Objective: Otitis media with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is characterized by otitis media refractory to conventional treatments. OMAAV can either be an aural manifestation of existing ANCA-associated vasculitis (AAV) or an initial aural manifestation of AAV. OMAAV occasionally causes irreversible profound sensorineural hearing loss that may require a cochlear implant, even in the latter case. In such cases, prompt diagnosis of OMAAV is important, but sometimes difficult. When diagnosing OMAAV, repetitive otitis media with effusion (OME) in adults is a complicated differential diagnosis. The precise evaluation of tympanic membrane (TM) findings would help to achieve prompt diagnosis. The objective of this study was to discriminate OMAAV from adult OME based on tympanic TM findings.

Methods: Ten patients with OMAAV and 10 with adult OME were included. We established a Scoring system of OMAAV Tympanic membrane (SCOT) to evaluate the TM findings of OMAAV, comprising the following three characteristic findings: thickening of the pars tensa, vasodilation of the pars tensa, and posterior wall swelling. Each TM finding in OMAAV and OME was scored from 0 to 3 by 20 otolaryngologists without knowledge of the diagnosis. The reliability of the scoring system in terms of consistency between examiners was evaluated by the intraclass correlation coefficients (ICC). Validity was tested by comparing the TM scores between OMAAV and OME and by analyzing the area under the curve (AUC) of the receiver operating characteristic (ROC) curve to discriminate OMAAV from OME. Correlations between the TM scores and various systemic markers of OMAAV, including white blood cell count, C-reactive protein, myeloperoxidase-anti-neutrophil cytoplasmic antibody, and Birmingham Vasculitis Activity Score, were examined.

Results: The ICC of each score was over 0.95. Each of the individual and total TM scores were significantly higher in OMAAV than in OME. The AUC of the ROC curve was 0.9134. The cut-off value set at 2 points had the best combination of sensitivity (93.0%) and specificity (74.0%) to distinguish OMAAV from OME. No significant correlations were found between the total score of SCOT and systemic markers. However, the total score of SCOT significantly correlated with the average hearing level of both air (p = 0.021) and bone conductions (p = 0.032).

Conclusion: The reliability and validity of SCOT in discriminating OMAAV from adult OME were demonstrated, suggesting that SCOT would be useful for the early diagnosis of OMAAV. The correlation between SCOT and hearing level suggests that SCOT is also useful to evaluate the disease status of OMAAV.

Cisplatin is a chemotherapeutic agent that is commonly used for the treatment of solid tumors, and its side effects include vestibulotoxicity. Previous studies have reported cisplatin-induced vestibulotoxicity in various animal models, but no study has investigated in vivo mouse vestibular dysfunction after cisplatin treatment. This study therefore aimed to investigate cisplatin-induced vestibulotoxicity in C57BL/6J mice. Vestibular function was assessed by recording the vestibulo-ocular reflex (VOR). This was performed during sinusoidal rotations in the horizontal plane at three frequencies (0.5, 1.0, and 2.5 Hz). A high-resolution, high-frequency digital infra-red camera was used with eye-tracking algorithms. Cisplatin decreased the VOR gain at 2.5 Hz compared to the vehicle control. Following cisplatin treatment, the animals showed no change in the optokinetic nystagmus response, suggesting that no major changes in visual or oculomotor functions had occurred. Our results suggest that vestibulotoxicity will become evident after high-dose cisplatin chemotherapy in future studies using high-frequency VOR tests.

NLRP3 gene encodes for NLRP3 protein, a key protein of the NLRP3 inflammasome. The NLRP3 inflammasome is an intracellular innate immune sensor expressed in immune cells, including monocytes and macrophages. Its activation leads to the secretion of interleukin-1β, a proinflammatory cytokine. We previously revealed that a missense NLRP3 mutation causes autosomal-dominant nonsyndromic hearing loss with abnormal activation of the NLRP3 inflammasome. In the family, hearing loss segregated without any other abnormal findings. This observation led us to explore the possibility that resident macrophage-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. Resident macrophage-like cells exist in the mouse cochlea. The NLRP3 inflammasome can be activated in the resident macrophage-like cells in the mouse cochlea, resulting in the secretion of IL-1β.

