vestibule. The six patients also had POU3F4 variants, and a genetic analysis revealed frameshift deletions in three patients, a missense variant in two patients of the same family, and a large deletion in one patient. Three of the six patients with POU3F4 variants were sporadic cases, and in one patient the genetic mutation occurred de novo. Conclusions: It was indicated that POU3F4 mutations can be predicted by incomplete partition type III anomaly by radiological examination of the inner ear. All six of the patients showed mixed hearing loss, but none showed fluctuations in hearing, which may be related to the lack of vestibular aqueduct enlargement at the operculum.

Deafness is one of the most common types of congenital impairments, and at least half of the cases are caused by hereditary mutations. Mutations of the gene KIAA1199 are associated with progressive hearing loss. Its expression is abundant in human cochlea, but interestingly the spatial expression patterns are different between mouse and rat cochleae; the pattern in humans has not been fully investigated. We performed immunohistochemical analysis of a nonhuman primate, common marmoset (Callithrix jacchus), cochlea with a KIAA1199-specific antibody. In the common marmoset cochlea, KIAA1199 protein expression was more widespread than in rodents, with all epithelial cells, including hair cells, expressing KIAA1199. Our results suggest that the primate pattern of KIAA1199 expression is wider in comparison with rodents and may play an essential role in the maintenance of cochlear epithelial cells.

Preoperative diagnosis of lymph node metastasis from thyroid carcinoma is usually confirmed by using fine needle aspiration cytology(FNAC)when thyroid carcinoma is suspected based on the clinical findings. However, the result of FNAC sometimes leads to a false negative, especially in cases of hypocellular lesions such as metastases with cystic change. Thyroglobulin measurement in fine needle aspirates(FNA-Tg)has been shown to be a useful technique to detect the protein specifically secreted by thyroid follicular cells. Elevated FNA-Tg levels in an extra-thyroidal lesion means that the lesion comprises thyroid-originated tissue, most of which suggests the metastasis from thyroid carcinoma. Thus, FNA-Tg is expected to improve the sensitivity of FNAC for the aforementioned purpose. Patients and Methods : From 2008 to 2012, 49 extra-thyroidal lesions from 43 patients with thyroid carcinoma were examined using both FNAC and FNA-Tg, followed by surgical resection with a histopathological diagnosis. The results were retrospectively reviewed and analyzed. Results : Among 49 lesions, 47 were metastatic lymph nodes from thyroid carcinoma-46 papillary carcinoma and one follicular carcinoma-, one was a metastatic lymph node from submandibular gland adenocarcinoma, and one was an ectopic thyroid gland. In the 47 cases of thyroid carcinoma, the sensitivity of FNAC was 57.4%(27/47), whereas that of FNA-Tg was 76.6%(36/47). When both methods were combined, the sensitivity increased to 93.6%(44/47). Metastasis from submandibular gland adenocarcinoma was considered to be an example of a false positive from FNAC, whereas an ectopic thyroid gland was an FNA-Tg false positive. Three lesions were negative for both FNAC and FNA-Tg, although metastases were suspected by imaging studies and confirmed by histopathological diagnosis, which were consistent with examples of a false negative from both FNAC and FNA-Tg findings. Conclusions : FNAC reflects whether the lesion has malignant cells, whereas FNA-Tg reflects whether the lesion has thyroid-originated tissue that specifically secrets thyroglobulin. Therefore, FNAC and FNA-Tg are considered to be complementary to each other for the preoperative diagnosis of lymph node metastasis from thyroid carcinoma. FNA-Tg was validated to improve the preoperative diagnostic sensitivity especially when combined with FNAC, however, it is attended with the possibility of a false positive or negative finding, which requires caution in interpretation of the findings.

We participated in a clinical trial for a hearing aid system in Japan, "Verification of the efficacy and safety of the middle ear implant MVS (Medel Vibrant System) in conductive and mixed hearing loss". We present a report of a case that we encountered in our department. MVS is a Vibrant Soundbridge® (VSB) middle ear implant device that is approved and is in wide use in Europe and the United States. It has been shown to have the potential to provide a high level of acoustic clarity and sound quality. Also, as compared to conventional hearing AIDS, there is no howling and the distortion frequency is lower. An additional advantage is the excellent transient response. The patient was a 33-year-old woman, with a history of bilateral hearing loss from birth, who was under observation whilst wearing a hearing aid. In an attempt to improve her hearing, we admitted her to our hospital. Based on the diagnosis of middle ear malformation and mixed hearing loss on both sides, we performed bilateral tympanoplasty. Since the hearing improvement following this procedure was poor on the right side, we prescribed a hearing aid. However, the patient did not adapt satisfactorily to this device. Four years after the initial diagnosis, we performed VSB middle ear implant surgery using the round window stimulation method, placing the transducer in the round window. The postoperative results were good. The speech inspection noise levels in both ears under a free-field, silent setting were 60 dBHL 85%, and 50 dBHL 100%. Thus, the postoperative course was good, the patient's satisfaction level improved and no adverse events occurred. VSB is likely to be a useful tool in rescue surgery for refractory middle ear cases. Also, it is useful as a standard rescue procedure in difficult hearing aid cases. In practice, otologic procedures are intended to improve the QOL and meet requirements in both diverse cases and individual patient conditions. Therefore, dissemination of VSB as one of the treatment choices for improving hearing loss is expected in the future.

