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Cerebral venous thrombosis as a manifestation of paraneoplastic angitis and otitis media, revealing non-Hodgkin B-cell lymphoma (NHBL), is extremely rare. A 57-year-old woman presented with headache, auditory disturbance and recalcitrant otitis media. Magnetic resonance imaging showed brain edema in the temporal lobe and transverse sinus thrombosis. External drainage under antibiotic treatment was repeated based on a diagnosis of invasive otitis media and mastoiditis associated with infectious sinus thrombosis, but the condition deteriorated progressively. Open surgery for otitis media was performed 6 years after the initial symptoms and after a tumorous lesion had been detected in the middle ear. Pathological findings revealed NHBL. We report a rare case of NHBL presenting as otitis media and mastoiditis associated with sinus thrombosis, and a literature review.

Mutations in SLC26A4 cause a broad phenotypic spectrum, from typical Pendred syndrome to nonsyndromic hearing loss associated with enlarged vestibular aqueduct. Identification of these mutations is important for accurate diagnosis, proper medical management and appropriate genetic counseling and requires updated information regarding spectrum, clinical characteristics and genotype-phenotype correlations, based on a large cohort. In 100 patients with bilateral enlarged vestibular aqueduct among 1511 Japanese hearing loss probands registered in our gene bank, goiter data were available for 79, of whom 15 had Pendred syndrome and 64 had nonsyndromic hearing loss. We clarified the mutation spectrum for the SLC26A4 mutations and also summarized hearing levels, progression, fluctuation and existence of genotype-phenotype correlation. SLC26A4 mutations were identified in 82 of the 100 patients (82.0%). Of the Pendred syndrome patients, 93% (14/15) were carriers, as were 77% (49/64) of the nonsyndromic hearing loss patients. Clinical characteristics of patients with SLC26A4 mutations were congenital, fluctuating and progressive hearing loss usually associated with vertigo and/or goiter. We found no genotype-phenotype correlations, indicating that, unlike in the case of GJB2 mutations, the phenotype cannot be predicted from the genotype. Our mutation analysis confirmed the importance of mutations in the SLC26A4 gene among hearing loss patients with enlarged vestibular aqueduct and revealed the mutation spectrum, essential information when performing genetic testing.

The 3-year progression-free survival rate of non-invasive salivary duct carcinoma (SDC) or adenocarcinoma not otherwise specified (NOS) was significantly better than that of invasive SDC or adenocarcinoma NOS in Carcinoma ex pleomorphic adenoma (CXPA). The presence of invasion is an important prognostic factor for SDC and adenocarcinoma NOS in CXPA.CXPA is a rare parotid gland malignant tumor for which therapy is not yet standardized. The purpose of this study was to review the characteristics of CXPA patients and to analyze their outcomes in the Northern Japan Head and Neck Cancer Society.The medical records of 33 patients who had been provided initial treatment in 12 institutes of northern Japan from 2002-2011 were reviewed as a multi-institutional retrospective study.The 3-year overall and progression-free survival rate of all patients was 79.9% and 76.8%, respectively. Both the 3-year overall and progression-free survival rates were 87.5% for patients with non-invasive SDC or adenocarcinoma NOS. The 3-year overall and progression-free survival rates for patients with invasive SDC or adenocarcinoma NOS were 60.4% and 30.5%, respectively. The progression-free survival rates for patients with invasive SDC or adenocarcinoma NOS was significantly poor (p 0.05).

We investigated the localization of periostin in middle ear specimens from patients with eosinophilic otitis media (EOM) and from a newly constructed animal model for EOM. Periostin-positive immunostaining was observed in the middle ear sections obtained from the EOM patients. Immunoreactivity for periostin was also seen in the animal model. These results suggest that periostin plays an important role in subepithelial fibrosis in the middle ear in EOM.The purpose of the present study was to investigate the role of periostin in the middle ear of EOM patients and an animal model.Histological and immunohistochemical analyses for periostin were carried out in the middle ear specimens of six EOM patients with/without asthma. An animal model of EOM was constructed by intraperitoneal and topical sensitization with ovalbumin (OVA). Histological and immunocytochemical analyses for periostin were also performed in this model.Immunoreactivities for periostin were observed in the basement membrane and extracellular matrix of the middle ear sections obtained from all EOM patients with/without asthma. In the animal model, eosinophil infiltration and middle ear mucosa thickness were observed. Moreover, periostin-positive immunostaining was shown in the extracellular matrix of the middle ear mucosa on the side topically boosted by OVA.

頭頸部癌の動注併用放射線療法における動注血管選択度の違いによる治療効果と，動注手技由来合併症を検討した。対象は動注化学療法を施行した頭頸部癌93症例，全247回の動注手技。病期はIV期が過半数。動注手技により超選択的動注群67例と非選択的動注群（金属コイルでの血流改変を併用）26例に分類。このうち根治照射を併用した粘膜扁平上皮癌初回治療例（56例）で一次治療効果を検討したところ，原発巣の治療効果は超選択的動注群42例中CR 27例（64.3%），PR 15例（35.7%），非選択的動注群14例中CR 10例（71.4%），PR 4例（28.6%）で，両群間に有意差はなかった。動注手技由来合併症は全93例で検討したが，超選択的動注群で67例中4例（6.0%），非選択的動注群で26例中1例（3.8%）に生じており両群間に有意差はなかった。放射線療法併用のもと，非選択的動注療法は超選択的動注法と同等に有効な動注法である。

