Published papers

Background: Transoral videolaryngoscopic surgery (TOVS) was developed as a new distinct surgical procedure for hypopharyngeal cancer (HPC) and supraglottic cancer (SGC) staged at up to T3. However, long-term treatment outcomes of TOVS remain to be validated. Methods: Under a straight broad intraluminal view provided by combined use of a distending laryngoscope and a videolaryngoscope, we performed en bloc tumor resection via direct bimanual handling of the ready-made straight-form surgical instruments and devices. We retrospectively analyzed functional and oncologic outcomes of 72 patients with HPC (n = 58) or SGC (n = 14) whose minimum follow-up was 24 months or until death. Results: The cohort comprised nine patients of Tis, 23 of T1, 33 of T2, and 7 of T3. Among 36 patients (50%) who underwent neck dissection simultaneously, all but one were pathologically node-positive. Twelve patients underwent postoperative concurrent chemoradiation (CCRT) as adjuvant treatment, and another four patients underwent radiation or CCRT for second or later primary cancer. The endotracheal tube was removed in an operation room in all but two patients who underwent temporary tracheostomy. Pharyngeal fistula was formed transiently in two patients. The median time until patients resumed oral intake and could take a soft meal was 2 and 5 days, respectively. Eventually, 69 patients (96%) took normal meals. The 5-year cause-specific survival (CSS), overall survival (OS), larynx-preserved CSS, and loco-regional controlled CSS were 87.3%, 77.9%, 86.0%, and 88.0%, respectively. Multivariate analysis revealed N2-3 as an independent prognostic factor in both CSS (hazard ratio [HR] = 25.51, P = 0.008) and OS (HR = 4.90, P = 0.022), which indirectly reflected higher risk of delayed distant metastasis. Conclusions: Considering its sound functional and oncological outcomes with various practical advantages, TOVS can be a dependable, less invasive, and cost-effective surgical option of an organ-function preservation strategy for HPC and SGC.

Cochlear spiral ligament fibrocytes (SLFs) play essential roles in the physiology of hearing including ion recycling and the generation of endocochlear potential. In adult animals, SLFs can repopulate after damages, yet little is known about the characteristics of proliferating cells that support SLFs’ self-renewal. Here we report in detail about the characteristics of cycling cells in the spiral ligament (SL). Fifteen P6 mice and six noise-exposed P28 mice were injected with 5-bromo-2′-deoxyuridine (BrdU) for 7 days and we chased BrdU retaining cells for as long as 60 days. Immunohistochemistry revealed that the BrdU positive IB4 (an endotherial marker) negative cells expressed an early SLF marker Pou3f4 but negative for cleaved-Caspase 3. Marker studies revealed that type 3 SLFs displayed significantly higher percentage of BrdU+ cells compared to other subtypes. Notably, the cells retained BrdU until P72, demonstrating they were dividing slowly. In the noise-damaged mice, in contrast to the loss of the other types, the number of type 3 SLFs did not altered and the BrdU incorporating- phosphorylated Histone H3 positive type 3 cells were increased from day 1 to 14 after noise exposure. Furthermore, the cells repopulating type 1 area, where the cells diminished profoundly after damage, were positive for the type 3 SLF markers. Collectively, in the latral wall of the cochlea, type 3 SLFs have the stem cell capacity and may contribute to the endogenous regeneration of lateral wall spiral ligament. Manipulating type 3 cells may be employed for potential regenerative therapies.

Objectives: The purpose of this study was to determine the validity and reliability of a Japanese version of the Khalfa hyperacusis questionnaire (KHQ) and proposed a threshold KHQ score for classifying hyperacusis. Methods: In total, 112 patients with hyperacusis (group A) and 103 patients without hyperacusis (group B). The patients in group A were further classified into the following subgroups: subjects with hyperacusis as their chief complaint (n = 26, group A1) and subjects with hyperacusis accompanied by chief complaints of tinnitus and/or hearing loss (n = 86, group A2). Results: The average total questionnaire score for patients in group A was 11.8 ± 9.7, which was statistically significantly higher than that of patients in group B, 5.7 ± 4.8. Cronbach’s coefficients for internal consistency were high for the total score (0.92). The average total scores for groups A1 and A2 were 18.1 ± 11.1 and 9.9 ± 8.4, respectively, and the difference between the groups was statistically significant. Conclusions: We developed a Japanese version of the KHQ. It showed high reliability and validity; suggesting its usefulness in clinical practice. We propose that a total KHQ score of 16 is an appropriate cutoff for classifying hyperacusis