Background: This study was designed to comparatively assess laryngeal function and quality of life (QOL) of patients after laser surgery (LS) or radiotherapy (RT) for early glottic cancer. Methods: Sixty-four patients with T1 glottic cancer treated with RT or type II cordectomy underwent both subjective and objective vocal assessments. The LS group was divided into the following: (1) vaporization with defocused mode (laser surgery [LS]-Vap); and (2) excision with focused mode using lower power (LS-Ex). Results: Auditory-perceptual evaluation and videostroboscopic images in the LS-Ex group worsened shortly after treatment and time-dependent recovery was quicker than in the LS-Vap group. The LS-Ex group showed equivalent posttherapeutic vocal function with the RT group by acoustics, aerodynamics, and self-assessment questionnaire analysis, whereas the LS-Vap group showed statistically significant worse function. Conclusion: The multidimensional assessment showed that early glottic cancer could be successfully treated by either RT or LS-Ex with equivalent posttherapeutic laryngeal function and QOL.

Stuttering may be related to developmental disability or mental diseases such as social anxiety disorder. However, there are few reports about these comorbid conditions in stuttering patients in Japan. In order to comprehend the relationship between stuttering and comorbid conditions, we conducted a chart review of 39 stuttering cases who sought consultation at Keio University Hospital in 2012 and 2013. Fifteen percent of the subjects had the following comorbid psychiatric conditions: mood disorder (depression and adjustment disorder), obsessive-compulsive disorder, epilepsy and tic disorder. Eighteen percent of the subjects had developmental disability, including definite or suspected developmental disability, and language development disorder. The age at which patients with developmental disability began stuttering was higher than that in patients without such disability. These findings suggest that clinical presentation of stuttering may be affected by comorbid developmental disability.

Background: Conventional approaches for removing parapharyngeal space tumors require a cervical skin incision and resection of soft tissues between the skin and parapharyngeal space. The surgical visual field for this conventional approach is limited. Methods: To decrease invasiveness during removal of benign parapharyngeal space tumors and to enhance the visual field, we devised a new approach called the modified endoscopic transnasal-transmaxillary-transpterygoid approach (MENMAP). The "surgical corridor" to the parapharyngeal space consists of the maxillary sinus, submucous tunnel under the lateral nasal wall, and the space created by removing the pterygoid process. Results: We successfully performed en bloc removal of a parapharyngeal space tumor using the MENMAP approach. The only surgical complication was hypoesthesia of the right hard palate and maxillary gingiva, which gradually improved. Conclusion: The MENMAP approach is a viable alternative for removing parapharyngeal space tumors, as it is safe, feasible, and less invasive.

Background Transcranial surgery is considered more appropriate than an endonasal endoscopic approach (EEA) for a large cavernous sinus meningioma with lateral extension. Case presentation A 6-cm-diameter hypervascular meningioma around cavernous sinus invaded the orbital apex and infratemporal fossa. 80% of the tumor was removed without too much blood loss via endoscopic endonasal transpterygoidal-infratemporal approach. Preoperative embolization from some feeding arteries was done, and 80% of the tumor staining disappeared. Discussion Tumor removal rates for giant meningioma are worse with EEA than with the transcranial approach because of various anatomical limitations and blood control. Recently, EEA has become more widely used with approaches such as the transpterygoidal approach. The operation can be done safely with preoperative embolization because the operative view is clear without bleeding. Conclusion Preoperative embolization for a large hypervascular tumor makes EEA more effective. A giant meningioma can be removed by EEA if the anatomical limitations can be identified and approached safely and effectively.

Background: Hochuekkito (HKT), a traditional Japanese herbal medicine, enhances the immunity of elderly or weak individuals. It is also known to have preventive effects against influenza clinically. However, the detailed mechanisms of the preventive effects have not been clarified. We examined the relationship between the preventive effects of HKT and autophagy, a known stress response and quality control mechanism, using Madin-Darby canine kidney cells and influenza A/PR/8/34 (H1N1) virus. Methods: The effect of HKT on autophagy in influenza A virus (IAV)-infected cells was assessed by Western blotting and fluorescence microscopy using an RFP-GFP-LC3B sensor kit. Results: In Western blotting, treatment with HKT before IAV infection (pre-HKT) tended to induce autophagy in IAV-infected cells at an early stage of infection, eventually suppressing IAV-induced autophagy. Moreover, several autolysosomes, indicative of normal autophagosome-lysosome fusion, were observed in Pre-HKT cells transduced with RFP-GFP-LC3B but not in untreated IAV-infected cells. Conclusions: These findings indicated that IAV-mediated inhibition of the fusion of autophagosomes with lysosomes was prevented by HKT treatment before infection. According to these results, we propose that this phenomenon is one of the preventive effects of HKT against IAV.