労災認定において詐聴, とくに誇大難聴が存在することは広く知られているところである。今回我々は2006年1月から2009年12月までの4年間に当科を受診し騒音性難聴の労災認定を希望した14症例を対象として, 従来施行してきた検査に加えて聴性定常反応検査 (ASSR) を行った。詐聴の診断はASSR閾値と純音聴力閾値を比較し, 純音聴力閾値がASSR閾値よりも高い場合を詐聴とした。結果は14症例中7例 (50%) を詐聴と診断し, その7例いずれも難聴の存在自体は明らかであり誇大難聴と考えられた。詐聴と診断した7例中6例は, 従来行ってきた検査からも詐聴と診断可能であり, ASSR検査結果と一致した。これまで騒音性難聴の意見書作成の際に, 詐聴の判断に苦慮するケースを少なからず経験してきたが, ASSR検査を行うことによりこれまでよりも正確に詐聴の診断ができる可能性が考えられた。

Objective: Intratympanic (IT) steroid therapy has been proposed as an alternative treatment option for patients with idiopathic sudden sensorineural hearing loss (ISSNHL). However, the number and frequency of IT treatments and drug delivery methods remain to be determined. The purpose of this study was to evaluate the efficacy of daily short-term IT dexamethasone (DEX) treatment alone in ISSNHL patients using laser-assisted myringotomy (LAM) for the drug delivery route as an initial and/or salvage treatment. Study Design: Retrospective study. Setting: University hospital. Patients: Seventy-six ISSNHL patients receiving IT DEX. Patients with low-tone hearing loss, unilateral or bilateral fluctuating hearing loss or contralateral hearing loss were excluded. Intervention: DEX (4 mg/ml) was injected through a perforation made by LAM. IT DEX administration was performed on 8 sequential days. Main Outcome Measures: Pre- and postprocedure hearing levels. The average hearing level was determined by 5 frequencies (250, 500, 1000, 2000 and 4000 Hz). Results: Nineteen out of 76 patients fit the criteria for initial treatment in the study (group I), while 24 patients, who had failed systemic therapy, received salvage treatment (group S). The mean age of the patients in groups I and S was 56.2 years with a range from 31 to 73 years of age and 46.0 years with a range from 11 to 76 years of age, respectively. The mean number of days from onset of symptoms to IT therapy in groups I and S was 4.8 days with a range of 1–23 days and 15.3 days with a range of 6–28 days, respectively. In group I, 18 of the 19 patients (95%) showed improvement of more than 10 dB in the pure-tone audiogram, with a mean improvement of 40 dB. Twelve patients (63%) recovered completely and 16 patients (84%) demonstrated successful results with an improvement of more than 30 dB. In group S, 14 of the 24 patients (58%) showed improvement of more than 10 dB with a mean improvement of 16 dB. Two (8%) of the 7 patients (29%) with successful results recovered completely. Conclusions: Daily short-term IT DEX administration using LAM for ISSNHL patients without concurrent therapy showed a high response rate and high cure rate and proved to be an alternative therapeutic option to high-dose systemic steroids as a first- and/or second-line treatment.

Mutations in the connexin26 gene (GJB2) are the most common genetic cause of congenital bilateral non-syndromic sensorineural hearing loss. Transgenic mice were established carrying human Cx26 with the R75W mutation that was identified in a deaf family with autosomal dominant negative inheritance [Kudo T et al. (2003) Hum Mol Genet 12:995-1004]. A dominant-negative Gjb2 R75W transgenic mouse model shows incomplete development of the cochlear supporting cells, resulting in profound deafness from birth [Inoshita A et al. (2008) Neuroscience 156:1039-1047]. The Cx26 defect in the Gjb2 R75W transgenic mouse is restricted to the supporting cells; it is unclear why the auditory response is severely disturbed in spite of the presence of outer hair cells (OHCs). The present study was designed to evaluate developmental changes in the in vivo and in vitro function of the OHC, and the fine structure of the OHC and adjacent supporting cells in the R75W transgenic mouse. No detectable distortion product otoacoustic emissions were observed at any frequencies in R75W transgenic mice throughout development. A characteristic phenotype observed in these mice was the absence of the tunnel of Corti, Nuel's space, and spaces surrounding the OHC; the OHC were compressed and squeezed by the surrounding supporting cells. On the other hand, the OHC developed normally. Structural features of the lateral wall, such as the membrane-bound subsurface cisterna beneath the plasma membrane, were intact. Prestin, the voltage-dependent motor protein, was observed by immunohistochemistry in the OHC basolateral membranes of both transgenic and non-transgenic mice. No significant differences in electromotility of isolated OHCs during development was observed between transgenic and control mice. The present study indicates that normal development of the supporting cells is indispensable for proper cellular function of the OHC.

Office treatment for chronic tympanic membrane (TM) perforations has limitations, and alternative methods to myringoplasty are sometimes needed. Serum lacks antigenicity and contains a large variety of growth factors known to modulate proliferation of various tissues to promote wound healing effects. Our purpose was to evaluate the feasibility of autologous serum eardrops therapy with a chitin membrane for closing TM perforations.In the outpatient clinic, the perforation margin was cauterized with silver nitrate, and the perforation was covered with a chitin membrane. Patients were instructed to apply autologous serum eardrops daily. Patients were examined every 2 weeks, and the procedure was repeated.We treated 19 sequential patients with chronic TM perforation in 1 ear between October 2005 and September 2007. Closure of the TM was achieved in 11 (58%) of 19 ears, and reduction of the perforation size was observed in 2 ears (11%). Closure rates for small, medium, and large perforations were 57 (8 of 14), 0 (0 of 1), and 75% (3 of 4), respectively. Closure rates for perforations attributable to intratympanic dexamethasone treatment, after myringoplasty and chronic otitis media were 67 (2 of 3), 67 (2 of 3), and 54% (7 of 13), respectively. Time for closure took from 15 to 175 days, with an average of 68 days (5.9 clinic visits). During autologous serum eardrop therapy with a chitin membrane, no remarkable side effects in the treated ears were observed. Measurement of the concentration of the epidermal growth factor, transforming growth factor beta1, fibronectin, and interleukin 6 in the serum showed no decrease in 14 days, suggesting activity remained stable in that period.Autologous serum eardrops therapy with a chitin membrane, which requires no surgical intervention, was found to be a promising office-based technique for the closure of chronic TM perforations because of its ease, safeness, and feasibility. However, additional studies are needed to independently analyze the specific benefits of the serum drops and the chitin membrane.

