A rapid and durable response to larotrectinib in a patient with NTRK fusion-positive secretory carcinoma originating from the external auditory canal.

For decades, no clear consensus existed on the standard treatment option for malignant tumors of the external auditory canal, an extremely rare disease. Here we report the case of a 55-year-old female patient with secretory carcinoma that originated from the left external auditory canal. Magnetic resonance imaging (MRI) at baseline showed that the tumor had extended to the medulla oblongata despite surgical and radiation treatments for more than 20 years from the initial diagnosis. Based on the results of a next-generation sequencing test of a formalin-fixed paraffin-embedded surgical specimen indicating that the tumor harbored ETV6-NTRK3 fusion, the patient was enrolled in a global basket study of larotrectinib, an oral selective tropomyosin receptor kinase (TRK) inhibitor. Three weeks after the start of larotrectinib treatment, MRI showed only small remnants of the tumor in the medulla oblongata and the patient's headache before the treatment had disappeared. Subsequent MRI after 12 weeks of treatment confirmed the complete disappearance of the tumor. The patient repeated grade 2 flu-like symptoms related to treatment, but did not experience any other grade 2 or worse treatment-related adverse events. TRK inhibitors, such as larotrectinib, exert potent antitumor activity against neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors in a tumor-agnostic manner. To the best of our knowledge, this is the first report on NTRK fusion-positive secretory carcinoma of the external auditory canal, and this report provides a valuable insight into the management of the extremely rare but now treatable malignancy.

Effects of hydrogen peroxide on vestibular hair cells in the guinea pig: importance of cell membrane impairment preceding cell death.

CONCLUSION: Our findings indicate that oxidative stress induces morphological changes in vestibular hair cells and subsequently leads to cell death after 2.5 h. OBJECTIVES: The aim of this study was to confirm the direct effects of oxidative stress on vestibular hair cells. MATERIALS AND METHODS: Vestibular hair cells isolated from guinea pigs were loaded with 1 or 10 mM H2O2, and morphological changes were observed. In addition, in a viability/cytotoxicity assay system, the numbers of dead cells in isolated cristae ampullares were counted 1, 3, and 5 h after loading with H2O2 or artificial perilymph (control). RESULTS: Reactive oxygen, in the form of H2O2, directly affects the cell membrane of isolated vestibular hair cells and causes swelling of the cell body, bleb formation, and shortening of the neck region. Morphological changes occur within 30 min after loading with H2O2, but a significant increase in the number of dead cells is noted only after 3 h.

Nasal hemangiopericytoma successfully treated with a combination of rIL-2 and extranasal approaches.

Hemangiopericytomas (HPCs) are uncommon vascular tumors originating from extracapillary cells called pericytes, and rarely occur in the nose or paranasal sinuses. We treated a 57-year-old man with nasal HPC who presented with nasal obstruction and hemorrhage. Nasal endoscopy showed a readily bleeding mass between the right nasal septum and inferior turbinate. Enhanced CT revealed a heterogeneous mass lesion with an enhancement effect that filled the right nasal cavity. A biopsy specimen was proved to exhibit a HPC histopathology. Recombinant interleukin-2 (rIL-2) was administered with a measurement of natural killer cell (NK cell) activity. Afterwards, wide excision with an extranasal approach was performed. The use of rIL-2 caused not only increased NK cell activity but also a reduction in the tumor size. With a combination of rIL-2 and wide excision with extranasal approaches, no local recurrence or metastasis has occurred over the last 4 years.

Use of trafermin to treat a skin ulcer after repair of a deep auricular laceration: a case report.

We used trafermin (recombinant human basic fibroblast growth factor) to treat a skin ulcer (diameter, 1 cm; depth, 2 mm) that developed after an extremely deep auricular laceration was sutured. Excellent results were obtained after use of trafermin for 2 weeks. To our knowledge, we report the first clinical use of trafermin in a patient with a skin ulcer resulting from auricular trauma. Trafermin may promise to be an effective treatment for skin ulcers.