Objective: To investigate the positive rate for the Cochlin tomo-protein (CTP: an inner ear-specific protein) detection test among patients with inner ear-related clinical manifestations and evaluate the clinical characteristics of definite perilymphatic fistula (PLF). Methods: We have performed an ELISA-based CTP detection test using middle ear lavage (MEL) samples from 497 cases of suspected PLF enrolled from 70 clinical centers nationwide between 2014 and 2015. In addition to the CTP-positive rate, audio-vestibular symptoms were compared between CTP-positive and -negative cases. Results: 8–50% of patients in category 1 (trauma, middle and inner ear disease cases), and about 20% of those in categories 2, 3 and 4 (external origin antecedent events, internal origin antecedent events, and without antecedent event, respectively) were positive for CTP. In category 1 cases, the earlier tested samples showed a higher CTP-positive rate, whereas no differences were observed in categories 2, 3 or 4. The characteristic clinical features in the earlier tested cases were nystagmus and fistula sign in CTP test-positive cases in category 1, and streaming water-like tinnitus in those in categories 2, 3 and 4. Conclusion: The present study clarified that CTP detection test-positive patients exist at considerable rates among patients with inner ear-related manifestations.

Background: Although the mitochondrial DNA (mtDNA) mutations m.1555A > G and m.3243A > G are the primary causes of maternally inherited sensorineural hearing loss (SNHL), several other mtDNA mutations are also reported to be associated with SNHL. Methods: Screening of m.1555A > G and m.3243A > G mutations was performed for 145 probands. Nine probands fulfilled the following criteria: 1) bilateral and symmetric SNHL, 2) ≥ 4 family members with SNHL with a maternal trait of inheritance in ≥ 2 generations, 3) onset of SNHL before the age of 40 years, 4) high-frequency SNHL, and 5) no record of environmental factors related to SNHL. Sequencing of additional mtDNA regions was performed for five subjects meeting the clinical criteria, but the screening results were negative. Results: Among the nine cases meeting the five clinical criteria detailed above, three had the m.1555A > G mutation in MTRNR1, one had a m.3243A > G mutation in MTTL1, and one case had a m.7511T > C mutation in MTTS1. In the family with the m.7511T > C mutation, penetrance of SNHL among maternally related subjects was 9/17 (53%). The age at onset varied from birth (congenital) to adulthood. Hearing levels varied from normal to moderately impaired, unlike previously reported subjects with this mutation, where some maternal family members presented with profound SNHL. Family members with the m.7511T > C mutation and SNHL did not exhibit any specific clinical characteristics distinct from those of other individuals with SNHL and different mtDNA mutations. Among the 136 probands who did not meet the criteria detailed above, one case had the m.1555A > G mutation, and three cases had the m.3243A > G mutation. Conclusions: Since five of nine probands with the clinical criteria used in this study had mtDNA mutations, these criteria may be helpful for identification of candidate patients likely to have mtDNA mutations.

Objective: The prognosis of terminal head and neck cancer is traditionally determined using indices such as the palliative prognosis index. We aimed to develop an alternative prognosis index using clinico-biological data. Methods: This retrospective case-series study included 33 head and neck cancer patients whose cancer recurred despite receiving radiation therapy between April 2010 and April 2014. Clinico-biological data were collected the day patients were diagnosed as terminal. Bivariate correlation analyses were performed on survival times and clinico-biological data. For multivariate regression analyses, patients were divided into two groups: (1) patients who survived >120 days, and (2) those who survived <120 days. Group clinico-biological data were used to determine survival-time cutoff points for the prognosis index. Results: Bivariate analyses revealed significant correlations between survival time and BMI, hemoglobin, albumin, C-reactive protein (CRP), Onodera’s Prognostic Nutritional Index (O-PNI), modified Glasgow Prognostic Score (mGPS), and Performance Status (PS). Multivariate analyses showed a strong correlation between survival time and BMI. The two groups differed significantly in BMI, albumin, CRP, O-PNI, and mGPS. In multivariate analyses BMI, CRP, and O-PNI differed significantly in the two groups. Conclusion: BMI ≤16.4, CRP ≥1.01, and O-PNI ≤33.4 are significant predictors of long-term survival in terminal cancer patients.

