Damage and loss of hair cells in the inner ear through aging, exposure to noise, environmental chemical toxins, medications, disease and genetic disorders cause hearing and balance disorders in millions of people each year. In the past, Otolaryngologists seldom envisioned treatments of the inner ear to prevent hearing or balance disorders, or treatments to restore the cells that are damaged or lost. Instead, prevention of hearing loss is mainly limited to peripheral protection (e.g., ear plugs), and treatment is based on either increasing the stimulation of remaining hair cells (amplification) or bypassing the hair cells entirely (cochlear implants). While enormous progress has been made during the past fifty years in those treatment modalities, I believe that during the next five decades biologically-based methods will allow prevention of hearing and balance disorders and replacement of lost receptor elements through regeneration or transplantation. This prediction is based on two important discoveries that occurred over the passed two decades. The first, with overwhelming importance to all of biology and medicine, is the discovery that most cell death is governed by the activation of a well-conserved and relatively small number of pathways that have been grouped together under the name of apoptosis. This important discovery forms the basis for research aimed at developing treatments that will prevent a significant percentage of hearing and balance disorders. The second discovery was of much more limited interest, but may become equally important for the field of Neuro-otology; the discovery that most vertebrates have the capacity to repair and restore function to the damaged inner ear through the regeneration of hair cells.

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Recent studies of human deafness genes gave a great impact on auditory medicine. Namely, genetic deafness affects about 1 in 2, 000 children and one to thirds of deafness patients are related to gene mutations. However, without an animal model for hereditary deafness, it is quite difficult to determine the anatomical, biochemical, and cellular basis for the phenotype, or to use gene rescue to prove unequivocally that the disease-causing gene has been identified. Here, I introduced two types of mouse models of gjb2 mutation. First, transgenic mice expressing a mutant connexin26 with R75W mutation identified in a deaf family with autosomal dominant inheritance was generated. Two lines of transgenic mice showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti, and degeneration of sensory hair cells. Despite robust expression of the transgene, no obvious structural change was observed in the stria vascularis or spiral ligament that is rich in connexin26 and generates the endolymph. The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained. Second, In order to confirm pathogenesis of Gjb2 mutation in recessive form, targeted disruption of Gjb2 using Cre recombinase controlled by PO was carried out. Targeted disruption of Gjb2 caused profound deafness from birth but has never reach maturation. Apparent degeneration of the organ of Corti was recognized, together with presumably secondary reduction of numbers of spiral ganglion cells. These findings confirmed a crucial role of Gjb2 in the cochlear function. Thus, development of animal models of non-syndromic deafness will provide us with a promising tool to create fundamental therapies and thereby to enable to rescue the impaired hearing.

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Hair cell (HC) and supporting cell (SC) productions are completed during early embryonic development of the mammalian cochlea. However, increasing evidence suggests that new HCs can be generated in mammalian sensory epithelium. To produce new HCs in a neonatal sensory epithelium, immature cells must be present, eventually proliferate and differentiate HCs.
We have first search for the presence of progenitors in the organ of Corti. Cultured immature nestin positive cells present in the newborn rat organ of Corti at the level of the great epithelial ridge can proliferate and subsequently differentiate into HCs and SCs together with the detection of nestin (+) cells in vivo at the spiral limbus in the P15 mature organ of Corti.
As a second approach, we have looked for the possibility of existing epithelial cells of the organ of Corti to differentiate into HCs. When fetal rat organ of Corti explants are cultured, supernumerary OHCs and supernumerary Deiters' cells are produced, without any additional cell proliferation. Supernumerary OHCs are produced at the distal edge of the organ of Corti. When the number of OHCs increases, while the total number of cells remains constant, the number of Hensen's cells decrease. In addition to existing OHCs, supernumerary OHCs, tectal cells and Hensen's cells expresse specific HC markers, i.e. jagged2 (Jag2) and Mathl in E19 organ of Corti explants after 5 days in vitro, suggesting that Hensen's cells retain the capacity to differentiate into OHCs. Roscovitine, a chemical inhibitor of cyclin-dependent kinases (CDKs), significantly increased the number of hair cells (HCs) and corresponding supporting cells (SCs) by triggering differentiation of precursor cells without interacting with cell proliferation.
In conclusion, new hairs cells can be generated presumably from the Hensen's cell progenitors and/or from progenitors located in the greater epithelial ridge area or in the inner sulcus area.