今回我々は, 多人数の町民を対象とした岩木健康増進プロジェクトの一環として, 20歳以上の弘前市の旧岩木町民のうち956名に対して, 聴覚検診とアンケート調査を行い, 年代別聴力像と種々の検査項目との関連について検討した。年代別平均聴力閾値は年代順に上昇しており, 特に高音域でその上昇幅が増大していた。また, 男女別聴力像では, 1,000Hzにおいては男女間に有意差を認めなかったが, 4,000Hzにおいては50歳代以降の男性が女性に比べて有意に閾値が上昇していた。男性の騒音暴露の機会が多いことが誘因と考えられ, 農業従事者が多いという調査地域の特性がその一因ではないかと考えた。さらに, 耳鳴, 耳閉感, 難聴については, それぞれ32.2%, 15.9%, 36.9%の人が自覚していた。難聴を自覚する人は70歳代以降で多くみられたが, 耳鳴を訴える人は80歳代で減少した。

新生児聴覚スクリーニング (以下スクリーニング) は全国的に実施率が増加傾向にある。今回我々は青森県内産科施設に対し, アンケート調査を行い, スクリーニング状況を調査した。結果, 産科施設の6割が検査機器を保有しており, 県内でも地域差が認められた。さらにH16年, 17年の県内スクリーニング施行症例数の概算と, 同年の県の出生数から求めるスクリーニング実施率は約25%であり, 全国の報告からしても低いという結果であった。機器を持たない施設では経済的, 人手不足の問題から, 今後も導入予定がないという回答であり, 青森県での実施率向上には, 機器保有施設での全例施行, または機器のない施設での出生児を機器保有施設で検査するなどの対策を検討するべきではないかと思われた。今後は検査実施率の向上に向け, 産婦人科, 小児科と更なる協力体制をと考えている。

Patients with vertigo caused by psychological problems have increased in recent years. It has been reported that many outpatients with vertigo also suffer from depression. Selective serotonin reuptake inhibitors are widely used for the treatment of depression because of their efficacy and relatively favorable side-effects profile compared to those of tricyclic antidepressants. We used Paroxetine to treat patients with vertigo who were diagnosed with depression by self-rating questionnaires for depression (SRQ-D). Twenty-six patients experienced relief after taking Paroxetine. Fifteen of them were relieved of their vertigo symptoms, 8 were improved, one was not changed, and two were worse. SRQ-D scores were compared between the day of commencement and the day after 4 weeks. Fifteen patients were normalized. Side effects occurred in seven patients; nausea in five and sleepiness in two. The average duration of taking the medicine was 24.4 weeks. Since Paroxetine showed beneficial clinical effects for patients with vertigo, this medicine might be useful for vertiginous patients with depression.

A 12-year-old male experienced left-sided hearing impairment, tinnitus, and vertigo after being hit by a volleyball. Pure tone audiometry showed severe, mixed left hearing loss and nystagmus to the right side. We diagnosed perilymphatic fistula and treated it conservatively. After ten days, his vertigo had disappeared and hearing on his left side showed improvement except at 2,000 and 8,000 Hz. However, he experienced slight dizziness after discharge from our hospital. About eleven months later, because of severe vertigo, he again came to our hospital. We diagnosed benign paroxysmal positional vertigo (BPPV) based on his symptoms and the characteristic nystagmus. We performed the Epley maneuver, and his vertigo and nystagmus disappeared the next day. Exploratory tympanotomy was carried out, but no sign of a perilymphatic fistula was detected. He experienced BPPV again, and so we tried the Epley and Lempert maneuver. We believed his prolonged dizziness was due to a partial collapse of the utricular wall, a condition called floating labyrinth. This phenomenon may occur with migration of otoliths from the utricle, leading to BPPV.

The development of motor protein activity in the lateral membrane of the mouse outer hair cell (OHC) from postnatal day 5 (P5) to P18 was investigated under whole-cell voltage clamp. Voltage-dependent, nonlinear capacitance (C (v)), which represents the conformational fluctuations of the motor molecule, progressively increased during development. At P12, the onset of hearing in the mouse, C (v) was about 70% of the mature level. C (v) saturated at P18 when hearing shows full maturation. On the other hand, C (lin), which represents the membrane area of the OHC, showed a relatively small increase with development, reaching steady state at P10. This early maturation of linear capacitance is further supported by morphological estimates of surface area during development. These results, in light of recent prestin knockout experiments and our results with quantitative polymerase chain reaction, suggest that, rather than the incorporation of new motors into the lateral membrane after P10, molecular motors mature to augment nonlinear capacitance. Thus, current estimates of motor protein density based on charge movement may be exaggerated. A corresponding indicator of motor maturation, the motor's operating voltage midpoint, V (pkcm), tended to shift to depolarized potentials during postnatal development, although it was unstable prior to P10. However, after P14, V (pkcm) reached a steady-state level near -67 mV, suggesting that intrinsic membrane tension or intracellular chloride, each of which can modulate V (pkcm), may mature at P14. These developmental data significantly alter our understanding of the cellular mechanisms that control cochlear amplification and provide a foundation for future analysis of genetic modifications of mouse auditory development.