In recent years, expectations of gene therapy for congenital hearing loss or inner ear regeneration have increased with the accumulation of molecular biological findings; however, obtaining scientific knowledge on human inner ear development has become progressively difficult due to ethical issues. Therefore, rodent models have been frequently used in the studies of inner ear regeneration and development, and many results have been achieved. However, the evolution of the cochlea from rodents to primates and humans has not been studied extensively.

The acquisition of the cochlea as a hearing organ is relatively new in evolutionary history. As a cochlea is present only in mammals, the structure of the cochlea has been known to show morphological differences among them. Scientific interest in the auditory organs of vertebrates, which have dynamically changed their morphology during evolution, is one of the oldest scientific challenges; this knowledge of “evolution” sometimes provides us with important insights when studying “development.”

In this study, we focus on the common marmoset, which is used as a primate model animal in our department. In addition, we report our recent findings on the varying effects of evolution and species in terms of inner ear development by comparing inner ear development in humans and rodent models based on evolutionary knowledge.

Objectives: We examined the mechanism of development of inner ear malformation in trisomy 18 syndrome from embryonic inner ear organogenesis.

Methods: The histopathological specimen was from a fetus that died at 35 weeks gestation and was diagnosed with trisomy 18 by chromosomal testing.

Results: In the pathological specimen of trisomy 18, the cochlea was as short as two turns, and the apical turn was hypoplastic. The modiolus was short, and the aperture of the cochlear nerve canal was stenotic. The cochlear duct showed formation of the organ of Corti. There were no abnormalities in the outer and inner hair cells, and no abnormalities in the stria vascularis. The saccule was hypoplastic. The utricle had an otolithic membrane and sensory epithelium. The anterior semicircular canal showed a normal luminal structure. The lateral semicircular canal was hypoplastic, and no cupula formation was observed at the crista ampullaris of the lateral semicircular canals. The posterior semicircular canal had a small lumen structure and was hypoplastic.

Conclusions: The development of the cochlear duct in the membranous labyrinth appeared to have stopped at six to eight weeks of fetal life. However, the differentiation of the organ of Corti continued, and the ossification of the bone labyrinth also progressed.

Estimating from the differentiation of otoliths and semicircular canals, inner ear development progressed until about 20 weeks of fetal life.

In considering the mechanism of inner ear malformation, it was necessary to classify the process of development by separating the cochlear duct and organ of Corti in the membranous labyrinth, ossification of the bone labyrinth, and ossification of the otic capsule.

When clinical trials are conducted in developed countries to develop new therapies, information on the safety of the new therapy and a non-clinical proof of concept (POC) that scientifically estimates its efficacy are required while assuming a molecular and cellular biological mechanism of action based on a scientific view of the disease. Usually, non-clinical POC on efficacy is obtained from therapeutic effects observed in animal models of diseases. The induced pluripotent stem cell (iPSC)-based drug discovered for the treatment of inner ear disorders in Pendred syndrome/DFNB4, which we have been researching for several years, was the first in developed countries to be administered to actual patients (FIP: First-in-patient study) by substituting an in vitro model using iPS cell technology in the conventional animal model of the disease. In this paper, we will describe the regulatory strategy prior to the FIP, which is indispensable in translational research, i.e., how to construct the logic for safety, tolerability, and efficacy in light of international regulations; how to ensure the responsibility to explain to the public required by the regulatory authorities; and how to conduct the actual initial clinical trials. We would like to explain how the iPSC-based drug discovery research in question has been accumulated.

In general, the process of industry-academia-government collaboration is essential for the social implementation of technologies originating from academia, including scientific perspectives, compliance with the relevant laws and regulations, and negotiations with exit companies. The more novel the seeds are, the more difficult negotiating them tends to be. The most important point in negotiating with academia, industry, and regulatory authorities, all of whom are in completely different positions, is to emphasize the goal of creating new treatments that benefit patients.