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Recent advances on stem cell biology are remarkable, and open the door for regeneration of various tissues or organs including inner ears. Here we report the potential of application of stem cell biology into therapeutic strategies for the treatment of inner ear diseases, focusing on the potential of embryonic stem (ES) cells. Es cells are pulripotent and have the ability for self-renewal. The targets for regeneration in the inner ear include sensory hair cells and associated neurons. ES cells can differentiate into various types of cells including neurons and hair cells. ES cells are, therefore, good candidates as transplants for cell therapy for inner ears. The methods for neural induction of ES cells have been established. We therefore attempted to investigate the potential of ES cell-derived neurons for regeneration of spiral ganglion neurons (SGNs). In this study, we used the stromal cell-derived inducing activity (SDIA), which can effectively induce neural differentiation of ES cells. We examined the possibility for neural connections between hair cells and ES cellderived neurons using explant culture techniques, and the potential of ES cell-derived neurons for functional restoration of SGNs. The results demonstrated that ES cell-derived neurons elongated their neuritis to hair cells and exhibited expression of synaptophysin, indicating the formation of synaptic connection with hair cells. After transplantation, robust survival of grafted ES cell-derived neurons was identified in the modiolus of cochlea. Grafted cells massively elongated their neurites in the modiolus. In some cases, functional recovery of SGNs was demonstrated by electrically evoked auditory brainstem responses. These findings strongly suggest a high potential of ES cell-derived neurons as transplants for replacement of SGNs.

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Hearing loss affects hundreds of millions of people around the world. Both genetic and environmental causes can lead to hearing deficits, resulting in a significant negative impact on the quality of life. The main reason for the severe outcome of these diseases is the lack of spontaneous regeneration in the auditory sensory epithelium. Two main alternatives exist for restoring hearing in ears with sensorineural hearing loss. The first one is the use of a cochlear implant, which is already in clinical use. The other possibility is to initiate hair cell regeneration, which is presently an important research goal. Manipulating the inner ear at the genetic level may be a feasible method for enhancing the outcome of cochlear implantation, and for inducing hair cell regeneration. Gene transfer allows for a direct influence on expression of specific genes in the tissue. This review describes advances in our laboratory in the use of gene therapy for enhancing the success of cochlear implants and for inducing hair cell regeneration in the mature living mammalian cochlea.

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Although a central perforation of the tympanic membrane (TM) is the typical finding of chronic otitis media without cholesteatoma, a keratinizing squamous epithelium on the tympanic side of the TM or in the tympanic cavity is occasionally found during surgery, albeit rarely. In our clinic, this disease was found in 28 of 2948 ears with central perforation of the TM without any other pathology indicating the possibility of cholesteatoma such as a retraction, an adhesion, or a debris accumulation around the perforation margin or in the tympanic cavity. The characteristic TM finding of this disease is an irregular margin of the perforation with a whitish remnant TM. This finding was found in 82% of these cases. When this TM finding is discovered preoperatively, a careful observation of the tympanic side of the TM is necessary during surgery. If the keratinizing epithelium is found on the tympanic side of the TM, that region of the remnant TM has to be excised because the closure of the perforation without removing the disease may cause a re-perforation or the formation of a new cholesteatoma.
Although the pathogenesis of this disease is still unclear, several theories are hypothesized in this paper, such as epidermis invasion from the perforation margin, rapture of the congenital cholesteatoma or of the intratympanic cholesteatoma, trauma, or ventilation tube insertion.

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Between January 1995 and May 1999, 163 cases with middle ear cholesteatoma were operated in Kansai Medical University Hospital. 33 cases (20.2%) were followed more than 5 years after surgery with the average duration of 69 months (60 to 84 months). For the canal reconstruction, bone pate with mixed bone powder and fibrin glue was used in all cases.
60 months after surgery, the mild deformation of the auditory canal was found, however the self-cleasing function of the external ear canal was preserved in all cases. Mild attic retraction was found in 9 of 33 cases (27.3%) and the self-cleansing function was lost in 3 cases of attic retraction pocket, but recurrent cholesteatoma was not observed.

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Fourteen patients who had treatment from 1996 to 2003 in our department were enrolled in this study. Analysis was made regarding the following perspectives: ages, gender, locations of tumor, histopathological diagnosis, chief complaints, the period from the onset of the disease to the first visit to our hospital, clinical stages, lymphatic metastasis, distant metastasis, operation procedures, radiation therapy, chemotherapy and prognosis. The fourteen patients comprised eight males and six females. Their ages ranged from 35 to 82 years old. The original sites of tumors were in the external ear canal in 10 cases and in the middle ear in four cases. Histopathological types were adenoid cystic carcinoma in one patient and squamous cell carcinoma in thirteen patients. Partial temporal bone dissection was performed in ten patients. Subtotal temporal bone dissection was performed in one patient and radical mastoidecomy in one patient. In the other two cases with apparent intracranial invasion, radical operation was not performed. The estimated five-year survival rates were 45% and 54% for all the patients and the patients treated with surgery, respectively. The analysis of the cases in which the disease recurred postoperatively showed the inadequacy of radicality of the operation. We concluded that appropriate preoperative evaluation of the disease and the choice of operative procedure are extremely important.

