山原 康平

A 62-year-old woman with poorly controlled type 2 diabetes mellitus presented with a fever and altered consciousness. The patient was diagnosed with diabetic ketoacidosis (DKA) with a positive blood culture for group A Streptococcus. Although the source of infection was initially unclear, contrast-enhanced CT revealed a retropharyngeal abscess (RPA) and descending necrotizing mediastinitis (DNM) that required surgical drainage. RPA with DNM is rare and potentially fatal in adults and is often missed without high clinical suspicion. In severe DKA, altered mental status and hemodynamic instability may obscure the underlying infection, emphasizing the importance of a thorough evaluation.

OBJECTIVE: To evaluate the safety and feasibility of transaxillary robotic thyroidectomy (TART) in Japan by comparing early cases with video-assisted neck surgery (VANS). METHODS: Single-center retrospective review of 31 consecutive thyroid lobectomies: 16 VANS (Nov 2020-Feb 2025) and 15 TART (Mar 2022-Feb 2025). TART used da Vinci Surgical system (da Vinci) Xi for early cases and predominantly da Vinci SP thereafter. Indications included differentiated cancer ≤4 cm, cN0, unilateral disease without extrathyroidal invasion, or follicular tumors 3-5 cm. Operative time, blood loss, hospital stay, complications, and cosmetic outcomes were evaluated and compared with statistical analysis. RESULTS: All procedures were completed without conversion to open surgery. Blood loss (16.5 g vs 25.8 g) and length of stay (6.3 vs 6.1 days) were comparable. Complications included two transient recurrent laryngeal nerve palsies after VANS and, after TART, one axillary bleed controlled under local anesthesia and one lymphatic leak; overall rates were similar. High cosmetic satisfaction was reported in both cohorts. CONCLUSION: Early experience shows TART is feasible and safe in Japan, achieving perioperative outcomes comparable to VANS with excellent cosmetic results.

This article describes an extremely rare case of pediatric congenital external auditory canal cholesteatoma (EACC) that extended beyond the external auditory canal. A five-year-old girl presented with progressive swelling in the posterior wall of the left external auditory canal. Computed tomography of the temporal bone revealed a well-defined round mass that compressed and eroded the posterior canal wall without invasion of the mastoid tegmen, sigmoid sinus, or tympanic membrane. Surgical exploration via a retroauricular approach confirmed the presence of a cholesteatoma extending from the external auditory canal to the mastoid cavity; furthermore, complete excision was achieved. There has been a recent increase in the number of reported EACC pediatric cases, especially in East Asia. However, few studies have clearly distinguished congenital and acquired forms, which could be largely attributed to challenges in differential diagnosis, particularly when lesions extend beyond the canal. Based on our findings, we propose radiological and clinical features that may facilitate differentiation between congenital and acquired EACC, even in advanced-stage cases. This article highlights the importance of accurate classification for elucidation of the pathogenesis of EACC and optimization of surgical decision-making in pediatric patients with EACC.

Stapediovestibular luxations are often caused by trauma to the external ear canal. Sealing the oval window while leaving the stapes in the vestibule is a safer procedure than stapedectomy, considering the risk of additional inner ear damage, but it risks recurrence. We report a rare case of oval window rupture recurrence 25 years after initial surgery and introduce a new method using cartilage to seal the oval window. A 37-year-old woman experienced a recurrence of oval window rupture after nasal blowing. She had a history of left ear ossicular chain dislocations and oval window rupture caused by an ear pick 25 years earlier, initially treated by sealing the oval window with soft tissues while leaving the depressed stapes in place. In the current surgery, a stapedectomy was performed, the oval window was sealed with cartilage, and an incus columella was placed on the cartilage. Complete resolution of vestibular symptoms and improvement in air conduction thresholds were observed. Postoperatively, no recurrence of oval window rupture was observed. Patients with stapediovestibular luxations face a long-term risk of oval window rupture recurrence if sealed only with soft tissues. Cartilage may offer a promising alternative for oval window sealing after stapedectomy due to its flexibility and durability.