Objectives: A nationwide epidemiological survey involving 23 hospitals in Japan was conducted and the predictive values of demographic data were examined statistically. Methods: A total of 642 patients from 23 hospitals, including 20 university hospitals, in Japan were enrolled in the study. Age ranged from 8 to 87 years, and all were diagnosed with acute low-tone sensorineural hearing loss (ALHL) between 1994 and 2016. Demographic data for the patients, such as symptoms, gender, mean age, and distribution of ALHL grading, were collected and analyzed in relation to prognosis using Student’s t-test, χ 2 test and logistic regression. Results: Female gender (p <.013), younger age (p <.001), low-grade hearing loss (p <.001), and shorter interval between onset and initial visit (p <.004) were significantly predictive of a good prognosis. The prognosis for definite ALHL was significantly better than that for probable ALHL (p <.007). Conclusions: The severity of initial hearing loss, interval between onset and initial visit and age were important prognostic indicators for ALHL, while female gender was an important prognostic indicator peculiar to ALHL.

Objective: To investigate the hearing prognosis of idiopathic sudden sensorineural hearing loss (SSNHL) treated with different initial therapies. Methods: Subjects consisted of patients diagnosed with idiopathic SSNHL within 7 days from onset and showing severe hearing loss (≥60 dB), who were registered in a Japanese multicenter database between April 2014 and March 2016. Subjects were divided into four groups according to initial therapy: (1) steroids, (2) steroids + Prostaglandins (PGs), (3) intratympanic steroids (ITS), and (4) no steroids. Hearing outcomes were compared among the groups. Results: In total, 1305 patients were enrolled. The final hearing level and hearing gain of patients treated with steroids + PGs were significantly higher than those of patients treated with steroids alone or no steroids. The ratio of good prognosis (complete recovery or marked improvement) in patients treated with steroids + PGs was higher than that in patients treated with steroids alone or no steroids. There was no difference in the prognosis of patients treated with steroids alone or no steroids. Conclusion: A large number of patients with idiopathic SSNHL were registered in a multicenter database. PG use in combination with steroid administration was associated with a good hearing prognosis in patients with severe hearing loss.

Objectives: To present the cardiovascular risk factors in idiopathic sudden sensorineural hearing loss (SSNHL) patients enrolled in a nationwide epidemiological survey of hearing disorders in Japan. Materials and methods: We compiled the cardiovascular risk factors in 3073 idiopathic SSNHL subjects (1621 men and 1452 women) and compared their proportions with controls as part of the National Health and Nutrition Survey in Japan, 2014. The cardiovascular risk factors consisted of drinking and smoking habits, a history of five conditions related to cardiovascular disease and body mass index. Results: The proportion of current smokers was significantly higher among men aged 50–59, 60–69 and 70+ and among women aged 30–39, 40–49 and 60–69. The proportion of patients with a history of diabetes mellitus was significantly higher among men aged 50–59, 60–69 and 70+, but not in women. In addition, male and female SSNHL subjects aged 60–69 showed lower proportions of current drinking; and female SSNHL subjects aged 60–69 showed higher proportions of overweight (BMI ≥25 kg/m2). Conclusions: The present cross-sectional study revealed showed significantly higher proportions of current smokers among both men and women as well as those with a history of diabetes mellitus among men across many age groups in patients with idiopathic SSNHL compared with the controls.