Malignant neoplasms of the salivary gland are uncommon entities in which surgical resection of the primary lesion has been accepted as a standard therapeutic option. The efficacy of radiation and systemic chemotherapy has been limited for patients with recurrent, metastatic, or unresectable disease because of unfavorable response rates and the short duration of the response. We treated one patient with recurrent adenoid cystic carcinoma arising from the sublingual gland and one patient with primary adenocarcinoma arising from the parotid gland with transfemoral intraarterial chemotherapy, based on full-dose cisplatin and docetaxel and concurrent external-beam radiotherapy. The doses of cisplatin and docetaxel in the two patients were 80-100 mg/m2 and 10-15 mg/m2, respectively. Docetaxel was infused first, followed by cisplatin. Both patients obtained complete responses. Although complications such as mucositis, anorexia, neutropenia, and ischemic colitis were observed, they were well tolerated and manageable. The concomitant chemoradiotherapy of cisplatin and docetaxel seemed to be a practicable option for patients with recurrent and unresectable salivary gland carcinomas.

The purpose of this study was to evaluate the efficacy of intratympanic administration of dexamethasone (IT-DEX) treatment on sudden sensorineural hearing loss (SSNHL) patients with diabetes by comparing the results with intravenous administration of dexamethasone (IV-DEX) treatment.Comparative study.University hospital and affiliated hospital.Ten sequential SSNHL patients with diabetes receiving IT-DEX and 21 sequential SSNHL patients with diabetes receiving IV-DEX. Patients with low tone hearing loss were excluded.In the IT-DEX group, two methods were applied to deliver DEX (4 mg/ml): injection through a perforation made by laser-assisted myringotomy or through a tympanostomy tube. IT-DEX administration was performed on 8 sequential days. In the IV-DEX group, DEX was administrated intravenously starting from an amount of 8 mg/d followed by taped doses for 10 days.Preprocedure and postprocedure hearing levels and complications.In the IT-DEX group, the average hearing level before the treatment was 79 dB. Overall, all 10 patients showed improvement of more than 10 dB in the pure-tone audiogram, with a mean improvement of 41 dB. Seven patients (70%) demonstrated successful results, and four recovered completely. In the IV-DEX group, 14 (67%) of the 21 patients showed improvement of more than 10 dB with a mean improvement of 25 dB. Thirteen patients (62%) demonstrated successful results. Free blood sugar during and after the IT-DEX treatment remained below the pretreatment levels, whereas four patients in the IV-DEX group demonstrated worsening of the hyperglycemia.IT-DEX treatment is at least as effective as IV-DEX treatment for SSNHL patients with diabetes.

Although dopaminergic neurons are thought to exist in the lateral olivocochlear efferent system and modulate the afferent nerve activity, the distribution of dopamine (DA) receptor subtypes is still obscure. In the present study, we investigated the localization of five subtypes of DA receptor (D1-5) by immunocytochemical analysis and the gene expression of D1-5 using RT-PCR procedure in the rat cochlea. Most, but not all, spiral ganglion neurons were immunolabeled with all the anti-DA receptor subunit antibodies and faint punctuate immunoreactivities were observed in inner hair cell regions. Gene expression for all receptors was detected. These results suggest that all DA receptor subtypes are present in spiral ganglion cells, and potentially regulate afferent neurotransmission.

When we treat patients with pollen allergy, we require correct information about pollen release. The total count of pollen and the date of first pollen release are strongly influenced by local weather conditions, so we wanted to predict local pollen release. Patients have degrees of sensitivity to pollen, with symptoms triggered in some cases by only small amounts. Therefore, we wanted to determine the previous dates of first pollen release (A), the first of two consecutive dates when one (count/cm2) or more grains were released (B), and the first of two consecutive dates when ten (count/cm2) or more grains were released (C). Aomori Prefecture has three different weather zones because it is surrounded by three oceans the Sea of Japan, the Pacific Ocean, and Mutsu Bay. We predicted pollen release in the major cities--Aomori, Hirosaki, and Hachinohe. Using nine years (1996-2004) of temperature data for each city from January 1 through February 1, we recorded the number of days in which the daily highest temperature was higher than each of five set temperatures (0 degree C, 1 degree C, 2 degrees C, 3 degrees C, 4 degrees C) up to the dates of A, B, and C. Multiple recordings were made for each year with the initial date of recording staggered at 10-day intervals. We then calculated the standard deviation and the efficient of variation of total days and totals of temperatures over set temperatures. For Aomori, results indicated that A was predicted as day 19 with temperatures over 4 degrees C after January 21. B was day 23 over 4 degrees C after January 21. C was the day 31 with over 4 degrees C after January 21. For Hirosaki, A was expected to be day 26 having temperatures over 0 degrees C after February 1. B was day 21 over 3 degrees C after February 1. C was day 30 over 3 degrees C after January 21. For Hachinohe, A was day 34 with temperatures over 0 degrees C after February 1. B was day 33 over 1 degree C after January 21. C was day 27 over 4 degrees C after January 21. We examined the day of pollen release in 2005.

Inflammatory pseudotumours in the maxillary sinus may present as malignant tumours and manifest locally aggressive features characteristic of such tumours. Despite their locally destructive features, they pursue a benign course after local excision.Inflammatory pseudotumour (plasma cell granuloma) is an uncommon non-neoplastic lesion comprising a proliferation of spindle myofibroblasts and chronic inflammatory cells. Despite its benign histopathological nature, it may exhibit aggressive behaviour that is yet to be characterized in the head and neck area.We present the cases of two adult patients with inflammatory pseudotumour arising from the maxillary sinus. Immunohistochemistry and polymerase chain reaction for immunoglobulin from tissue sections were performed to confirm the polyclonality of the infiltrating plasma cells.CT and MRI disclosed expansive soft masses eroding surrounding soft and bony tissues. Histopathologically, the lesions were unencapsulated and composed of numerous plasma cells, histiocytes and spindle cells with minimal nuclear pleomorphism.