Cisplatin, an effective anti-neoplastic drug widely used in oncology protocols, has an adverse effect such as ototoxicity, for which no current treatment exists. Histological lesions in the cochlea after cisplatin administration are most prominent in outer hair cells in the organ of Corti. We have previously reported that insulin-like growth factor 1 (IGF1) protects cochlear hair cells (HCs) against several types of damage to the cochlea, including noise exposure, ischemia, surgical trauma, and aminoglycoside, resulting in hearing recovery. In the present study, we investigated the efficacy of IGF1 as a molecule to protect inner ear auditory sensory HCs against cisplatin using cochlear explant culture systems of postnatal day 2 mice. Administration of IGF1 to the explants grown in the medium containing cisplatin markedly protected outer HCs from cisplatin-induced damage. Pharmacological inhibition of IGF1 receptor (IGF1R) using an IGF1R antagonist or inhibitor markedly attenuated the protective activity of IGF1, indicating that IGF1R is specifically required for IGF1 effects in HCs against cisplatin. As a protective mechanism against cisplatin, we found that the administration of IGF1 reduces cisplatin-induced oxidative stress. IGF1 effects on the maintenance of HC numbers are achieved by inhibiting the apoptosis of HCs, not by inducing the proliferation of HCs or supporting cells (SCs). We conclude that treatment with IGF1 could be an efficient and safe approach to treat cisplatin-induced ototoxicity.

Countless therapeutic antibodies are currently available for the treatment of a broad range of diseases. Some target molecules of therapeutic antibodies are involved in the pathogenesis of sensorineural hearing loss (SNHL), suggesting that SNHL may be a novel target for monoclonal antibody (mAb) therapy. When considering mAb therapy for SNHL, understanding of the pharmacokinetics of mAbs after local application into the middle ear is crucial. To reveal the fundamental characteristics of mAb pharmacokinetics following local application into the middle ear of guinea pigs, we performed pharmacokinetic analyses of mouse monoclonal antibodies to FLAG-tag (FLAG-mAbs), which have no specific binding sites in the middle and inner ear. FLAG-mAbs were rapidly transferred from the middle ear to the cochlear fluid, indicating high permeability of the round window membrane to mAbs. FLAG-mAbs were eliminated from the cochlear fluid 3 h after application, similar to small molecules. Whole-body autoradiography and quantitative assessments of cerebrospinal fluid and serum demonstrated that the biodistribution of FLAG-mAbs was limited to the middle and inner ear. Altogether, the pharmacokinetics of mAbs are similar to those of small molecules when locally applied into the middle ear, suggesting the necessity of drug delivery systems for appropriate mAb delivery to the cochlear fluid after local application into the middle ear.

OBJECTIVE: Bone conduction hearing aids are the only non-surgical devices used for conductive hearing loss. However, they are impractical for lifelong use since they require close contact of the transducer with the head skin, causing skin erosion and discomfort. Bone conduction hearing implants and active middle ear implants do not present these issues; however, they require surgery and can sometimes cause issues in the skin surrounding the devices. This study aimed to develop a new bone conduction hearing device that does not exert pressure on the skin or require surgery. METHODS: Our device modified a piezoelectric element by using the skin of a pinna as one of the two electrodes of a conventional piezoelectric device. We compared the sound transmission of a speaker, a conventional piezoelectric device, or the new device to the Guinea pig cochlea, a physiological sound transducer to the auditory nerve, in normal and air-conductive hearing loss conditions. RESULTS: The novel device transmitted sound to the cochlea even after causing air-conductive hearing loss. Its bone conduction was more efficient than the speaker and the conventional piezoelectric device. CONCLUSION: We developed a novel type of bone conduction device that efficiently transmits sound to the cochlea by skipping the external auditory canal, tympanic membrane, and middle ear ossicles. This device does not exert pressure on the skin that can result in skin damage, an adverse effect of a conventional bone conduction hearing aid. SIGNIFICANCE: Our novel hearing device can be used as a substitute for current bone-conduction hearing devices.