We performed a retrospective review of five patients with carotid body tumors at our institution between 1997 and 2005. Out of the five patients, three patients were treated by surgical resection of the tumor, and 2 patients were observed. It would seem that it is difficult to suspect this disease based only on the clinical findings, because the disease was suspected in only one patient at the first medical examination. Imaging tests are important for establishment of the diagnosis. Color Doppler sonography and MR angiography in addition to MRI are useful. Angiography and balloon Matas test are important for selection of candidates for the operation. The resected tumors were all classified in Shamblin's group II. Delayed cerebral infarction was caused in one patient postoperatively, although the carotid artery was preserved. The dissection in a tumor-adventitial plane using the bipolar coagulation technique under the microscope was performed in the other two cases. Histological examination of the specimen revealed no tumor cells in the excision stump. Dissection in the tumor-adventitial plane using bipolar coagulation under the microscope is important for carotid artery preservation and radical resection of Shamblin's group I and II tumors. It is necessary to compare the risk of the operation with the problems of observation in the process of decision making and to achieve reliable informed consent. Moreover, it is necessary to examine the indications for operation in individual cases referring to the age, past history, expected Shamblin's classification, and result of the balloon Matas test. A multidisciplinary approach should be used, involving the fields of otolaryngology, radiology, neurosurgery and vascular surgery to treat these patients.

Otitis media with effusion is a common disease and is the most common cause of hearing impairment among children. It is important to treat this condition in children to provide them a better quality of life. "Ear popper®" is a new device distributed in the US for non-surgical treatment of middle ear effusion. The device allows easy insufflation of the eustachian tube. We used the "Ear popper®" for the treatment of middle ear effusion in 18 patients. The patients ranged in age from 2 to 9 years old, and were composed of 8 males and 10 females. Successful insufflation without any problems was achieved in 17 out of the 18 patients at our hospital. This was confirmed by visual observation of the tympanic membrane, impedance audiometry and pure-tone audiometry. The new device is portable and easy to use. Although in this clinical trial, the use of this device was restricted only to doctors at the hospital, we are currently attempting to introduce the use of this device at home by the patients by themselves, just as in the U.S.A. We consider that the home treatment of persistent otitis media with effusion in children with "Ear popper®" is highly efficacious.

Here we report the first case of the development of intracranial solitary plasmacytoma in the inner ear after allogeneic stem cell transplantation (allo-SCT) in a 39-year-old Japanese female with primary plasma cell leukemia (PCL). A point to note is that this is not a case on multiple myeloma but on PCL. She was successfully treated with local irradiation and survived more than 6 years from the time of diagnosis and transplantation. This case elucidates the biology of PCL and stresses the need for an individual approach to the clinical management of patients with plasma cell neoplasm undergoing allo-SCT.

Liposarcoma is a soft tissue malignant tumor that is common in adults, though the incidence of this type of tumor in the head and neck region is extremely low. Herein, we report a case of myxoid liposarcoma occurring in the retropharyngeal space. We were unable to make a proper diagnosis of this tumor prior to surgery because of the radiographic findings and the anatomical location resembled those of neurogenic tumor. Myxoid liposarcoma often recurs. So its excision must be carried out carefully and radical dissection is recommended. In the past, liposarcomas arising in the retropharyngeal space were not radically resected because the extent of resection in the head and neck area risked poor functional outcome. In the present case, functional resection and radiotherapy were performed and proved to be efficacious in that no recurrence was observed for 2 years.

From 1989 to 2005, 28 patients--20 men and 8 women--with cervical lymph node metastasis from an unknown primary carcinoma were treated and studied retrospectively. In histological diagnosis, open biopsy was conducted in 11 patients and non-open biopsy (FNA or frozen section diagnosis during surgery) in 17. Blind biopsy under general anesthesia was conducted in 10 patients, showing one primary tumor in the nasopharynx. Tonsillectomy for diagnosis was not done. In region of maximum-size lymph node metastasis, the upper cervical region accounted for 22 cases (79%). The N stage of cervical lymph nodes was as follows: N2a in 4, N2b in 14, N2c in 3, and N3 in 7. The histopathological diagnosis of cervical lymph node was as follows: squamous cell carcinoma in 21, adenocarcinoma in 3, mucoepidermoid carcinoma in 2, and others in 2. Therapy was as follows: only neck dissection in 7, neck dissection with postoperative radiation therapy in 13, and irradiation and chemotherapy in 8. All patients treated with irradiation and chemotherapy had been judged to be inoperable. Seven patients were found to have a subsequent primary tumor. Primary tumor sites were as follows: tonsils in 3 and upper gingiva, base of tongue, lung, and nasopharynx in 1 each. FDG-PET was conducted in 7 patients but revealed no primary tumor. Overall 5-year survival in this study was 46%. We should pay particular attention to the tonsils for detecting primary tumors in patients with cervical metastasis from an unknown primary carcinoma.