Objectives/Hypothesis: In conductive hearing loss (HL), even though preoperative examinations including audiometry, tympanometry, and computed tomography (CT) scan are applied, exploratory tympanotomy is necessary to make an exact diagnosis of ossicular interruption and stapes fixation. Precise preoperative diagnosis would be useful for patient counseling, surgical indications, and planning. The advantages of office-based OtoScan laser-assisted myringotomy (LAM), which makes a circular and non-hemorrhagic perforation, prompted us to investigate other uses of LAM in addition to ventilation and drainage of the tympanic cavity. To make presurgical diagnosis in conductive HL, endoscopes with an outer diameter of 1.7 or 1.9 mm were used to inspect the middle ear pathology through perforations with a diameter of 2 mm made by LAM. Methods: In the outpatient clinic, a circular perforation with a diameter of 2 mm was made in the tympanic membrane with LAM. An endoscopic view of the ossicular chain through a 70° angled tip endoscope held immediately to the outer side of the perforation was obtained to diagnose conduction disturbance loci in conductive HL cases. Results: Ossicular chain abnormalities were easily and safely detected by clean endoscopic views obtained through a nonhemorrhagic circular perforation. When necessary, insertion of the tip of the endoscope into the tympanic cavity provided additional views of epitympanum. Conclusion: We suggest that transtympanic endoscopy through the perforation made by LAM is an effective and safe office-based procedure for diagnosis in conductive HL cases and could be an alternative procedure to replace exploratory tympanotomy.

We surveyed the prevalence of obesity in the general population in Jamaica, and examined the relationship between it and lifestyle. The survey population consisted of 1935 inhabitants, whose body weight, marital status, educational history, and other obesity-associated lifestyle factors were surveyed. Six major findings emerged. The first finding is that the proportion of obesity in women was very high, and there was a big gender difference. Secondly, a lower prevalence towards obesity was associated with cohabitation of the subjects in both genders, and higher educational levels in female subjects. Thirdly, the proportion of the subjects who considered their weight to be quite acceptable was higher in the obese/overweight groups in both genders, although they felt physically unfit. Fourthly, exercise frequency showed a negative correlation with the body mass index (BMI) in men but not in women, and the frequency of exercising was apparently lower in women than in men. Fifthly, as for dietary factors, in both genders, vegetables showed a negative correlation with the BMI. Finally, non-smokers were also associated with a lower obesity prevalence in men. These findings suggest that social and lifestyle factors such as the educational level, marital status and dietary habits of the general population influence Jamaican obesity.

頭頸部癌の再発, 転移症例に対する治療は, 一次治療がすでに行われており, その治療法は限定せざるを得ない。そこで我々は Tumor Dormancy Therapy の観点から, 2000年6月より Docetaxel (TXT) Weekly 投与を用いた外来化学療法を行っており, 今回その有効性と安全性について検討した。当科で治療を行った頭頸部癌再発・転移症例36例を対象としてTXT20または30mg/bodyを3週連続投与後に1週休薬といった方法を繰り返し行った。投与回数は3回から72回, 最大総投与量は2160mgに達した。治療効果はCR4例, PR4例, NC17例, PD11例であり奏効率は22.2%, NC以上の効果が69.4%に認められ, 非常に有効な治療法であると考えられた。また Grade3 以上の副作用として, 肝機能障害が1例にのみ認められ, 安全性が高く十分に外来で施行可能な治療法であると考えられた。

In conductive hearing loss with an intact ear drum, even though preoperative examinations including audiometry, tympanometry and CT scan are applied, exploratory tympanotomy is necessary to make an exact diagnosis of ossicular interruption and stapes fixation. In the exploratory tympanotomy, if an ossicular problem is detected during the procedure, it is usually followed by ossicular reconstruction surgery.Our current strategy for treatment of conductive hearing loss without tympanic membrane perforation is presented.The presurgical diagnosis is made in the outpatient clinic by transtympanic endoscopy through the circular and non-hemorrhagic perforation made by laser-assisted myringotomy (LAM). An endoscopic view of the ossicular chain through 30- or 70-degree angled tip endoscopes held immediately to the outer side of the perforation was obtained to diagnose conduction disturbance locus in conductive hearing loss cases. Precise preoperative diagnosis is useful for patient counseling, surgical indications and planning.When an ossicular interruption is diagnosed, endoscopic transtympanic tympanoplasty (ETT), a newly developed minimally invasive procedure, is planned. In the endoscopic visualization through the dry, circular myringotomy perforation using a 1.9mm diameter rigid angled endoscope, ossiculoplasty was performed by inserting a trimmed tragal cartilage through the myringotomy perforation. As opposed to conventional methods, this procedure does not require surgical exposure such as otosclerosis drilling and skin incision, and avoids the substantial risk of unnecessary injury to the chorda tympani. ETT for a disrupted ossicular chain is an adequate and minimally invasive procedure and should prove a useful surgical procedure in future endoscopic tympanoplasty.

Although apoptotic changes in auditory neurons induced by injury to peripheral processes (dendrites) have been intensively studied, apoptotic changes in auditory neurons induced by injury to central processes (axons of spiral ganglion cells, SGCs) have not been reported previously, probably due to lack of an experimental model. The present study reports for the first time the appearance, extent, and time course of SGC apoptosis following injury to the central processes. Apoptosis was studied in a rat model that consisted of compression of the auditory nerve in the cerebellopontine (CP) angle cistern with intraoperative recordings of auditory nerve compound action potentials (CAPs) to ensure highly reproducible results. Rats were killed between day 0 and day 14 after compression and apoptosis of SGCs was evaluated quantitatively as well as qualitatively by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining, anti-activated caspase-3 immunostaining, Hoechst 33342 staining, and electron microscopy. The average number of TUNEL-positive apoptotic SGCs in each cochlear turn increased from day 1 to day 5 and then decreased gradually to an undetectable level on day 14 after compression. The average proportion of apoptotic SGCs identified in any cochlear turn on any day was always lower than 10%. The results of our present study should be useful in determining the therapeutic time window for rescuing auditory neurons undergoing apoptosis due to injury during surgery in the CP angle.

