Kaoru Ogawa

Mucoepidermoid Carcinoma of the Head and Neck : Clinical Analysis of 43 Patients

OBJECTIVEnIt is well known that mucoepidermoid carcinoma (MEC) displays a variety of biological behaviors. While the high-grade type is a highly aggressive tumor, its low-grade counterpart usually demonstrates a more benign nature and several systems have, therefore, been proposed to grade this neoplasm.nnnMETHODSnThis report analyzes 43 patients suffering from head and neck MEC, who were treated in our department during the period from 1989 to 2005. The relationship between clinical and pathologic characteristics and survival rate was investigated.nnnRESULTSnThe 5-year overall and disease-free survival rate was 62.3 and 57.2%. Multivariate analysis demonstrated that the parameters that significantly affected survival were the patients age (P = 0.040) and treatment method (P = 0.011).nnnCONCLUSIONSnThe patients age and treatment method is the prognostic parameter in this study. Although complete surgical resection is the standard treatment for MEC, we should aggressively consider adjunctive radiotherapy in those cases that have a high risk of recurrence and poor prognosis.

Bcl-2 Genes Regulate Noise-Induced Hearing Loss

Proteins of the Bcl‐2 family have been implicated in control of apoptotic pathways modulating neuronal cell death, including noise‐induced hearing loss. In this study, we assessed the expressions of anti‐ and proapoptotic Bcl‐2 genes, represented by Bcl‐xL and Bak following noise exposures, which yielded temporary threshold shift (TTS) or permanent threshold shift (PTS). Auditory brainstem responses (ABRs) were assessed at 4, 8, and 16 kHz before exposure and on days 1, 3, 7, and 10 following exposure to 100 dB SPL, 4 kHz OBN, 1 hr (TTS) or 120 dB SPL, 4 kHz OBN, 5 hr (PTS). On day 10, subjects were euthanized. ABR thresholds increased following both exposures, fully recovered following the TTS exposure, and showed a 22.6 dB (4 kHz), 42.5 dB (8 kHz), and 44.9 dB (16 kHz) mean shift on day 10 following the PTS exposure. PTS was accompanied by outer hair cell loss progressing epically and basally from the 4‐kHz region. Additional animals were euthanized for immunohistochemical assessment. BcL‐xL was robustly expressed in outer hair cells following TTS exposure, whereas Bak was expressed following PTS exposure. These results indicate an important role of the Bcl‐2 family proteins in regulating sensory cell survival or death following intense noise. Bcl‐xL plays an essential role in prevention of sensory cell death following TTS levels of noise, and PTS exposure provokes the expression of Bak and, with that, cell death.

Noninvasive in vivo delivery of transgene via adeno-associated virus into supporting cells of the neonatal mouse cochlea.

There are a number of genetic diseases that affect the cochlea early in life, which require normal gene transfer in the early developmental stage to prevent deafness. The delivery of adenovirus (AdV) and adeno-associated virus (AAV) was investigated to elucidate the efficiency and cellular specificity of transgene expression in the neonatal mouse cochlea. The extent of AdV transfection is comparable to that obtained with adult mice. AAV-directed gene transfer after injection into the scala media through a cochleostomy showed transgene expression in the supporting cells, inner hair cells (IHCs), and lateral wall with resulting hearing loss. On the other hand, gene expression was observed in Deiters cells, IHCs, and lateral wall without hearing loss after the application of AAV into the scala tympani through the round window. These findings indicate that injection of AAV into the scala tympani of the neonatal mouse cochlea therefore has the potential to efficiently and noninvasively introduce transgenes to the cochlear supporting cells, and this modality is thus considered to be a promising strategy to prevent hereditary prelingual deafness.

Bisphosphonate Therapy Ameliorates Hearing Loss in Mice Lacking Osteoprotegerin

Three auditory ossicles including the malleus, incus, and stapes conduct sound in the middle ear from the tympanic membrane to the inner ear. Auditory ossicles are massively resorbed by osteoclasts in Opg−/− mice, which lack osteoprotegerin (OPG), a soluble decoy receptor for the osteoclastogenic cytokine RANKL. Opg−/− mice exhibit progressive hearing loss and are a model for juvenile Pagets disease. However, effects of antiresorptive treatment on auditory ossicles and on hearing function in Opg−/− mice are unknown. We intraperitoneally injected Opg−/− mice with bisphosphonate risedronate 5 d/wk for 9 wk. Morphology of auditory ossicles was examined microscopically, radiographically, and histologically. Hearing function was monitored by measuring the auditory brain stem response (ABR). Control Opg−/− mice exhibited thinning of all three ossicles and tibia. In contrast, risedronate treatment significantly inhibited bone loss in auditory ossicles as well as in long bones of Opg−/− mice. Bony fusion of the junction between the stapes and the otic capsule was reduced after treatment. Moreover, ABR measurement showed that hearing in Opg−/− mice was significantly improved by risedronate treatment. These data suggest that hearing loss in pathologies characterized by excessive resorption of the auditory ossicles may be prevented by bisphosphonates.