Insulin-like growth factor 1 (IGF1) exerts an influence on almost every organ system in the body and plays an important role in growth, development, and metabolism. In the nervous system, IGF1 acts by promoting the development and growth of neurons and glial cells, differentiation of Schwann cells and their migration to axons, neurite outgrowth, and neuronal survival. The lack of IGF1 is associated with several pathological conditions, including severe prenatal growth retardation, postnatal growth failure, microcephaly, mental retardation, and bilateral sensorineural hearing loss. In addition to its physiological effects, based on the findings of in vivo and in vitro experiments and clinical trials, IGF1 is considered to play a potential role in the treatment of various types of neuronal damage. In this review, we discuss the potential use of IGF1 as a therapeutic molecule in the nervous system: (1) auditory system, including hair cells, cochlear ribbon synapses, auditory nerve, and central nervous systems, and (2) other peripheral nervous systems, especially the olfactory system and facial nerve. The role of IGF1 in the progression of age-related sensory deficits, especially hearing loss and olfactory dysfunction, is also discussed. Recent studies on IGF1 demonstrated that exogenous IGF1 can be applied in many fields, thus supporting the continued evaluation of IGF1 as a potential therapeutic molecule. Additional scientific investigations should be conducted to further supplement recent findings.

OBJECTIVE: Although both sarcopenia and systemic inflammation affect the outcomes of head and neck cancer (HNC) patients, the association between sarcopenia and systemic inflammation and the combined prognostic effect of these factors in HNC patients remain unknown. This study aimed to evaluate the effect of sarcopenia with systemic inflammation on survival and disease control in HNC patients. METHODS: We retrospectively reviewed medical records of HNC patients treated between 2009 and 2016. The skeletal muscle area was measured using a single computed tomography image slice at the level of the third cervical vertebra. A prognostic score (SPLR) was developed based on sarcopenia and the platelet-lymphocyte ratio (PLR), and its prognostic value was evaluated. RESULTS: Overall, 164 patients were enrolled. In the multivariate analysis, sarcopenia was significantly associated with poor overall survival (OS) (p < 0.01). However, neither sarcopenia nor a high PLR was an independent prognostic factor for disease-free survival (DFS) or locoregional recurrence-free survival (LRFS). A high PLR was an independent predictor for sarcopenia (p < 0.01). A high SPLR was associated with older age, lower serum hemoglobin, and lower body mass index (all p < 0.05). Multivariate analysis revealed that SPLR was a significant independent predictor of OS, DFS, and LRFS (all p < 0.05). CONCLUSIONS: Systemic inflammation is significantly associated with sarcopenia. The survival and oncological effects of sarcopenia were enhanced when PLR was high. Thus, the combination of these two parameters may be useful for identifying HNC patients at a risk of poor survival outcomes.

OBJECTIVES: Malnutrition and inflammation are common in patients with head and neck cancer and are closely associated with prognosis. Although several parameters for evaluating nutritional/inflammatory status have been assessed in relation to the prognosis of patients with head and neck cancer, previous studies primarily included patients with advanced-stage disease. To date, there is no consensus regarding the most reliable parameter for predicting the prognosis of early and advanced-stage head and neck cancer. This study sought to evaluate nutritional/inflammatory prognostic factors before treatment in patients with early and advanced-stage head and neck cancer. METHODS: We retrospectively reviewed medical records of patients treated between 2008 and 2015 at our institution in order to evaluate the effects of nutritional/inflammatory parameters, including C-reactive protein/albumin ratio, modified Glasgow prognostic score, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and Geriatric Nutritional Risk Index, on overall survival. Effects of potential risk factors on overall survival were analyzed by computing Kaplan-Meier estimates; curves were compared using the log-rank test. RESULTS: A total of 164 patients were enrolled. C-reactive protein/albumin ratio, modified Glasgow prognostic score, platelet/lymphocyte ratio, and Geriatric Nutritional Risk Index were found to be statistically significantly correlated with overall survival. Only the Geriatric Nutritional Risk Index remained statistically significant in the multivariate analysis. The three-year survival rates according to the four-group Geriatric Nutritional Risk Index scores for normal, low, moderate, and high risk were 95.5%, 84.3%, 53.8%, and 23.4%, respectively. CONCLUSION: The Geriatric Nutritional Risk Index is therefore a useful prognostic factor for patients with early and advanced-stage head and neck cancer.