Reduced expression of the p16 gene product (protein), an inhibitor of cyclin-D-dependent protein kinase which regulates cell cycle at the G1/S boundary, is implicated in tumor progression in various neoplasms. Hypermethylation of the p16 promoter gene has recently been suggested to be one of the reasons for the reduced protein expression. To explore the role of p16 in the biological behavior of adenoid cystic carcinomas (ACC), we investigated the immunohistochemical expression of p16 protein in 38 ACC tumors (32 primary, 3 recurrent, and 3 metastatic tumors) and the methylation status of its promoter gene. We also examined their relationships to the histological grade of malignancy. Positive reaction of p16 protein was demonstrated in the nuclei of luminar cuboidal cells in areas with tubular patterns. The reactions were reduced in the areas with solid or large cribriform patterns. The levels of p16 expression correlated with the histological grade of malignancy. Recurrent or metastatic tumors did not differ with respect to histological grades from the original tumor except for 1 case, in which p16 expression was reduced compared to the primary tumor. Methylation-specific PCR demonstrated the hypermethylation status of the p16 promoter gene in 4 of 22 primary tumors (21%), all of which showed negative or low expression of the p16 protein. The study indicated that p16 expression was reduced in ACC cases of higher histological grade of malignancy and that hypermethylation of its promoter gene may be involved in its process in some cases.

Japanese cedar is the most common pollinosis allergen in Japan. Predictions of total pollen counts and the first 2 or more days of the Japanese cedar pollen season are beneficial to patients. We developed predictive methods for those 2 factors in Hirosaki. We conducted an atmospheric Japanese cedar pollen survey from 1996 to 2002 in Hirosaki and compared yearly data with the male flowering index counted in 50 cedar trees in the preceding autumn. The male flowering index correlated highly positively with total cedar pollen counts in regression analysis, indicating its usefulness in predicting total pollen counts. Although the number of days from January 1 to the first day of continuous pollen emission showed no correlation with the cumulative maximum temperature during these days, the number of days from the day of first detection of pollen emission (minimum of 1 particle per sq. cm) to the first day of continuous pollen emission correlated highly with the cumulative maximum temperature and cumulative amount of snowfall on these days, suggesting that it is possible to predict the first day of continuous pollen emission by the cumulated daily maximum temperature after the day of first detection of pollen emission.

Gamma-aminobutyric acid (GABA) is thought to be the major inhibitory neurotransmitter in the central nervous system. Although it is distributed in the olivo-cochlear bundles, which constitute the mammalian cochlear efferent system, its function in the cochlea is still obscure. In this study, we investigated the localization of GABAa receptor subunits (alpha1-6, beta1-3, gamma) in the rat cochlea in order to determine the role of GABA in the cochlea. Most spiral ganglion cells were intensely immunolabeled with all the anti-GABAa receptor subunit antibodies. In the organ of Corti, punctate immunoreactivities were observed in inner hair cell regions corresponding to the distribution of GABA. These data suggest that GABAa receptor was present in afferent nerve terminals in inner hair cell regions, and that GABA regulated afferent nerve transmission contacting efferent nerve endings by means of the axo-dendritic synapse function.

It has been reported that the sensitization to house dust-mites (HD-mites) is one factor which affects the onset of Japanese cedar (JC) pollinosis. So, we investigated whether sensitization to HD-mites affected the incidence and age of onset of JC pollinosis in 126 outpatients and 351 medical students.Allergic subjects who visited allergy clinics in Hirosaki University Hospital were classified into two groups based on the CAP results for JC and HD-mites; one was JC-positive and HD-mite-negative, and the other was JC-positive and HD-mite-positive. The former showed a higher age at onset of JC pollinosis than the latter. With regard to the CAP score for JC, there were no significant differences. This result seems to suggest that sensitization to HD-mites affects the onset of JC pollinosis.The medical students were also divided in the same manner. The incidence of JC pollinosis in the JC-positive and HD-mite-negative group was significantly higher than that in the JC-positive and HD-mite-positive group. Regarding orchard grass (OG) pollinosis, the incidence in the HD-mite-negative group was significantly higher than that in the HD-mite-positive group. Since pollinosis is related to the degree of exposure to the dominant pollen antigen, the students were divided by their native area (Kanto area, JC dominant; Tohoku/Hokkaido area, OG dominant). The incidence of JC pollinosis was highest in JC-positive and HD-mite-negative students from the Kanto area, and that of OG pollinosis was highest in OG-positive and HD-mite-negative students from the Tohoku/Hokkaido area. These results suggested that exposure to the dominant pollen antigen is most important to onset of pollinosis, although sensitization to HD-mites affects the onset of JC pollinosis.

We report a case of unilateral idiopathic stenosis of the internal auditory canal, without middle or inner ear anomalies. The patient, a 17-year-old female, presented with right deafness. High resolution computed tomography of the temporal bone showed stenosis of the right internal auditory canal. ABR stimulated from the right ear showed no response and bilateral DPOAE levels were within normal limits. These results implied that the outer hair cell function was well preserved, although damage to the inner hair cells and/or cochlea nerve was severe. It seems that evaluation by both ABR and OAE is necessary to determine the cause of hearing loss due to idiopathic stenosis of the internal auditory canal.