Objective To examine the relationship between prognosis of 2 different facial palsies and pretreatment hematologic laboratory values. Study Design Multicenter case series with chart review. Setting Three tertiary care hospitals. Subjects and Methods We examined the clinical records of 468 facial palsy patients who were treated with an antiviral drug in combination with either oral or intravenous corticosteroids in participating hospitals between 2010 and 2014. Patients were divided into a Bell's palsy group or a Hunt's palsy group. We used the Yanagihara facial nerve grading system to grade the severity of facial palsy. "Recovery" from facial palsy was defined as achieving a Yanagihara score ≥36 points within 6 months of onset and having no accompanying facial contracture or synkinesis. We collected information about pretreatment hematologic findings, demographic data, and electrophysiologic test results of the Bell and Hunt group patients who recovered and those who did not. We then compared these data across the 2 palsy groups. Results In the Bell's palsy group, recovered and unrecovered patients differed significantly in age, sex, electroneuronography score, stapedial muscle reflex, neutrophil rate, lymphocyte rate, neutrophil-to-lymphocyte ratio, and initial Yanagihara score. In the Hunt's palsy group, recovered and unrecovered patients differed in age, electroneuronography score, stapedial muscle reflex, monocyte rate, platelet count, mean corpuscular volume, and initial Yanagihara score. Conclusions Pretreatment hematologic findings, which reflect the severity of inflammation and bone marrow dysfunction caused by a virus infection, are useful for predicting the prognosis of facial palsy.

Background & aims: Malnutrition is common in patients with head and neck cancer (HNSCC). It may be related to severe adverse toxicity as a result of radiotherapy. The aim was to investigate nutritional screening factors for severe adverse events. Methods: A retrospective chart review of 101 patients who underwent radiotherapy from 2009 to 2013 was performed. The relationships among severe adverse events and pretreatment nutritional parameters, including static variables (serum albumin, total protein, total lymphocyte counts, body mass index), dynamic variables (retinol-binding protein, transferrin, pre-albumin), and nutritional screening tools (Onodera's Prognostic Nutrition Index [O-PNI]; Nutrition Risk Index; Controlling Nutritional Status [CONUT] score; Nutritional Risk Screening 2002) were evaluated in addition to patient and treatment factors. Results: According to the static parameters, approximately 30% of patients were malnourished before treatment. Twenty-four patients exhibited severe adverse events. On univariate analysis, combined chemotherapy, advanced staging, O-PNI <40, and CONUT score ≥5 were significant predictors of severe adverse events. Multivariate analysis revealed that O-PNI <40 and combined chemotherapy independently predict severe adverse events. Conclusions: O-PNI is considered a useful nutritional factor for predicting severe adverse events in HNSCC patients undergoing chemoradiotherapy and facilitates the planning of aggressive nutritional interventions prior to treatment.

Wolfram syndrome is an autosomal recessive disorder of the neuroendocrine system, known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) syndrome, and considered an endoplasmic reticulum disease. Patients show mutations in WFS1, which encodes the 890 amino acid protein wolframin. Although Wfs1 knockout mice develop diabetes, their hearing level is completely normal. In this study, we examined the expression of wolframin in the cochlea of a nonhuman primate common marmoset (Callithrix jacchus) to elucidate the discrepancy in the phenotype between species and the pathophysiology of Wolfram syndrome-associated deafness. The marmoset cochlea showed wolframin immunoreactivity not only in the spiral ligament type I fibrocytes, spiral ganglion neurons, outer hair cells, and supporting cells, but in the stria vascularis basal cells, where wolframin expression was not observed in the previous mouse study. Considering the absence of the deafness phenotype in Wfs1 knockout mice, the expression of wolframin in the basal cells of primates may play an essential role in the maintenance of hearing. Elucidating the function of wolframin protein in the basal cells of primates would be essential for understanding the pathogenesis of hearing loss in patients with Wolfram syndrome, which may lead to the discovery of new therapeutics.

