Published papers

The spatiotemporal distribution of drugs in the inner ear cannot be precisely evaluated because of its small area and complex structure. In the present study, we used hyaluronic acid (HA)-dispersed luciferin to image transgenic mice and to determine the effect of HA on controlled drug delivery to the cochlea. GFAP-luc mice, which express luciferase in cochlear spiral ganglion cells, were subcutaneously administered HA-luciferin (HA-sc) or luciferin dissolved in saline (NS-sc) or intraperitoneally administered luciferin dissolved in saline (NS-ip). The bioluminescence of luciferin was monitored in vivo in real time. The peak time and half-life of fluorescence emission were significantly increased in HA-sctreated mice compared with those in NS-sc- and NS-ip-treated mice; however, significant differences were not observed in peak photon counts. We detected differences in the pharmacokinetics of luciferin in the inner ear, including its sustained release, in the presence of HA. The results indicate the clinical potential of using HA for controlled drug delivery to the cochlea.

Objective: To document the clinical features and associated pure-tone audiometry data in patients with enlargement of the vestibular aqueduct (EVA), and to identify risk factors for fluctuating hearing loss (HL) and vertigo/dizziness in EVA patients. Methods: In this nationwide survey in Japan, a first survey sheet was mailed to 662 board-certified otolaryngology departments to identify the ones treating EVA patients. A second survey sheet, which contained solicited clinical information and the results of the hearing tests, was mailed to all facilities that reported treating EVA cases. We analyzed clinical information, including age at the time of the most recent evaluation, gender, EVA side, age at onset, initial symptoms, precipitating factors, and etiology from survey responses, and assessed 4-frequency (500, 1000, 2000, and 4000. Hz) pure-tone average (PTA) from accompanying pure-tone audiometry data. A multivariate logistic regression analysis was utilized to identify the possible risk factors for fluctuating HL and vertigo/dizziness. Results: In total, 513 hospitals (response rate, 77.5%) responded to the first survey, and 113 reported treating patients with EVA. Seventy-nine out of the 113 hospitals (response rate 69.9%) responded to the second survey, and the data of 380 EVA patients were registered and analyzed. Of the 380 patients, 221 (58.2%) were female, suggesting female preponderance. The patient age ranged from 0 to 73 years (mean, 16.7 years; median, 13 years; interquartile range, 6-24 years). EVA was bilateral in 91.1% of the patients (346/380). The most prevalent initial symptom was HL (341/380), followed by vertigo/dizziness/imbalance (34/380). Sudden HL occurred secondary to head trauma in 5.3% of the patients and upper respiratory infection in 5.0%. Pure-tone audiometry showed profound HL (PTA >91. dB) in 316 (52.0%) of the 608 ears in the 304 patients tested, and asymmetric HL, defined as >10. dB, in 147 (48.4%) of the 304 patients. The mean PTA was 83.7. dB (median, 91.3. dB; interquartile range, 71.3-103.8. dB), and the severity in PTA did not correlate with age. Multivariate logistic regression identified age ≥10 years (compared to age of 0-9 years), bilateral HL (compared to unilateral HL/normal hearing), a history of head trauma, and Pendred syndrome (compared to the other EVA-associated disorders) as significant risk factors for fluctuating HL and/or vertigo/dizziness. Conclusion: The present nationwide survey of 380 EVA patients provided a more precise description of the clinical features, including risk factors for fluctuating HL and vertigo/dizziness.

MYH9 disorder is a rare autosomal-dominant disorder. We previously reported that it is caused by mutations in the gene for nonmuscle myosin heavy chain IIA (NMMHC-IIA). MYH9 disorder causes congenital macrothrombocytopenia accompanied by progressive sensorineural hearing loss, nephropathy, and cataract. However, there are few reports that describe the audiological features of MYH9 disorder. The objective of this study was to characterize auditory and other phenotypes of patients with MYH9 disorder. We examined nine subjects from one Japanese family. Audiological, ophthalmological, hematological, and imaging examinations were used to assess clinical features. We carried out genetic analysis of the causative gene, MYH9. Five subjects exhibited macrothrombocytopenia and neutrophil cytoplasmic inclusion bodies. Immunofluorescence analysis of neutrophil NMMHC-IIA revealed abnormal type II localization. Two subjects had high-frequency dominant hearing loss, which was adult onset and progressive. Only one subject had cataract. MYH9 sequencing analysis of all thrombocytopenic subjects revealed a heterozygous c.4270G>A mutation in exon 30 (p.D1424N). We identified five patients with MYH9 disorder from the family. The hearing impairment associated with MYH9 disorder in this family was characterized as adult onset, progressive, and high-frequency dominant. Hematological manifestations of MYH9 disorder show complete penetrance, whereas extra-hematological manifestations show incomplete penetrance and variable expressivity in this family.