We report a case of otogenic intracranial complication. The patient was a 34-year-old female who complained of left otalgia and headache. She was hospitalized because of deterioration of her level of consciousness and high fever. On examination, her cerebrospinal fluid showed an elevated cell count. A bacterial culture of the otorrhea and cerebrospinal fluid found Streptococcus pneumoniae. A CT scan showed left acute otitis media and mastoiditis with paranasal sinusitis of the same side. This patient was successfully treated with intravenous antibiotic therapy without surgery. After she recovered, a CT scan with coronal sections showed bony defects and a thin bony wall in the left tympanic and mastoidal tegmina. This suggested that in this case the bacterial meningitis was secondary to acute otitis media and mastoiditis.When headache and high fever persist in patients with otitis media, we should suspect intracranial complications.

The excessive glutamate released from the type I and type II hair cells and the supporting cells injure the bouton-type endings and the nerve chalices in 30 min ischemia, and neuronal damage of glutamate was slight in 10 min ischemia.In the present study, we investigated by means of post-embedding immunoelectron microscopic analysis whether neuronal damage in the vestibular end organs is associated with the change of cellular glutamate concentration during ischemia.Transient local anoxia (10 min, 30 min) of guinea pig inner ear was induced by pressing the left labyrinthine artery. The right sides were used as controls. The morphological changes of the vestibular end organs and the areal gold particle densities representing glutamate were compared in the ischemia side and the control side.The areal gold particle densities of the type I and type II hair cells and the supporting cells in the ischemic side were lower than those of the control side. There were no remarkable morphological changes compared to the control side in 10 min ischemia. In 30 min ischemia, the bouton-type endings were swollen and intercellular spaces between the type I hair cells and the nerve chalices were enlarged.

Mutation analysis of the PDS gene and the EYA1 gene, which are reported to be responsible for hearing loss associated with ear anomalies, was performed in 24 deaf patients with various middle and inner ear anomalies. The present study was done to clarify the spectrum of middle and inner ear malformations covered by these two genes. PDS mutations were found only in patients with enlarged vestibular aqueducts and EYA1 mutations were detected only in patients with ear pits and cervical fistulae, indicating that these two genes are associated with particular forms of middle and inner ear malformation. The genetic approach provides a strong tool for the diagnosis of hearing loss associated with ear anomalies.

The localization of three glutathione S-transferase (GST) isoforms in the rat cochlea was examined using specific antibodies against each isoform. GST immunoreactivities were found in particular parts of the cochlea, including the intermediate cells and the basal cells of the stria vascularis and various types of fibrocytes in the spiral ligament. The different cell types showed varying combinations of GST isoforms. The GST immunopositive cells identified in the present study may play a central role in the metabolism and inactivation of endogenous and exogenous ototoxic compounds. The specific arrangements also indicated a possible contribution to the detoxification process in the form of a blood-labyrinth barrier.

We treated a patient suffering from a huge lipoma of the neck, which extended into the parapharyngeal space. CT scans and MRI were useful for the diagnosis and we extirpated the lipoma by incising the parotid gland. CT scans, MRI and operative findings showed that this was a case of a very rare lipoma originating in the deep lobe of the parotid gland.

Recent genetic studies have shown that hereditary susceptibility to aminoglycoside antibiotics is caused by the 1555 A→G mitochondrial mutation. We found the 1555 mutation in 4 out of 68 postlingual deaf patients who were candidates for cochlear implantation. All 4 patients developed bilateral profound hearing loss following administration of aminoglycosides. The pedigree of the family shows exclusively maternal transmission of hearing impairment in each case. On comparison with neuro-otological findings from aminoglycoside-induced deaf patients without the 1555 mutation, four distinct characteristics were noted: (1) a progressive nature of hearing loss; (2) better residual pure-tone thresholds; (3) lower thresholds for electrical promontory stimulation, and (4) well-preserved vestibular function. Although other factors such as differing dosages and/or administration routes may also be involved, profound hearing loss associated with the 1555 mutation may be due to a different pathogenic mechanism, i.e., strial dysfunction rather than a direct insult to the hair cells.

Advances in molecular genetics have recently revealed that mutations in the EYA1 gene are responsible for branchio-oto-renal (BOR) syndrome in European and other populations. This is the first report confirming that an EYA1 gene mutation is also disease-causing in an Asian population. We have described one Japanese BOR syndrome family showing a novel mutation in exon 7 of the EYA1 gene. There was extensive variation of clinical phenotypes within this family. When the physician is confronted with a BOR family showing a wide variation in clinical expression, molecular genetic testing helps to achieve accurate diagnosis.

The most common form of inner ear abnormality, enlarged vestibular aqueduct (EVA), is of particular interest because it is associated with characteristic clinical findings, including fluctuating and sometimes progressive sensorineural hearing loss and disequilibrium symptoms. Although EVA has been reported to be inherited in a recessive manner, nothing else is known about the genetic basis of this hearing loss. Here we report on the localization of the gene responsible for sensorineural hearing loss associated with EVA to chromosomal region 7q31, with maximum multipoint LOD score of 3.647. The EVA candidate gene region lies in a 1.7-cM interval between the flanking markers D7S501 and D7S2425. Interestingly, this region overlaps the region containing the gene responsible for Pendred syndrome, called PDS, which was identified recently. However, the present subjects did not fulfill the criteria for Pendred syndrome. It is hypothesized that different mutations within the PDS gene may cause different phenotypes ranging from EVA to the Mondini deformity seen in Pendred syndrome.

To characterize the synapses between hair cells and afferent nerve endings in the rat vestibular end organs, the ultrastructural localization of AMPA receptor subunits (GluR1–4) was examined by postembedding immunogold cytochemistry. Immunoreactivities for GluR2/3 and GluR4 were associated with the synapses between type I hair cells and the surrounding chaliceal nerve endings and with the bouton type nerve endings contacting type II hair cells. There was no detectable immunoreactivity for GluR1. A third type of immunoreactive synapse was found between the outer face of chalices and type II hair cells. While the linear densities of gold particles (particles per micrometer postsynaptic specialization) of bouton type endings and chaliceal nerve endings were the same, the former type of ending showed larger postsynaptic specializations and, hence, a higher number of receptor molecules. These data indicate that there are three types of putative glutamatergic synapse in the vestibular end organ.