Objective: To report the treatment efficacy of continual intratympanic steroid injection (ITSI) therapy in a patient with refractory sensorineural hearing loss accompanied by relapsing polychondritis. Patient: A 49-year-old female diagnosed with relapsing polychondritis at the age of 45 years and who had been treated with corticosteroids and immunosuppressants developed sensorineural hearing loss in the left ear. Intervention: Her unilateral hearing loss did not recover despite receiving one cyclophosphamide pulse treatment, one methylprednisolone pulse treatment, and weekly leukapheresis. Thus, we decided to initiate weekly ITSI therapy. Main outcome measure: Pure tone audiometry. Results: A week after the first ITSI treatment, the patient's hearing improved. We continued ITSI therapy and attempted to extend the interval between treatments, but her hearing worsened when ITSI therapy was delivered at 2- to 3-week intervals. Thus, we returned ITSI therapy to once per week for 21 months (total of 71 treatments). She experienced no adverse events, like tympanic perforation, and 1 year after terminating the therapy, her hearing remained stable and did not worsen. Conclusions: Continual, weekly ITSI therapy was effective in treating sensorineural hearing loss accompanied by relapsing polychondritis. ITSI therapy may be a promising treatment option for sensorineural hearing loss caused by autoimmune disease.

Chondrodysplasia punctata (CP) is a systemic disorder of chondrogenesis. The most prominent features of patients with CP are abnormal faces characterized by a flat nose and short stature. CP patients show various types and levels of hearing loss. This disease is rare, and no successful tympanoplasties with hearing recovery have been reported. Here, we report on a CP case, in which hearing recovery was successfully treated with tympanoplasty.

BACKGROUND: Preoperative diagnosis of lymph node metastasis from thyroid carcinoma is usually confirmed by using fine needle aspiration cytology (FNAC) when thyroid carcinoma is suspected based on the clinical findings. However, the result of FNAC sometimes leads to a false negative, especially in cases of hypocellular lesions such as metastases with cystic change. Thyroglobulin measurement in fine needle aspirates (FNA-Tg) has been shown to be a useful technique to detect the protein specifically secreted by thyroid follicular cells. Elevated FNA-Tg levels in an extra-thyroidal lesion means that the lesion comprises thyroid-originated tissue, most of which suggests the metastasis from thyroid carcinoma. Thus, FNA-Tg is expected to improve the sensitivity of FNAC for the aforementioned purpose.PATIENTS AND METHODS: From 2008 to 2012, 49 extra-thyroidal lesions from 43 patients with thyroid carcinoma were examined using both FNAC and FNA-Tg, followed by surgical resection with a histopathological diagnosis. The results were retrospectively reviewed and analyzed.RESULTS: Among 49 lesions, 47 were metastatic lymph nodes from thyroid carcinoma (46 papillary carcinoma and one follicular carcinoma), one was a metastatic lymph node from submandibular gland adenocarcinoma, and one was an ectopic thyroid gland. In the 47 cases of thyroid carcinoma, the sensitivity of FNAC was 57.4% (27/47), whereas that of FNA-Tg was 76.6% (36/47). When both methods were combined, the sensitivity increased to 93.6% (44/47). Metastasis from submandibular gland adenocarcinoma was considered to be an example of a false positive from FNAC, whereas an ectopic thyroid gland was an FNA-Tg false positive. Three lesions were negative for both FNAC and FNA-Tg, although metastases were suspected by imaging studies and confirmed by histopathological diagnosis, which were consistent with examples of a false negative from both FNAC and FNA-Tg findings.CONCLUSIONS: FNAC reflects whether the lesion has malignant cells, whereas FNA-Tg reflects whether the lesion has thyroid-originated tissue that specifically secrets thyroglobulin. Therefore, FNAC and FNA-Tg are considered to be complementary to each other for the preoperative diagnosis of lymph node metastasis from thyroid carcinoma. FNA-Tg was validated to improve the preoperative diagnostic sensitivity especially when combined with FNAC, however, it is attended with the possibility of a false positive or negative finding, which requires caution in interpretation of the findings.

A vascularized middle turbinate flap (MTF) might be useful in the repair of lesions in the anterior olfactory groove. The sizes of the MTF and inferior turbinate flap (ITF) and these distances up to the frontal base were analyzed by computed tomography (CT) using a picture archiving and communication system (PACS) in 20 patients. The minimum flap measurement to reconstruct the skull base was defined as the distance from the basal plate to the medial slope or lateral slope edge of the MTF and the ITF on the coronal view. Next, we reviewed clinical data from three patients with dural deficits who underwent endoscopic vascularized MTF reconstruction. The distance to the frontal base from the ITF was significantly longer than that from the MTF. The minimum length of the MTF measured by coronal CT was similar to the distance to the frontal base. In contrast, the minimum length of the ITF was shorter than the distance to the frontal base. These results suggest that the MTF might be superior to the ITF for coverage of the anterior frontal base. Three patients who underwent MTF reconstruction for a defect in the anterior olfactory groove had good outcomes and no complications. The MTF is a good option for reconstruction of defects in the anterior part of the olfactory groove.