["Restricted ablation" of elongated uvula mucosa by the injection of the ethanol/steroid mixture: a new treatment for snoring and OSAS].

We developed a "Submucosal Ethanol/Steroid (E/S) Injection Method (SEIM)" using an injection prepared by dissolving steroid with powerful antiinflammatory effect, which has the excellent effect of contractile reduction in oral tissues. In this clinical trial, the ablation effect of SEIM on the abnormally elongated uvula and the soft palate was examined in each one clinical case of obstructive sleep apnea syndrome (OSAS) and simple snoring. In the OSAS, we found that the uvula was reduced from 15 to 10mm, the visual analog scale (VAS) of snoring was reduced from 10 to 4 points, and the respiration disturbance index of the apnea-hypopnea index (AHI) improved from 35.3 to 26.1 after treatment. In simple snoring, the uvula was reduced from 11 to 8.5mm and VAS was relieved from 7 to 2 points after treatment. Our approach will produce a great clinical significance for not only OSAS or simple snoring but also treatment of the allergic rhinitis, etc, because the contractile tissue reduction can be attained safely in these diseases without open surgical wounds and unnecessary deformation or destruction of the mucosal structure.

[Histological study on the effects of ethanol injection on mouth mucosa contraction loss].

We previously reported that a loss of contraction in the mucosal tissue of the palate arch is effectively induced by ethanol injections of moderate concentration and dosage. The present study was performed to obtain more information on how such ethanol injections induce contraction loss in mucosa tissue. Guinea pigs of both sexes were used in this study. The left arch of the palate mucosa was injected with 2 microliters of 70% ethanol and used as the experimental group. The right arch of the palate mucosa of the same animal was injected with saline and used as a control. One, three, five, eight, 10, 30, 50, and 90 days after injection, the mucosal tissues that received the injection were resected under anesthesia and processed for light microscopy using standard procedures. One day after the ethanol injection, severe coagulative degeneration of the mucosal tissue of the palate was seen. However, the damaged area was strictly restricted to the arch of the palate. Coagulative degeneration of the tissue peaked three days after the injection. Thereafter, the mucosal epithelial and mucosal connective tissues regenerated, and the damaged mucosal tissue quickly began to repair. An apparent cicatricial contraction loss was observed 10 days after the ethanol injection, along with the progression of fibrotic changes in the submucosal connective tissue of the arch of the palate. The regenerative action of the mucosal arch of the palate abated 30 days after the ethanol injection, and the reduced mucosal tissue appeared to have become denser as a result of an increase in dense fibrous connective tissue in the submucosal layer. No cell malignancies were seen throughout the entire 90-day observation period. In conclusion, cicatricial contraction loss of the mucosal arch of the palate resulting from the injection of an appropriate concentration and dosage of ethanol leads to the regeneration of the mucosal epithelium and fibrotic changes in the submucosa. The ethanol injection described here seems to be extremely safe, since it exerted no malignant effects on the cells and tissues either morphologically or functionally.

[Experimental study of contraction loss effects of mouth mucosa by ethanol injection].

We began treating patients with simple snoring and obstructive sleep apnea syndrome (OSAS) with the coblator radiofrequency generator in our outpatient clinic from April 2001. Good clinical results have been obtained, but we noticed a contractile effect on mucosa from ethanol, which possesses marked sclerotic degenerative action on tissue as well as radiofrequency energy. We conducted a series of experiments in a guinea pig model to investigate the efficacy of local ethanol injection in contracting mouth mucosa. To examine the influence on respiration of liquid injection, physiological saline was gradually injected in decrements into the arch of the palate mucosa. We found that the safe dosage that did not bring about edema and subsequent dyspnea was under 10 microliters. Based on this finding, ethanol in concentrations of 50%, 70%, and 100% at volumes of 1, 2, 4, 8, and 10 microliters was injected into the arch of the palate mucosa in guinea pigs and changes in local field mucosa were observed daily. In the 50% ethanol injection, no clear contractile effect on mucosa could be observed at any dosage. In contrast, the 100% ethanol injection led to strong tissue impairment that caused extensive necrotic collapse of the local field mucosa, even when the dosage was down to the minimum of 1 microliter. We found that, injection of 70% ethanol at 1 or 2 microliters, however, resulted in formation of a local field mucosa wound of lesser degree that healed completely within a few days, associated with moderate contraction of mucosal tissue. We concluded that in moderate dosage, 70% ethanol seems to have the potential for the treatment of endermosis, such as uvuloptosia (elongated uvula) and hypertrophy of palate mucosa, as a useful mucosa contractile agent.