OBJECTIVE: Rapid epithelialization is crucial to maintain tracheal patency and prevent potential graft failure in tracheal reconstruction after tracheal resection for cancer with tracheal infiltration or tracheal stenosis. Insulin-like growth factor 1 is a liver-secreted endocrine molecule that controls cell proliferation, differentiation, and apoptosis and has been reported to promote epithelialization in several organs. Here, we utilized mouse tracheal organ cultures to examine the effect of insulin-like growth factor 1 on tracheal epithelialization. METHODS: The trachea was resected from thirteen-week-old female ICR mice, and cut into small plate-shaped tracheal sections. First, the expression of insulin-like growth factor 1 receptor was assessed by immunohistochemistry. Secondly, the tracheal sections were cultured for seven days in the culture medium, and the morphological change during the seven-day culture was assessed by immunohistochemistry, hematoxylin and eosin staining, and scanning electron microscopy. Moreover, the tracheal sections were cultured for 48 h with different concentration of insulin-like growth factor 1 (0, 0.1, 1 and 10 µg/mL) in the culture medium, and the extension length of the tracheal epithelium during culture was measured in order to assess the effect of topical IGF1 on tracheal epithelialization. RESULTS: Immunohistochemistry showed that insulin-like growth factor 1 receptor was expressed in tracheal epithelium. Immunohistochemistry, hematoxylin and eosin staining, and scanning electron microscopy showed that the tracheal organ cultures were stable for at least seven days without apparent morphological damage. The effect of insulin-like growth factor 1 on tracheal epithelialization was examined in plate-shaped tracheal sections cultured in medium supplemented with or without insulin-like growth factor 1 for 48 h. We also found that the epithelial edge of plate-shaped tracheal sections extended further along the surface of the tracheal section in culture medium containing insulin-like growth factor 1 compared with that in culture medium without insulin-like growth factor 1. CONCLUSION: The current study using an in vitro mouse tracheal organ culture model demonstrated that topical insulin-like growth factor 1 treatment promoted the extension of tracheal epithelium, suggesting the potential utility of insulin-like growth factor 1 in aiding rapid tracheal epithelialization in patients requiring tracheal reconstruction using tissue-engineered tracheas.

OBJECTIVES: Data on the adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome are scarce. European studies reported that unlike pediatric-onset PFAPA, tonsillectomy is ineffective for adult-onset PFAPA. The aims of this study were (1) to assess the response to tonsillectomy in a cohort of Japanese adult-onset PFAPA patients and (2) to evaluate the histologic appearance of tonsils in adult-onset PFAPA patients and to compare them with those of tonsils from age- and sex-matched controls with chronic tonsillitis. METHODS: In this retrospective cohort study, 5 adults with PFAPA and 15 controls who had undergone tonsillectomy were recruited. The size of the tonsil germinal centers was measured by hematoxylin and eosin staining, and the number and density of B and T lymphocytes in germinal centers were measured by immunohistochemistry, using CD3, CD4 and CD8 as T cell markers and CD20 as B cell marker. RESULTS: All patients had complete remission of the symptoms after surgery. PFAPA patients had significantly smaller germinal center areas than controls. The number and density of CD8+ cells in germinal centers were significantly lower in tonsils from PFAPA compared with controls. No differences were found between the two groups in CD3+, CD4+, and CD20+ cells. These results are compatible with the tonsillar features of pediatric-onset PFAPA. CONCLUSION: Our report demonstrates that tonsillectomy might be effective for adult-onset PFAPA and that tonsils of adult- and pediatric-onset PFAPA share the same histological features. These results suggest that the pathogenic mechanisms of adult- and pediatric-onset PFAPA are identical.