Hearing impairment is the most frequent sensory deficit in humans. Deafness genes, which harbor pathogenic mutations that have been identified in families with hereditary hearing loss, are commonly expressed in the auditory end organ or the cochlea and may contribute to normal hearing function, yet some of the mouse models carrying these mutations fail to recapitulate the hearing loss phenotype. In this study, we find that distinct expression patterns of those deafness genes in the cochlea of a non-human primate, the common marmoset (Callithrix jacchus). We examined 20 genes whose expression in the cochlea has already been reported. The deafness genes GJB3, CRYM, GRHL2, DFNA5, and ATP6B1 were expressed in marmoset cochleae in patterns different from those in mouse cochleae. Of note, all those genes are causative for progressive hearing loss in humans, but not in mice. The other tested genes, including the deafness gene COCH, in which mutation recapitulates deafness in mice, were expressed in a similar manner in both species. The result suggests that the discrepancy in the expression between rodents and primates may account for the phenotypic difference. This limitation of the rodent models can be bypassed by using non-human primate models such as the marmoset.

Ion homeostasis in the inner ear is essential for proper hearing. Anion exchangers are one of the transporters responsible for the maintenance of homeostasis, but their expression profile in the primate cochlea has not been fully characterized. However, species-specific overlapping expression patterns and functional compensation in other organs, such as the kidney, pancreas and small intestine, have been reported. Here, we determined the expression patterns of the anion exchangers SLC26A4, SLC26A5, SLC26A6, SLC26A7, SLC26A11, SLC4A2 and SLC4A3 in the cochlea of a non-human primate, the common marmoset (Callithrix jacchus). Although the pattern of expression of SLC26A4 and SLC26A5 was similar to that in rodents, SLC26A7, SLC4A2, SLC4A3 exhibited different distributions. Notably, five transporters, SLC26A4, SLC26A6, SLC26A11 SLC4A2 and SLC4A3, were expressed in the cells of the outer sulcus. Our results reveal a species-specific distribution pattern of anion exchangers in the cochlea, particularly in the outer sulcus cells, suggesting functional compensation among these exchangers. This "primate-specific" pattern may be related to the human-specific hearing loss phenotypes of channelopathy disorders, including the SLC26A4-related diseases Pendred syndrome/DFNB4.

Conclusion The sigmoid-incision (S-I) rescue flap technique has the advantage of both reduced-invasiveness and providing a sufficient surgical corridor for endoscopic endonasal skull base surgery (EESBS). Objective Skull base reconstruction with nasoseptal flap (NSF) is critically important in managing post-operative cerebrospinal fluid (CSF) leakage after tumor removal by EESBS. The NSF needs to be elevated before sphenoidotomy and posterior septectomy to preserve the pedicle. However, most extradural surgery without CSF leakage does not require NSF and, therefore, NSF preparation is often futile. As a result, a rescue flap technique to overcome this problem has been developed, whereby a new S-I rescue flap method is used that enables wide exposure of the sphenoidal rostrum and smooth manipulation of surgical instruments to preserve the NSF pedicle. Materials and methods Starting in April 2014, 19 cases underwent EESBS with S-I rescue flap. Results All patients underwent tumor resection under an adequate operative field with smooth manipulation of surgical instruments. Two complications were experienced. One patient had CSF leak after removal of the nasal packing, but the leakage was successfully closed by conventional NSF. Another patient had epistaxis from the septal wall, but this was controlled by electrocautery.