OBJECTIVES/HYPOTHESIS: We have previously shown that gene therapy using Insulin-like growth factor (IGF)-I, glial cell line-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF), or a combination of these trophic factors, is a treatment option for recurrent laryngeal nerve (RLN) palsy. However, there remain some difficulties preventing this option from becoming a common clinical therapy for RLN injury. Thus, we need to develop novel treatment option that overcomes the problems of gene therapy.R(-)-1- (benzothiophen-5-yl)-2-[2-N,N-diethylamino]ethoxy]ethanol hydrochloride (T-588), a synthetic compound, is known to have neuroprotective effects on neural cells. In the present study, the possibility of new drug treatments using T-588 for RLN injury was assessed using rat models. STUDY DESIGN: Animal study. METHODS: Animals were administered T-588 for 4 weeks. The neuroprotective effects of T-588 administration after vagal nerve avulsion and neurofunctional recovery after recurrent laryngeal nerve crush were studied using motoneuron cell counting, evaluation of choline acetyltransferase immunoreactivity, the electrophysiologic examination, and the re-mobilization of the vocal fold. RESULTS: T-588 administration successfully prevented motoneuron loss and ameliorated the choline acetyltransferase immunoreactivity in the ipsilateral nucleus ambiguus after vagal nerve avulsion. Significant improvements of motor nerve conduction velocity of the RLN and vocal fold movement were observed in the treatment group when compared to controls. CONCLUSION: These results indicate that oral administration of T-588 might be a promising therapeutic option in treating peripheral nerve injury.

From 1989 to 2005, 28 patients-20 men and 8 women-with cervical lymph node metastasis from an unknown primary carcinoma were treated and studied retrospectively. In histological diagnosis, open biopsy was conducted in 11 patients and non-open biopsy (FNA or frozen section diagnosis during surgery) in 17. Blind biopsy under general anesthesia was conducted in 10 patients, showing one primary tumor in the nasopharynx. Tonsillectomy for diagnosis was not done. In region of maximum-size lymph node metastasis, the upper cervical region accounted for 22 cases (79%). The N stage of cervical lymph nodes was as follows : N2a in 4, N2b in 14, N2c in 3, and N3 in 7. The histopathological diagnosis of cervical lymph node was as follows : squamous cell carcinoma in 21, adenocarcinoma in 3, mucoepidermoid carcinoma in 2, and others in 2. Therapy was as follows : only neck dissection in 7, neck dissection with postoperative radiation therapy in 13, and irradiation and chemotherapy in 8. All patients treated with irradiation and chemotherapy had been judged to be inoperable, Seven patients were found to have a subsequent primary tumor. Primary tumor sites were as follows : tonsils in 3 and upper gingiva, base of tongue, lung, and nasopharynx in 1 each. FDG-PET was conducted in 7 patients but revealed no primary tumor. Overall 5-year survival in this study was 46%. We should pay particular attention to the tonsils for detecting primary tumors in patients with cervical metastasis from an unknown primary carcinoma.