Aquaporins (AQPs) confer a high water permeability on cell membranes and play important parts in secretory and absorptive epithelia in kidney and other organs. Here we investigate whether AQPs are expressed in the sensory epithelia of the inner ear, where a precise volume regulation is crucial. By use of specific antibodies it was found that the inner ear contains AQP1 and 4 while being devoid of detectable levels of AQP2, 3 or 5. Immunofluorescence and postembedding immunogold labelling revealed a strictly non-epithelial distribution of AQP1, confirming previous data. In contrast, AQP4 protein and mRNA (visualized by in situ hybridization) were concentrated in select types of supporting cell, including Hensen's cells and inner sulcus cells. Immunogold particles signalling AQP4 were confined to the basolateral plasma membrane of Hensen's cells and to the basal plasma membrane of Claudius cells and inner sulcus cells. AQP4 was also found in supporting cells of the vestibular end organs, but was absent from transitional epithelial cells and dark cells. Strong labelling for AQP4 and AQP4-mRNA was associated with the central part of the cochlear and vestibular nerves. Hair cells were consistently unlabelled. Our findings indicate that AQP4 may facilitate osmotically driven water fluxes in the sensory epithelia of the inner ear and thus contribute to the volume and ion homeostasis at these sites.

Mutations in mitochondrial DNA, which are maternally inherited, have been thought to be one of the causes of sensorineural hearing loss. Two mitochondrial mutational sites (A1555G, A7445G) have been reported to be responsible for non-syndromic hearing impairments. The A1555G mutation causes increased susceptibility to aminoglycoside antibiotic-induced hearing loss as well as non-syndromic sensorineural hearing loss. Our wide screening study showed that there may be a great number of subjects within the Japanese population who have the A1555G mutation. Recent reports suggest that high-risk populations may exist throughout the world. The aminoglycoside-induced hearing loss associated with a mitochondrial mutation is commonly bilateral, symmetric, high frequency involved, and is sometimes associated with progressive sensorineural hearing loss.

Mitochondrial mutations are known to be one of the causes of non-syndromic sensorineural hearing loss (SNHL). Of these mutations, a 1555A→G mutation has been reported to cause susceptibility to aminoglycoside antibiotics. The pedigrees shown in this study revealed maternal inheritance exclusively of the hearing impairment, consistent with the hypothesis of a mitochondrial inheritance. Although the hearing loss found in these patients sharing the 1555 mutation exhibited individual variation, there were some common features. Many subjects who harbor this mitochondrial mutation exhibited mild, high frequency, progressive hearing loss even without aminoglycoside injections. Regardless of aminoglycoside exposure, the hearing loss was usually associated with permanent tinnitus. Most of our patients had no history of vestibular dysfunction, such as dizziness and/or vertigo. The results presented here support the hypothesis that the A1555G mutation may play a more general role in causing hearing loss. This indicates the necessity for widespread screening of this mutation in the general population.

Glial cells play an important role in the removal and metabolism of synaptically released glutamate in the central nervous system (CNS). It is not clear how glutamate is handled at peripheral glutamate synapses, which are not associated with glia. Glutamate is a likely transmitter in the synapse between the hair cells and afferent dendrites of the vestibular end organ. Immunocytochemistry was performed to investigate the distribution at this site of the high affinity glutamate transporter GLAST and glutamate metabolizing enzyme glutamine synthetase. Confocal microscopy revealed that GLAST and glutamine synthetase were co-localized in supporting cells apposed to the immunonegative hair cells. Postembedding immunoelectron microscopy revealed that GLAST was heterogeneously distributed along the plasma membranes of the supporting cells, with higher concentrations basally (at the level of the afferent synapses) than apically. Both immunoreactivities were also present in non-neuronal cells in the vestibular ganglion. The present findings suggest that glutamate released at the afferent synapse of vestibular hair cells may be taken up by adjacent supporting cells and converted into glutamine. Thus, at this peripheral synapse, the supporting cells may carry out functions similar to those of glial cells in the CNS.

The expression of glutathione S-transferase (GST)-pi and four oncogene products, c-Jun, c-Fos, c-H-Ras, and c-Myc, in human squamous cell carcinomas of the head and neck was investigated immunohistochemically before and after radiation therapy, to examine whether these oncogene products might be involved in GST-pi expression, and also to examine the relationship between their expression and therapeutic response. Clinical response to radiation was evaluated in terms of both tumor regression and relapse over two-year follow-up periods. The overall positive rates in 83 carcinoma specimens before therapy were 60.2% for GST-pi and 28.9-51.8% for the individual oncogene products, the positive rates for the oncogene products being higher in GST-pi-positive than in GST-pi-negative cancers. c-Jun was most highly correlated with GST-pi expression. Following radiation, the expression of GST-pi and the oncogene products was altered in about a half of 30 patients. Eleven of the 18 patients who exhibited prior positivity for GST-pi showed negative conversion, while 4 of the 12 patients with prior negativity demonstrated positive conversion. In most cases, changes in c-Jun staining coincided with those in GST-pi. Regarding clinical response to radiation therapy, the positive rates for GST-pi and c-Jun before radiation were higher in the residual cancer or relapse cases than in the group showing complete response without relapse. Examination of 26 patients with laryngeal cancer revealed that relapse occurred more frequently in cases exhibiting positive reactions for GST-pi, c-Jun, or c-H-Ras. These results suggest a direct link between c-Jun and GST-pi in head and neck cancers before and after radiation. Although GST-pi and the oncogene products can be influenced by radiation, GST-pi and c-H-Ras expression may be a risk factor for relapse of laryngeal cancer.