We present a case of perilymphatic fistula (PLF) with inner ear anomalies having sudden, progressive sensorineural hearing loss and describe the fistula repair surgeries. We focus on the diagnosis methods of PLF and clinical course of PLF with inner ear anomaly. The cochlin-tomoprotein (CTP) detection test is very useful for the surgeons to encourage the earlier operation to sudden hearing loss cases. It is also helpful to define the diagnosis of PLF after operation. We could not get the good result as to hearing from the fistula repair surgery mainly because surgery was held 1 month after the onset. The results of the case, as well as recommendations of other reports, suggest that patients with sudden sensorineural hearing loss and PLF may need repair surgery within at most 2 weeks from the onset. We describe how to diagnose PLF more accurately using CTP detection combined with intraoperative findings.

In the context of acquired sensorineural hearing loss (SNHL), cochlear hair cells have long been thought to be among the most vulnerable elements in mammalian cochleae. However, recent studies have indicated that the synaptic connection between inner hair cells (IHC) and spiral ganglion neurons (SGN) can be an important target for the treatment of SNHL. Our previous studies in patients with sudden SNHL demonstrated delayed and gradual hearing recovery following topical application of insulin-like growth factor 1 (IGF-1), suggesting that not only protective but also regenerative mechanisms may account for hearing recovery after treatment with IGF-1. We then hypothesized that IGF-1 has the potential to drive the regeneration of IHC-SGN synapses. To test this hypothesis, we investigated the effects of IGF-1 on IHC-SGN synapses using cochlear explant cultures from postnatal day 2 mice that had been damaged by exposure to the excitatory amino acids N-methyl-d-aspartate and kainate. Cochlear explants that lost IHC-SGN synapses upon exposure to excitatory amino acids were cultured with exogenous IGF-1 for an additional 48 h. We observed increased numbers of IHC-SGN synapses after exogenous IGF-1 application. Pharmacological inhibition of the IGF-1 receptor attenuated the restoration of IHC-SGN synapses by exogenous IGF-1. These findings indicated that IGF-1 induces regeneration of IHC-SGN synapses in cochlear explant cultures from postnatal day 2 mice. Therefore, in a future study we will perform in vivo experiments using adult mice to ascertain the effects of IGF-1 on the regeneration of IHC-SGN synapses.

Malignant metastases to the thyroid are rare and even rarer from colorectal cancer (CRC). Most cases of CRC metastasis to the thyroid involve metastases to other organs as well, particularly the liver and/or lung. There are only three reports of CRC metastasizing to the thyroid without involvement of another site. Patients with solitary thyroid metastasis from CRC have a poor prognosis after surgery, whereas resection is beneficial in their counterparts with a solitary liver or lung metastasis. This difference could be the result of delayed diagnosis of thyroid metastasis in patients with CRC, given that postoperative follow-up examination of the thyroid is not routinely performed. Here we describe a patient who was found to have a solitary metastasis of sigmoid cancer to the thyroid on postoperative imaging and has had prolonged disease-free survival after thyroidectomy. Our experience suggests that a low threshold of suspicion is crucial for timely diagnosis of thyroid metastasis from CRC and that resection can improve disease-free survival.

Adult-onset periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome is a rare condition, having been reported in only three patients in Japan till date. While almost all pediatric PFAPA patients respond well to tonsillectomy, some European studies have reported that tonsillectomy may be ineffective for adult-onset PFAPA. All the Japanese patients with adult-onset PFAPA had been treated orally so far (cimetidine with or without prednisone), instead of tonsillectomy. We reported a case involving a 37-year-old Japanese man with PFAPA syndrome who presented with a history of febrile episodes associated with pharyngitis, cervical adenitis, and aphthous stomatitis for one year. The patient had been undergoing oral medication therapy without any significant improvement. Tonsillectomy was performed for the patient, and complete resolution of PFAPA was achieved. Our experience suggests that a tonsillectomy is a viable option for the treatment of adult-onset PFAPA.