[Immunohistochemical study for monoamine neurons in the brain of unilateral inner ear impaired rats].

Patients with inner ear impairment have complaints of vertigo and also occasionally depression. The present study was undertaken in order to evaluate changes in monoamines which have reportedly been closely related to depression, using cisplatin-induced unilateral inner-ear impaired rats. A dose of 0.5 mg/kg of cisplatin was injected into the right tympanic cavity under pentobarbital Na+ anesthesia. One or two weeks later, animals were fixed with paraformaldehyde, and thereafter immunohistochemical stainings for monoamine-containing cells in the brain were carried out. To visualize 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA) neurons, we used mouse antibodies against 5-HT, NA, and DA syntheses, i.e., tryptophan hydroxylase (TRH), tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH). The number of TRH immunoreactive neurons significantly decreased in the lateral dorsal raphe nucleus of the ipsilateral side when compared with the contralateral side. The number of DA neurons, which were immunoreactive to TH, but not to DBH, significantly decreased in the hypothalamus of the ipsilateral side. The number of NA neurons which were immunoreactive to both TH and DBH significantly decreased in the locus coeruleus and ventral lateral pons of the ipsilateral side. An additional control study with saline-injected rats showed a lack of differences in monoamine syntheses between the injected and contralateral sides, the expressions of the synthesis on both sides being similar to that obtained in the contralateral side in cisplatin-injected rats. These results indicated the decreases in monoamine syntheses at the ipsilateral side only in the cisplatin-administered rats. We conclude that inner ear impairment may diminish the ipsilateral amount of monoamines in the brain but not the cotralateral, possibly inducing a vestibular compensation such as an upregulation of monoamine receptors.

Effects of MRI contrast agents (Omniscan) on vestibular end organs.

CONCLUSION: These findings indicate that application of 4-16-fold diluted Omniscan could have depressant effects on the frog vestibular end organs. Based on cochlear studies on cytotoxicity using 8-fold diluted Omniscan, 16-fold diluted Omniscan is optimal for the inner ear and its application could be useful for visualization of endolymphatic hydrops as well as the control of vertiginous attacks in Meniere's disease. OBJECTIVES: Endolymphatic hydrops could be visualized recently by intratympanic injection of Omniscan diluted 8- or 16-fold with saline using three-dimensional fluid attenuated inversion recovery (3-D FLAIR) MRI. However, the effects of the Omniscan on vestibular end organs are not clearly understood. The purpose of this study was to investigate the effects of Omniscan on vestibular end organs both morphologically and physiologically. MATERIALS AND METHODS: Vestibular hair cells isolated from bullfrogs were loaded with 4-32-fold diluted Omniscan (gadolinium hydrate) and morphological changes were observed. Moreover, compound action potentials of posterior semicircular canals were also observed after application of Omniscan. RESULTS: Application of 4-16-fold diluted Omniscan caused morphological damage of isolated vestibular hair cells and decreased action potentials of the posterior semicircular canal. After application of 32-fold diluted Omniscan, no apparent changes were noted even after 20 min, both morphologically and physiologically.

Five cases of chondroma involving the external auditory canal.