The processes involved in the development and practical use of the new treatment begin with fundamental research, through nonclinical and clinical trial studies, regulatory affairs, leading to approval by the National Health Insurance. It takes more than 10 years to complete, and many hurdles to overcome exist in these processes. The most important factors are how to move seeds forward into clinical trials, patent acquisition, and finding a support company. Nevertheless, under the aegis of the Foundation for Biomedical Research and Innovation, we were able to take a big step towards the practical application of regenerative treatment for tympanic membrane (TM) perforation.

This regenerative treatment for TM perforation was approved in November 2019 by the National Health Insurance in Japan. Before its approval, Retympa^® (Norvel Pharma Inc, Tokyo, Japan), as a specialized medicine for TM perforation, received pharmaceutical approval in Japan. Post-marketing surveillance is ongoing to investigate the efficacy and safety of Retympa^® for several years. One year after the approval in Kitano hospital, the TM perforation closure rate (89/91 ears) reached 98%, and favorable hearing improvement was achieved with a small air-bone gap. No severe adverse events were observed. However, only 20%–30% of patients with perforations met the eligibility criteria for TM regeneration. Finding ways to increase the number of eligible patients in the future is, thus, essential. Subsequently, we will develop a new tympanoplasty procedure for patients with chronic otitis media, combined with cleaning the tympanic cavity and the TM regeneration trans-canal, trans-TM, using an endoscope.

Moreover, we have already started the overseas expansion and would soon like to spread this treatment to advanced and developing countries.

Perilymphatic fistula (PLF) is defined as an abnormal connection between the perilymph-filled space and the middle ear or cranial spaces. PLF can occur owing to direct stapes injury, vigorous blowing of the nose, or could even be idiopathic. Although the main symptoms of PLF include hearing loss, vertigo, and tinnitus, it is known that PLF manifests through various symptoms. We determined the number of cochlin–tomoprotein (CTP)-positive patients who had sudden sensorineural hearing loss or repeated vertigo in our hospital. Between October 2013 and March 2019, 125 ears of 121 patients who had sudden sensorineural hearing loss, including suspected PLF, and repeated vertigo were examined for CTP levels in saline rinses. We carefully obtained the anamnesis of all patients and defined an episode of sudden sensorineural hearing loss or repeated vertigo, which may cause PLF, as suspected PLF and other episodes as idiopathic cases. Of the 121 patients, only 4 (3%) were CTP positive—these were suspected PLF patients. Three of the CTP-positive cases belonged to category 1, while the other case belonged to category 3 (after vigorous blowing of the nose). The 98 idiopathic cases were all CTP negative. Although the inner ear structure of the elderly is fragile, the 51 elderly patients aged >60 years in this study, excluding those with suspected PLF, were all CTP negative. In conclusion, if there is a valid reason to suspect PLF in cases of acute sensorineural hearing loss or dizziness, PLF is supposed; however, the possibility of PLF is low in idiopathic cases.

The CI532 implant features a pre-curved electrode. However, when pre-curved electrodes are inserted into the scala vestibuli, which is a frequent procedure, the electrode tip usually folds over itself (tip-fold-over). To date, we have performed surgeries placing implant CI532 in 32 ears at our hospital, and have observed two cases of tip-fold-over. We examined videos in detail to determine the cause. In both cases (Cases 1 and 2), the sheath handle was oriented towards the basilar membrane when the tip-fold-over occurred. Proper insertion was possible when it was oriented toward the modiolus. In our hospital, there have been three cases of improper insertion orientation and tip-fold-over occurred in two of these three cases. Therefore, we considered that the orientation of the sheath handle was important. In addition, when the electrode was inside the sheath, the insertion-related rotation surface of the electrode was slightly displaced from the sheath handle surface. While no tip-fold-over was observed in these cases, the electrode’s rotation surface should be checked before inserting it into the sheath. Moreover, if the displacement of the rotation surface is observed when performing bilateral cochlear implant surgery, it is necessary to consider the recommended angle of insertion.