The hybrid or electric-acoustic stimulation cochlear implant is indicated in patients with a residual hearing at low frequencies. It provides electric and acoustic stimulation for compensating for high- and low-frequency sounds, respectively. However, the implantation procedure damages the cochlea, resulting in loss of the residual-hearing and diminished effects of the acoustic-hearing in several patients. To prevent hearing loss after implantation, corticosteroids have been used clinically although their effects are limited. As an alternative to corticosteroids, insulin-like growth factor 1 (IGF1) has shown potent effects in various types of cochlear injury. In this study, the effects of IGF1 on hearing preservation were examined after cochlear implantation to a normal-hearing guinea pig model. The electrode was inserted in an atraumatic way through the round window membrane of guinea pigs with the application of a gelatin-sponge soaked with IGF1 or saline. The auditory brainstem response (ABR) was recorded pre-operatively, immediately after cochlear implantation, and 7, 14, 28, and 56 days after electrode insertion. In comparison to the control group, the IGF1-treated group showed better hearing preservation at low frequencies, 7 days after surgery. IGF1 application was effective at low frequencies (2 and 4 kHz) throughout the period of examination. Histological studies revealed that outer hair cell numbers, in the IGF1-treated group, were maintained in the cochlear region responsible for low-frequency hearing (upper midbasal turn) and that there was less fibrous tissue formation around the electrode. Both the outer hair cell counts and the extent of fibrosis significantly correlated with the ABR threshold shifts at low frequencies. These results indicate that IGF1 might attenuate loss of low-frequency hearing after cochlear implantation, suggesting its possible clinical use in soft surgeries involving cochlear implants with electric-acoustic stimulation for hearing preservation.

Systemic corticosteroids have been the mainstay of treatment for various hearing disorders for more than 30 yr. Accordingly, numerous studies have described glucocorticoids (GCs) and stressors to be protective in the auditory organ against damage associated with a variety of health conditions, including noise exposure. Conversely, stressors are also predictive risk factors for hearing disorders. How both of these contrasting stress actions are linked has remained elusive. Here, we demonstrate that higher corticosterone levels during acoustic trauma in female rats is highly correlated with a decline of auditory fiber responses in high-frequency cochlear regions, and that hearing thresholds and the outer hair cell functions (distortion products of otoacoustic emissions) are left unaffected. Moreover, when GC receptor (GR) or mineralocorticoid receptor (MR) activation was antagonized by mifepristone or spironolactone, respectively, GR, but not MR, inhibition significantly and permanently attenuated trauma-induced effects on auditory fiber responses, including inner hair cell ribbon loss and related reductions of early and late auditory brainstem responses. These findings strongly imply that higher corticosterone stress levels profoundly impair auditory nerve processing, which may influence central auditory acuity. These changes are likely GR mediated as they are prevented by mifepristone.-Singer, W., Kasini, K., Manthey, M., Eckert, P., Armbruster, P., Vogt, M. A., Jaumann, M., Dotta, M., Yamahara, K., Harasztosi, C., Zimmermann, U., Knipper, M., Rüttiger, L. The glucocorticoid antagonist mifepristone attenuates sound-induced long-term deficits in auditory nerve response and central auditory processing in female rats.