A cartilaginous tumor located in the external auditory canal is a rare finding. Only 48 cases of chondromas of the external auditory canal have been documented in the literature. The natural course of these tumors as well as the diagnosis and management has not been well established. We have encountered five cases of external auditory canal chondroma. The patients consisted of three males, ages 12, 14, and 29, and two females, ages 2 and 3, respectively. Otoscopic examination demonstrated a tiny firm tumor protruding from the anterior wall of the bony external auditory canal. Surgery was performed all cases, and the tumor proved to be a chondroma histologically. All cases could be approached through the ear canal. The postoperative courses were uneventful and no recurrences were found during the follow-up periods. From our experiences, it is important to recognize that chondromas are in the differential of small exophytic tumors on the anterior or superior wall of the external auditory canal and can be removed safely and effectively through the transcanal approach.

The role of malocclusion in non-obese patients with obstructive sleep apnea syndrome.

OBJECTIVE: The maxillofacial characteristics of patients with obstructive sleep apnea syndrome (OSAS) have previously been analyzed using standard cephalometric analysis. Malocclusion influences the occurrence of sleep apnea, but the pathology of malocclusion in OSAS has not yet been fully investigated. Therefore, we investigated malocclusion in patients with OSAS using cephalometric and dental analysis. METHODS: Cephalometric and dental analyses were performed to evaluate malocclusion in 97 male patients with OSAS (49.7+/-11.7 years). The number of apnea and hypopnea episodes per hour (apnea-hypopnea index: AHI) was determined by standard polysomnography. RESULTS: The overall prevalence of severe overjet (the horizontal distance between the upper and lower incisors of >or=6 mm) was 43.3%. AHI was significantly correlated with body mass index (BMI) in obese OSAS patients (r=0.385, p=0.010), whereas it was significantly correlated with overjet in non-obese OSAS patients (BMI<25 kg/m2) (r=0.313, p=0.022). Multiple regression analysis revealed that BMI was the significant factor contributing to increased AHI in all patients, and overjet was in non-obese OSAS patients. There were no significant differences between non-obese and obese OSAS patients in the angle of protrusion of the superior alveolar base (SNA) or in the angle of protrusion between the superior and inferior alveolar bases (ANB). The angle of protrusion of the inferior alveolar base (SNB) was significantly smaller in non-obese than in obese OSAS patients. CONCLUSION: We have shown that overjet was associated with the severity of OSAS in non-obese patients. Our findings suggest that malocclusion may play an important role in the development of sleep apnea/hypopnea.

A quantitative analysis of cedar pollen-specific immunoglobulins in nasal lavage supported the local production of specific IgE, not of specific IgG.

Many studies have proved the relevance of local immune responses, rather than systemic immunity, to the pathogenesis of allergic rhinitis. Indeed, allergen-specific B lymphocyte undergoes class switching to IgE in situ. However, the relative contribution of in situ production to the amount in serum is still ambiguous. Here, a quantitative comparison of the local concentration of allergen-specific IgE with the systemic concentration was explored for the estimation. Among seasonal rhinitis patients, total and Japanese cedar pollen (JCP)-specific IgE, IgA and IgG antibodies were quantified in nasal lavage fluid (NLF) and serum with the time-resolved fluorescence immunosorbent assay. Although the total amounts of IgE and IgG classes in the NLF, which were apparently passive discharge from the mucosal tissue, were smaller and variable, the relative proportions of JCP-specific antibodies could be quantitatively compared between NLF and serum or between subjects. The proportions of specific IgE in the NLF were remarkably higher than in serum (average 13.2-fold) in most subjects, which strongly supported the predominant in situ production of the specific IgE and subsequent dilutions in the systemic circulations. Similar but smaller values were obtained for IgA (average 3.7-fold). In contrast, the specific proportions of IgG in the NLF were surprisingly consistent with serum (average 1.0-fold), suggesting that the specific IgG was mostly produced in the downstream lymphoid organs. The local productions of specific IgE would encourage the topical therapies and the usage of the NLF for the diagnosis of allergic rhinitis.