Conclusion Cochlear implantation (CI) for Japanese single-sided deafness patients resulted in improved speech perception, increased sound localization accuracy, and reduced tinnitus handicap. Objectives This study reports results for five adult SSD cases with CI, focusing on the benefits they obtained in terms of speech recognition, sound localization, and tinnitus handicap. Methods Five Japanese patients meeting the eligibility criteria were included in this study. All patients were implanted with a fully inserted MED-EL Concerto FLEX28® implant (MED-EL, Innsbruck, Austria). Speech perception outcomes in noise, as well as sound localization and tinnitus disturbance, were assessed pre-surgically and at 1, 3, 6, and 12 months after CI activation. Results The Japanese monosyllable test score in noise improved gradually after implantation. In some cases, speech perception ability appeared unstable, particularly in the first 1–6 months after implantation. The sound localization ability showed marked improvement in all cases, with the disturbance to daily life caused by tinnitus also decreasing in all cases from the early post-operative period.

Conclusion The results suggest that SOD1 rs4998557 could be associated with susceptibility to SSNHL in the Japanese population. Objectives To assess the gene association with sudden sensorineural hearing loss (SSNHL). Methods A two-stage case control study was conducted to explore the relationship of the candidate genes to SSNHL. The 192 gene samples from SSNHL patients registered in the intractable inner ear disease gene bank were enrolled. As the candidate genes, 39 SNPs from 31 genes were selected for the first stage study. The second stage study examined whether the SOD1 gene polymorphisms, defined by significant differences between cases and controls in the first stage study, are associated with SSNHL. Results Significant differences were observed in four SNPs from three genes, Glutathione-S-transferase pai 1 (GSTP1), proteine kinase C heta (PRKCH), and superoxide dismutase 1 (SOD1), in terms of allele frequency between SSNHL patients and HapMap controls. In the SOD1 gene, a significant difference was observed in the dominant model study of the SNP rs4998557 in the second stage study. Furthermore, as a result of dividing SSNHL patients based on the clinical data, the difference was more apparent in the case of the over 60 dB group and the tinnitus–positive group.

Background: Among salivary gland malignancies, the prognosis of salivary duct carcinoma (SDC) is assumed to be the poorest. However, because of its low incidence, reliable survival estimates and prognostic factors based on a large number of patients remain to be elucidated, thereby making it impossible to standardize the optimal treatment for SDC. Methods: We performed this multi-institutional, retrospective analysis by collecting the clinical information of 141 patients with SDC without distant metastasis who underwent curative surgery as the initial treatment to elucidate overall survival (OS) and disease-free survival (DFS) along with their prognostic factors. Results: The 3-year OS and DFS rates were 70.5 and 38.2 %, respectively. Multivariate analysis revealed that age ≥65 years (p <0.001) and N1 and N2 (p = 0.047 and

When a thyroid nodule has malignant features found by some examinations (e.g. Echo, FNAC, CT), we perform surgical resection. But if the thyroid nodule does not have malignant feature, there is still the possibility of malignancy, especially when the nodule is large. In the case of large pre-operatively benign thyroid nodules, we therefore consider a diagnostic lobectomy. There is, however, no definite recommendation how large a nodule should be before a lobectomy is performed, and how many malignancies exist in pre-opera-tively benign nodules. In our hospital, we consider surgical resection when the diameter of the thyroid nodule is over 3 cm. In this study, we analyze pre-operatively benign thyroid nodules in which surgical resection was performed in our hospital, how many malignant nodules there were and what the characteristics were between benign or malignant nodule. From 2005 April to 2012 June, 351 patients underwent a lobectomy in our hospital, 70 of which were pre-operatively benign thyroid nodules with diameters of over 3 cm. We analyzed the pathological findings and compared the nodule diameters, serum thyroglobulin, FNAC's classification and some characteristics of echography between pathologically benign and malignant cases. Fifty-eight patients (83%) had pathologically benign nodules, and 12 patients (17%) had malignant nodules. In 58 benign nodules, 33 nodules (47%) were adenomatous goiter, 24 patients (34%) had follicular adenomas and 1 nodule (1%) was an atypical adenoma. In the 12 malignant patients, 8 patients (11%) had papillary adenocarcinoma and 4 patients (6%) had follicular adenocarcinoma. Almost no significant characteristics were found concerning malignancy, in diameter, serum thyroglobulin, class of FNAC and features of echography. As for complications after surgery, hypothyroidism occured in four patients (6%), and neither hypoparathyroidism nor vocal fold paralysis occurred. We concluded that pre-operatively benign thyroid nodule that were over 3 cm in diameter had about a 17% possibility of malignancy. Examinations may not distinguish whether such pre-operatively benign tumors are benign or malignant before surgical resection. We should therefore consider whether to perform therapeutic surgery or not in such patients.