In Japan, electric acoustic stimulation (EAS) has been approved only with the use of a short electrode array (e.g., Flex24^TM) and specific audio processors with built-in acoustic stimulation components, such as DUET2 ^TM and SONNET EAS ^TM manufactured by MED-EL. We herein report a case showing the EAS benefit from the combined use of the DUET2 processor and the Flex28 electrode array, which has not yet been approved for EAS in Japan. A 53-year-old female with bilateral sensorineural hearing loss who underwent EAS surgery using a Flex24 electrode in her left ear, followed by late-onset deterioration of residual hearing in the operated ear 2 years and 4 months after implantation. She underwent a second cochlear implant surgery at the age of 59 years using a Flex28 electrode and an RONDO2 audio processor in her right ear. Because adequate preservation of low-frequency residual hearing was confirmed 6 months after implantation, she started to use her DUET2 audio processor on the right ear for EAS. The Japanese monosyllable scores examined 18 months postoperatively were better with EAS than with electric stimulation alone either under quiet or background noise conditions. This case study suggests the importance of the clinical availability of the EAS processor based on hearing capabilities regardless of the length and shape of the implanted electrode array.

A 28-year-old man complained of ear pain, tinnitus, hearing loss, and vertigo during an airplane trip. Standard pure-tone audiometry indicated complete deafness in the left ear, and CT showed air bubbles in the inner ear and cranial cavity. On the basis of these findings, aviation perilymphatic fistula with pneumolabyrinth and pneumocephalus was diagnosed. The patient was treated medically with antibiotic and corticosteroid drugs after emergency hospitalization, and underwent surgery for closure of the fistula four days after the onset. Although perilymph leakage was not observed through the oval window and round window niche, both windows were covered with subcutaneous tissue and ear cartilage and fixed with fibrin glue. The head floating sensation immediately disappeared postoperatively. Hearing was improved to an average of 70.0 dB, and no intracranial complications were observed. The intraoperative Cochlin-tomoprotein (CTP) detection test was negative. It was considered that CTP was depleted when the sample was collected due to the large amount of perilymph leakage.

Cartilage conduction (CC) was discovered by Hosoi in 2004. There are three pathways for CC. The first is called a direct air pathway, in which the transducer vibrates the air directly. The second is called a cartilage-air pathway, in which the transducer vibrates the aural cartilage and tissue, generating air conduction sound in the ear canal. The third is a cartilage-bone pathway, in which the vibration in the cartilage is transmitted to the skull. Cartilage conduction hearing aids (CC-HAs) have been developed and used clinically in Japan since 2017. The best indication of CC-HAs is in atresia of the external auditory canal. The indication for postoperative ears, such as lateral healing, cavity problem, and tympanosclerosis, is controversial. We had an experience of fitting CC-HAs for a patient with bilateral postoperative retroaulicular fistula. We performed normal air conduction hearing aids with ear molds, but we could not manage the feedback problem because the ear canal and fistula were connected. Subsequently, we attempted using CC-HAs. In this case, among the three pathways, the cartilage-bone pathway seemed to be the most effective, and we could manage the feedback problem. CC-HAs have a good indication for hearing loss with postoperative auricular fistula.

Traumatic ossicular chain disruption is not a rare condition. However, incus dislocation into the exterior of the tympanic cavity is very rare. Herein, we report a rare case of a patient who sustained head injury in a fall and developed dislocation of the incus under the external auditory meatus skin without a bone fracture. The patient, a 51-year-old man, was transported to our emergency department for head injury, and was referred to our department the following day due to continued bleeding from the external ear canal. Computed tomography (CT) showed ossicular chain disruption, and tympanoplasty was performed approximately six months after the injury. Intraoperatively, we pulled up the dislocated incus after confirming its integrity under the external auditory meatus skin and made a reconstruction between the malleus and stapes head. In this case, preoperative 3D-CT was performed to confirm the location of the dislocated incus and to assess the ear drum as well as the middle ear cavity; this enabled safe and successful performance of the surgery.