Background: The relation of connexins and carcinogenesis has been studied in various organs and cell lines, with connexins currently being considered tumor suppressors. Materials and Methods: The expression of connexin-26 (Cx26) and connexin-30 (Cx30) in human head and neck carcinomas, as well as in adjacent normal mucosa, was evaluated by immunohistochemistry. Furthermore, the expression of these connexins with regard to apoptosis and cell differentiation was investigated. Results: In the cancer tissues, Cx30 expression was drastically reduced compared to apparently normal mucosa while Cx26 expression was almost the same. The intracellular distribution patterns of Cx26 and Cx30 in cancer cells differed between cancer locations. In the cancer tissues, expression of Cx26 and Cx30 was not related to apoptosis assessed by TdT-mediated dUTP-biotin nick end labeling (TUNEL) reaction or to cell differentiation assessed by immunoreaction to involucrin. Conclusion: The present results suggest that connexins may play a role in the carcinogenesis of head and neck cancer.

Introduction: Dizziness and vertigo are symptoms of various psychiatric conditions like major depression, somatoform disorder, anxiety disorders, and so on. Phobic postural vertigo (PPV) was first reported by Brandt T et al. in 1994. PPV occurs chiefly in patients with an obsessive-compulsive or narcissistic personality. The diagnosis is based on six characteristics proposed by Brandt et al. The key for a correct diagnosis is spontaneous (sometimes stimulus-induced) postural vertigo and unsteadiness in maintaining an upright position and walking. Methods: The characteristics of patients with PPV were reviewed in 16 patients from June 2002 to November 2006 in our hospital. Some psychological evaluations were preformed by a self-rating questionnaire. MAS (Manifest Anxiety Scale) was used to evaluate the level of anxiety, and the Japanese version of MOCI (Maudsley's Obsessional Compulsive Inventory) was employed to evaluate the obsessive-compulsive personality. Results: We encountered 16 PPV patients. Fourteen were female and 2 were male. The average age was 55±15.5 years old. Many of the patients showed depression and a high level of anxiety. The average MOCI score was 10.8, and this indicated an obsessive-compulsive or narcissistic personality. Treatment involved drug therapy with SSRI (Selective serotonin reuptake inhibitors), antidepressants, anxiolytics like benzodiazepine (BZD), and psychotherapy including cognitive behavior therapy and autogenic training. Conclusion: The diagnosis of PPV was important to improve the prognosis. The key for a correct diagnosis is not anxiety but the subjective dizziness itself. An obsessional personality is often observed.

Background: After Le Fort I osteotomy, there is sometimes a secondary deformity (relapse), with the lower segment deviating from the intraoperatively fixed position. It is hyopothesized that the structural stability of the reconstructed maxilla is affected by the diameter of the fixation screws. The present study aims to elucidate the relationship between the diameters of the screws and the structural stability of the maxilla after Le Fort I osteotomy. Methods: 3D models were produced on a workstation from 20 dry skulls and a Le Fort I operation was simulated on them. The upper and lower segments of the divided maxilla in each of the 20 models were connected using four plates and 16 screws. Five different diameters of the fixation screws were tested. Thus altogether 100 models were produced. A 180 N load was applied to the molar region for each model. Using finite element analysis, the resultant stresses and deviations of the lower segments were calculated. Finally, referring to these values, the relationships between screw diameters and stability of the lower segment were evaluated. Result: The stability of the lower segment was greatest when the diameter of the fixation screws was equal to the thickness of the bone at each fixation site. Conclusion: In performing Le Fort I osteotomy, it is recommended that bone thickness is measured at each fixation site in advance, and the diameter of the fixation screws matched accordingly; thereby optimum stability of the reconstructed maxilla can be anticipated.

Laryngeal carcinoma presenting as a cervical abscess is rare, so that its diagnosis is not easy. We described a case of laryngeal squamous cell carcinoma presenting as a prelaryngeal large abscess. Markedly swollen false vocal fold inhibited fiberscopic examination of the vocal folds. CT scan indicated destruction of the thyroid cartilage. Although biopsies from the abscess did not reveal malignancy, laryngeal squamous cell carcinoma was confirmed by laryngomicrosurgery with laryngeal vestibulectomy. The patient was treated by total laryngectomy with neck dissection followed by radiotherapy. The abscess was thought to be formed not by direct extension and necrosis of the tumor, but by the leakage of air and mucus through the fistula on the destroyed thyroid cartilage. Precise observation and biopsy under directscopic vestibulectomy played an important role in diagnosis of malignancy inherent in severe inflammatory tissues.