Extrapulmonary small cell carcinoma arising from the pharynx is rare. We have experienced 4 cases of pharyngeal small cell carcinoma. All the patients were male, and the mean age was 66 years old. The primary site was the oropharynx in 2 cases and the hypopharynx in 2 cases. All the patients initially underwent surgical resection, followed by chemotherapy or chemoradiotherapy. Three patients died because of distant metastasis. One patient is still alive without disease. Twentyfour cases of pharyngeal small cell carcinoma have been reported to date. An analysis of these 28 cases, including our 4 cases, revealed that 20 of the cases had died because of pharyngeal small cell carcinoma. Thus, pharyngeal small cell carcinoma appears to be associated with a relatively poor prognosis similar to that of pulmonary small cell carcinoma. Patients with T3/4 or metastatic diseases have an especially poor prognosis. When the primary site is resectable with minimum invasion, surgery followed by chemotherapy or chemoradiotherapy might offer a better chance of inhibiting local recurrence, compared with other strategies.

In the diagnosis of cholesteatoma, non-echo-planar diffusion-weighted MRI using the PROPELLER(periodically rotated overlapping parallel lines with enhanced reconstruction)technique has been reported to be useful. However, interpretation of positive findings is subjective and the decision criteria remain unclear. It is necessary to establish an objective standard for evaluation of the signal intensity. The aim of this study was to establish whether diffusion MRI using the PROPELLER technique is effective for the diagnosis of cholesteatoma. Furthermore, we investigated whether objective evaluation is possible by comparing the signal intensities and determining which region of brain is the most suitable for such comparison. We evaluated 35 ears with a postoperative diagnosis of cholesteatoma for which preoperative evaluation had been performed by MRI using the PROPRLLER technique. We determined a lesion as positive if it showed a higher intensity than the cerebellar white matter. Furthermore, for objective evaluation, we set regions of interest and compared the highest signal intensity of the target lesion with that of the following parts of the brain ; cerebellum, cerebellar white matter, temporal lobe, temporal lobe white matter. The sensitivity/positive-predictive value were 85.7%, and the specificity/negative-predictive value was 42.9%. The smallest lesion observed was 3.8 mm in diameter. In addition, in 4 of the 35 ears, no lesion could be detected. Objective evaluation by comparison of the highest signal intensities of the regions of interest matched with the diagnosis after surgery in 26 of the 31 ears. The findings suggested that the cerebellar white matter was the most suitable among the 4 regions evaluated for such comparison. This method is thought to be useful, especially in cases where macroscopic evaluation of the lesions is difficult.

We retrospectively reviewed nine cases of olfactory neuroblastoma in Keio University School of Medicine from 2010 to 2015. The surgical approach was the endoscopic endonasal approach, either alone or in combination with craniotomy, performed by a team of head and neck surgeons and a neurosurgeon. The distribution of patients according to the modified Kadish classification （A/B/C/D) and Dulguerov classification （T1/T2/ T3/T4) was 1/4/4/0 and 1/4/2/2. Tumors of six cases were removed by the endoscopic endonasal approach alone; three cases needed craniotomy to resect intra-dual tumors. Three-layered skull base reconstruction using fascia, pericranial flap and nasoseptal flap was used for five cases. None of the cases experienced cerebrospinal fluid leakage postoperatively. Seven patients received postoperative radiotherapy. Three cases experienced tumor recurrence, and underwent salvage surgery or radiotherapy. All cases remained alive, though the average observation time was less than 3 years. Recent reports have demonstrated that the endoscopic endonasal approach has a comparable control rate to the open approach for olfactory neuroblastoma. We believe that endoscopic endonasal skull base surgery should play a key role in the treatment of olfactory neuroblastoma in the years ahead.