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Nineteen patients with perilymph fistula (PLF) were treated surgically in Kanto Medical Center NTT EC from 2001 to 2003. These 19 patients consisted of 17 with spontaneous PLF, one with PLF after stapedotomy for otosclerosis, and one with PLF due to inner ear malformation (Mondini type). Each patient underwent surgery for closure of PLF.
In 17 patients with spontaneous PLF, only 4 could be identified with perilymphatic leakage. Although these 17 showed good controls of vertigo or dizziness after surgery, improvements of hearing remained poor. The characteristic of our patients with spontaneous PLF was that some had only vestibular symptoms (showing normal hearing), and many patients underwent surgery in spite of a long term from onset as they had repeated vestibular symptoms in many times.
The patient with hearing loss after stapedotomy showed no improvement of hearing. The patient with inner ear malformation repeated meningitis due to PLF and has never experienced such infections after surgery.
Closure of spontaneous PLF seems to be significant not only for recovering hearing but also for controlling vestibular symptoms. In addition, we showed the effectiveness of the surgery for patients with a long term from the onset. The closure of PLF for patient with inner ear malformation was also effective for controlling infections.

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Twenty-eight patients (30 ears) underwent caloric tests with ENG (Electro-nystagmography) before and after stapes surgery. The purpose of this study was to examine the differences of vestibular function as well as to determine the correlation between vestibular and cochlear functions. There were 9 male ears and 21 female ears. Twenty-four ears had otosclerosis and 6 ears had stapes anomaly. Before surgery, 27 ears (90%) had normal caloric response and 3 ears (10%) had hypofunction. Based on the results of caloric tests, the ears were classified into three groups. Group (1) had a normal caloric response before surgery. There was a temporary deterioration in caloric response, whereby after which the ear recovered. Group (2) also had a normal caloric response before surgery. In this group, the ear suffered long-turn vestibular damage after surgery. In some cases, the last tests were not able to carried out. Group (3) had cases both normal and hypofunction before surgery. There was no change after surgery. There were 7 ears (23%) in Group (1), 5 ears (17%) in Group (2) and 18 ears (60%) in Group (3). Some cases had temporary hearing loss after surgery. However, the bone conduction hearing level and AB gap improved after surgery in all cases. There was no correlation between the vestibular and the cochlear functions. The cochlear function in cases with long-turn vestibular damage showed good hearing levels after stapes surgery, suggesting that the vestibular damage and the cochlear damage can occur independently.

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The first case was a 41-year-old female who complained of left tinnitus. The second was a 55-year-old female who complained of dizziness.
Otoscopic examination revealed a reddish and pulsative mass in the tympanic cavity through the tympanic membrane in each ear. Tumor was diagnosed as glomus tumors by CT, MRI and MRA. Preoperative angiography findings revealed that each tumor was fed by the assending pharyngeal arteries, which were embolized. The tumor was completely removed by transcanal tympanotomy with a small amount of bleeding in each case.
Preoperative embolization was very useful to control intraoperative blood loss.

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Chondroblastomas are rare, benign neoplasms of bone, first described by Ewing in 1928. It has been reported that chondroblastomas mostly originate from epiphyses of long bones including the tibia, humerus and femur, and rarely arise from the head and neck region. We report a case of chondroblastoma that arose in the right temporal bone.
A 65-year-old man presented with a soft tissue mass, approximately 5 mm in diameter, of the right external ear. CT showed a mass with bony defect of the right external ear canal. MRI demonstrated a low signal mass on T1-weighted images, which was represented as a irregular intensity signal on T2-weighted images.
The patient underwent surgery through a postauricular incision. The tumor was located in the epitympanum anterolateral to the malleus head accompanied by a bony defect of the anterosuperior wall of the external ear canal. The tumor was resected together with the external ear canal skin. Histopathologically, small round tumor cells and multinucleated giant cells were observed in the eosinophilic stroma with intercellular calcification, so-called “chicken wire calcification”. The tumor cells were immunopositive for S-100 protein. Based on these findings, the tumor was diagnosed as a chondroblastoma. The patient has been followed without evidence of tumor recurrence for 13 months.

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In a 77-year-old female with glomus tympanicum tumor, otoscopic examination revealed a reddish pulsatile mass in the tympanic cavity expanding laterally. CT findings showed the tumor occupying the tympanum and irregular bony wall of the promontry. Angiographic findings revealed that the main feeding artery of the tumor was the branch of the middle meningeal artery. Preoperative embolization was performed and the tumor was completely resected using the transmastoid extended facial recess approach. The total amount of bleeding during the surgery was 20 ml. KTP laser was useful to shrink and coagulate the tumor without bleeding.

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For the development of middle ear cholesteatoma, closing of the ventilative route via the supratubal recess in the tympanic diaphragm is indispensable. Closure of the eustachian tube by a acute otitis media results in negative pressure in the whole middle ear cavity, and the tympanic isthmus route is closed by the retracted tympanic membrane and ossicles in the middle ear of all people.
In the ear with an open supratubal recess route, which is usual in the normal ear, the atticomastoid cavity returns to normal pressure after the re-opening of the eustachian tube, and the Shrapnell's membrane stays in the normal position.
In an ear with a closed supratubal recess route, which is usual in an ear with cholesteatoma, the atticomastoid cavity stays under negative pressure even after the re-opening of the eustachian tube, and the Shrapnell's membrane retracts into the epitympanic cavity, developing into cholesteatoma.

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