Sendai Virus Vector-Mediated Transgene Expression in the Cochlea in vivo

We injected a recombinant Sendai virus (SeV) vector into the guinea pig cochlea using two different approaches – the scala media and scala tympani – and investigated which cell types took up the vector. The hearing threshold shift and distribution of transfected cells in animals using the scala media approach were different compared to those using the scala tympani approach. SeV can transfect very different types of cells, including stria vascularis, spiral ganglion neurons, and sensory epithelia of the organ of Corti, and fibrocytes of the scala tympani. Because SeV vectors can potentially deliver stimuli to the cochlea to induce hair cell regeneration, it may be a powerful tool for repairing the organ of Corti.

Neuroprotective effects of T-817MA against noise-induced hearing loss

Oxidative stress, including reactive oxygen species and other free radicals, is thought to play an important role in neuronal cell death, including noise-induced hearing loss. 1-{3-[2-(1-Benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate (T-817MA), a novel neurotrophic agent, protects against oxidative stress-induced neurotoxicity. This study examines the effects of T-817MA in noise-induced ototoxicity in the cochlea. Guinea pigs received treatment with T-817MA-enhanced water (0.2, 0.7 mg/ml) or untreated water (control) beginning 10 days prior to noise exposure and continuing through this study. All subjects were exposed to 4-kHz octave-band noise at 120-dB SPL for 5h. Auditory thresholds were assessed by sound-evoked auditory brainstem response at 4, 8, and 16kHz, prior to and 10 days following noise exposure. Hair cell damage was analyzed by quantitative histology. T-817MA significantly reduced threshold deficits and hair cell death. These results suggest T-817MA reduces noise-induced hearing loss and cochlear damage, suggesting functional and morphological protection.

Long-Term Prognosis of Steroid-Dependent Sensorineural Hearing Loss

We report on the long-term follow-up of 15 patients with steroid-dependent sensorineural hearing loss (SDSNHL), which was steroid dose dependent. We classified the patients into 2 groups: group A consisted of 6 patients with systemic SDSNHL, and group B consisted of 9 patients with inner-ear-specific SDSNHL without systemic disease. Group B patients were further classified as patients with slowly or rapidly progressive hearing loss. The yearly rate of hearing deterioration was greater in group B than in group A. Thus, the long-term hearing prognosis of patients in group B was worse than those in group A. Although SDSNHL may have immune-related origins, we hypothesize that hearing deterioration may be caused by proinflammatory cytokines because many of our cases exhibited abnormal immunological laboratory values and because many of these cases responded favorably to steroid treatment.

Inferior meatal antrostomy impairs dynamic stability of the orbital walls

OBJECTIVESnThe medial wall of the maxillary sinus, or the bony buttress, plays an important role in supporting the orbital floor. Since part of the bony buttress is removed in the inferior meatal antrostomy (IMA), it is expected that the IMA makes the orbital floor likely to develop serious fractures in traumatic situations. We conducted the present study to elucidate the effect of the IMA on the vulnerability of the orbital floor.nnnMETHODSnAfter producing CAD (Computer Assisted Design) models simulating twelve skulls, we performed simulation antrostomy for each of the twelve CAD models in both the middle meatus and the inferior meatus. According to the site of the antrostomy, the models were categorized as the MMA (middle meatal antrostomy) or IMA groups. We then applied an impact on the orbital region of each model. Using the finite element method, we calculated the area of the orbital wall fracture induced by the impact. Then we compared the area of the orbital wall fractures between the MMA and IMA groups.nnnRESULTSnThe orbital wall fracture areas were significantly greater in the IMA group than in the MMA group.nnnCONCLUSIONSnThe patients who underwent IMA are likely to develop serious orbital fractures if their orbits receive traumatic impacts. Hence, surgeons should be prudent in their indications for IMA.

GFAP aggregates in the cochlear nerve increase the noise vulnerability of sensory cells in the organ of Corti in the murine model of Alexander disease

Outer hair cell (OHC) loss in the auditory sensory epithelium is a primary cause of noise-induced sensory-neural hearing loss (SNHL). To clarify the participation of glial cells in SNHL, we used an Alexander disease (AxD) mouse model. These transgenic mice harbor the AxD causal mutant of the human glial fibrillary acidic protein (GFAP) under the control of the mouse GFAP promoter. It is thought that GFAP aggregates compromise the function of astrocytes. In the auditory pathway, the formation of GFAP aggregates was observed only in GFAP-positive cells of the cochlear nerve. The presence of GFAP aggregates did not change auditory function at the threshold level. To assess the change in vulnerability to auditory excitotoxicity, both transgenic and control mice were treated with intense noise exposure. Auditory threshold shifts were assessed by auditory brainstem responses (ABR) at 1 and 4 weeks after noise exposure, and OHC damage was analyzed by quantitative histology at 4 weeks after exposure. Transgenic mice showed more severe ABR deficits and OHC damage, suggesting that cochlear nerve glial cells with GFAP aggregates play a role in noise susceptibility. Thus, we should focus more on the roles of cochlear nerve glial cells in SNHL.