The TPF protocol composed of docetaxel, cisplatine and 5-fluorouracil, is the most commonly used chemotherapy regimen for the treatment of head and neck cancer. Recently, the importance of maintaining a relative dose-intensity (RDI) has been shown. Therefore, the treatment and prevention of febrile neutropenia, which can reduce the RDI of the TPF protocol, are important. Here, we compare patient outcomes before and after the introduction of pegfilgrastim for primary prophylaxis. The first group is consisted of 60 patients (88 chemotherapy courses) treated between January 2011 and October 2014 who did not receive prophylaxis. The second group consisted of 14 patients (20 chemotherapy courses) treated between November 2014 and July 2016 using pegfilgrastim. We examined the frequency of neutropenia (grade 3 and 4), febrile neutropenia (FN) and treatment-related death, the amount of granulocyte-colony stimulating factor (G-CSF) used, the cost for FN treatment and the hospitalization period. In the first group, there were 74 neutropenia events, 34 cases of FN and 2 treatment-related deaths; the average hospitalization period was 18.5 days. In the second group, there were 74 neutropenia events, 34 case of FN, and 0 treatment-related death; the average hospitalization period was 18.5 days. The frequency of adverse events, the amount of G-CSF used, the cost for FN and the hospitalization period were all significantly reduced by the introduction of pegfilgrastim. In conclusion, the administration of pegfilgrastim for the primary prophylaxis of FN was effective when included in the TPF protocol for the treatment of head and neck cancer.

AIM: This study aimed to assess the efficacy of endoscopic endonasal surgery, conducted by a team of neurosurgeons and otolaryngologists.MATERIAL AND METHODS: We studied 40 patients who were undergoing surgery for primary non-functional pituitary adenomas with Knosp grades 1 to 3, at Keio University Hospital between 2005 and 2012. We compared the endoscopic endonasal transsphenoidal approach (team-eTSS; T-eTSS), with a microscopic transsphenoidal approach (mTSS). Analyses were conducted for differences between the two groups in tumor resection rates, operating durations, and complications from the non-functional pituitary adenomas. We also compared the heminostril and binostril approaches for T-eTSS.RESULTS: Tumor resection rates were higher when the surgeries were conducted by T-eTSS than mTSS. In particular, when the maximum tumor diameter was more than 25 mm, resection rates were significantly higher for T-eTSS than for mTSS. There were no unexpected complications in either group. There was no significant difference in resection rates between the heminostril and binostril approaches when T-eTSS was performed.CONCLUSION: T-eTSS is an efficacious surgical option for non-functional pituitary adenomas, particularly when the adenoma is of large size. Benefits of the heminostril approach are evident.

Based on a series of studies including brain function tests, we reinforced and improved treatment for tinnitus by developing a tinnitus retraining therapy (TRT) that incorporates the "tinnitus pain model"; our laboratory subsequently introduced this therapy in 2013. This model provides a clinical explanation that tinnitus manifests and worsens through nerve synchronization of the auditory path and the non-auditory path with the pain network. Therefore, the target of tinnitus therapy based on this model is the auditory path generating the tinnitus and the pain network that worsens the tinnitus. The therapy mainly uses "acoustic therapy" and "directive counseling", which are the same as the original TRT. What characterizes this method is the central use of a hearing aid in the "acoustic therapy" targeting tinnitus patients with hearing loss. TRT incorporating the "tinnitus pain model" would be ideal for the establishment of an outpatient department dedicated to hearing loss and tinnitus. In actual practices, however, many hospitals avoid offering "directive counseling", as it is often difficult to provide sufficient counseling in a general outpatient setting. This report examined the tinnitus treatment practice of a municipal hospital with two otolaryngologists. The hospital administered TRT incorporating the "tinnitus pain model" to 62 cases (average age: 68.7 years, prevalence period: 16 months [median]). All the cases were treated with "directive counseling", while 32 cases used hearing aids as a part of "acoustic therapy". The tinnitus handicap inventory (THI) score showed a statistically significant reduction after treatment from 49.3±23.0 to 24.8±21.1. The improvement rate, based on an "improvement of 20 THI points or above" and "16 or lower final THI points" as the statistical criteria, was 62.9%. The proactive involvement of municipal hospitals in tinnitus treatment may reduce the frequency of doctor shopping by tinnitus patients and could help to break the "vicious circle" of tinnitus treatment practices.

Objectives: We describe a novel scoring system, the facial Palsy Prognosis Prediction score (PPP score), which we test for reliability in predicting pre-therapeutic prognosis of facial palsy. We aimed to use readily available patient data that all clinicians have access to before starting treatment. Design: Multicenter case series with chart review. Setting: Three tertiary care hospitals. Participants: We obtained haematological and demographic data from 468 facial palsy patients who were treated between 2010 and 2014 in three tertiary care hospitals. Patients were categorised as having Bell's palsy or Ramsey Hunt's palsy. Main outcome measures: We compared the data of recovered and unrecovered patients. PPP scores consisted of combinatorial threshold values of continuous patient data (eg platelet count) and categorical variables (eg gender) that best predicted recovery. We created separate PPP scores for Bell's palsy patients (PPP-B) and for Ramsey Hunt's palsy patients (PPP-H). Results: The PPP-B score included age (≥65 years), gender (male) and neutrophil-to-lymphocyte ratio (≥2.9). The PPP-H score included age (≥50 years), monocyte rate (≥6.0%), mean corpuscular volume (≥95 fl) and platelet count (≤200 000 /μL). Patient recovery rate significantly decreased with increasing PPP scores (both PPP-B and PPP-H) in a step-wise manner. PPP scores (ie PPP-B score and PPP-H score) ≥2 were associated with worse than average prognosis. Conclusions: Palsy Prognosis Prediction scores are useful for predicting prognosis of facial palsy before beginning treatment.

Objective: To assess the effects of tinnitus treatments on sleep disorders in patients with tinnitus. Design: Subjects completed the Pittsburg Sleep Quality Index (PSQI), Tinnitus Handicap Inventory (THI), Self-rating Depression Scale (SDS), and State Trait Anxiety Inventory (STAI). The questionnaire results and the patients’ sex, age, time since the onset of tinnitus, and mean hearing level were examined, and differences between a sleep disorder group and a normal sleep group were examined. Patients completed the questionnaires again after initiating tinnitus treatments (counselling and use of sound generators), and the change in questionnaire scores at follow-up was evaluated. Study sample: Patients (N = 100) with tinnitus who visited Keio University Hospital and started treatment without medication between 2005 and 2008. Results: Sixty-six percent of the patients had sleep disorders. Compared with patients without sleep disorders, patients with sleep disorders had significantly higher SDS and STAI scores at the first visit. The mean PSQI scores showed significant improvement at follow-up. Conclusions: Sleep disorders in patients with tinnitus improved after tinnitus treatments. Complex interactions between depressive symptoms and anxiety may occur in these patients. The improvement in sleep disorders at follow-up was correlated with improvements in tinnitus severity and state anxiety.

Background: The Tinnitus Sample Case History Questionnaire was determined as a standardized questionnaire for obtaining patient case histories and for characterizing patients into subgroups at the Tinnitus Research Initiative in 2006. In this study, we developed a Japanese version of this questionnaire for evaluating the clinical characteristics of patients with tinnitus. The Japanese version of the questionnaire will be available for evaluating treatments for tinnitus and for comparing data on tinnitus in research centers. Aims/Objectives: To evaluate the clinical characteristics of patients with tinnitus in Japan using a newly developed Japanese version of Tinnitus Sample Case History Questionnaire. Study design: This was a prospective study based on patient records. Setting: University hospitals, general hospitals, and clinics. Subjects and methods: We collected patient data using a Japanese translated version of the Tinnitus Sample Case History Questionnaire. In total, 584 patients who visited our institutions in Japan between August 2012 and March 2014 were included (280 males and 304 females; age 13–92 years; mean age, 60.8). We examined patients after dividing them into two groups according to the presence or absence of hyperacusis. The collected results were compared with those from the Tinnitus Research Initiative database. Results: Compared with the TRI database, there were significantly more elderly female patients and fewer patients with trauma-associated tinnitus. There was a statistically lower ratio of patients with hyperacusis. We found that patients with tinnitus in addition to hyperacusis had greater tinnitus severity and exhibited higher rates of various complications. Conclusion: The Japanese version of the Tinnitus Sample Case History Questionnaire developed in this study can be a useful tool for evaluating patients with tinnitus in Japan. The results of this multicenter study reflect the characteristics of patients with tinnitus who require medical care in Japan. Our data provides a preliminary basis for an international comparison of tinnitus epidemiology.