OBJECTIVE: A few chronic tinnitus patients show normal hearing thresholds in the pure tone audiometry from 125Hz to 8000Hz (≤20dB). We report the characteristics of the course of those patients underwent tinnitus retraining therapy (TRT) compared with other patients suffering from chronic and severe tinnitus. METHODS: We identified 13 patients with normal hearing thresholds among 242 patients suffering over 3 months, Tinnitus Handicap Inventory (THI) ≥16/100, and follow up period is over 6 months. We divided into two groups - tinnitus with normal audiometry and with hearing loss - and contrasted these patients with age, gender, tinnitus duration, instruments for TRT, loudness and pitch of the tinnitus, THI and Visual Analogue Scale (VAS) scores. RESULTS: The pitch-match of the tinnitus was higher and tinnitus duration was shorter in normal audiometry. The age is younger and the tinnitus loudness was smaller in normal hearing group significantly. THI of normal audiogram group showed significant improvement on 18 months treatment, though it once got worse on 12 months. THI of hearing loss group showed significant decreases in first 3 months and decreased slightly until 48 months treatment. The VAS scores of annoyance also showed a large decrease in first 3 months and decreased slightly until 24 months. Both THI after 48 months and VAS scores after 24 months treatment showed almost stable until 72 months in hearing loss group. CONCLUSION: Chronic tinnitus with normal audiometry and with hearing loss both showed adaptation with TRT. Normal audiometry group with chronic tinnitus may have damage in high frequency though there were not significant differences between two groups as to tinnitus pitch-match. They also need at least 18 months TRT to become adaptation, while 48 months treatment is enough and first 3 months treatment is very important for hearing loss with chronic tinnitus.

The presence of a cartilaginous mass on the bony external auditory canal is an unusual finding. Currently, two different diagnoses have been used to describe this type of mass: chondroma and cartilaginous choristoma. There is currently no consensus on which diagnosis is appropriate for this type of lesion. Choristoma is defined as a tumor-like growth of normal tissue occurring in an abnormal location. Histological examination alone cannot be used to distinguish between cartilaginous choristoma and chondroma, as both lesions comprise normal mature hyaline cartilage. To diagnose a mass as cartilaginous choristoma on the bony external auditory canal, it is necessary to confirm that it does not originate from the underlying periosteum. Here, we present the cases of two patients with typical cartilaginous masses on the bony external auditory canal, in which the surgical findings showed that the masses were not in contact with the underlying periosteum, indicating that cartilaginous choristoma-not chondroma-is an appropriate diagnosis for these mass lesions. The clinical findings (characteristic appearance and location) reported here may aid clinicians in the diagnostic and surgical management of these cartilaginous masses.

Sensorineural hearing loss (SNHL) is mainly caused by the damage of cochlear hair cells (HCs). As HCs and supporting cells (SCs) do not proliferate in postnatal mammals, the loss of HCs and SCs is irreversible, emphasizing the importance of preserving their numbers to prevent SNHL. It is known that insulin-like growth factor 1 (IGF1) is instrumental in the treatment of SNHL. Our previous study indicates that IGF1 protects HCs against aminoglycoside by activating IGF1 receptor and its two major downstream pathways, PI3K/AKT and MEK/ERK, in SCs, which results in the upregulation of the expression of the Netrin1-encoding gene (Ntn1). However, the mechanisms underlying IGF1-induced protection of HCs via SC activation as well as the role of NTN1 in this process have not been elucidated. Here, we demonstrated that NTN1, similar to IGF1, promoted HC survival. NTN1 blocking antibody attenuated IGF1-induced HC protection from aminoglycoside, indicating that NTN1 is the effector molecule of IGF1 signaling during HC protection. In situ hybridization demonstrated that IGF1 potently induced Ntn1 expression in SCs. NTN1 receptors were abundantly expressed in the cochlea; among them, UNC5B mediated IGF1 protective effects on HCs, as NTN1 binding to UNC5B inhibited HC apoptosis. These results provide new insights into the mechanisms underlying IGF1 protection of cochlear HCs, suggesting a possibility of using NTN1 as a new treatment for SNHL.

Sensorineural hearing loss (SNHL) is mainly caused by cochlear hair cell damage. Because cochlear hair cells and supporting cells lose their ability to proliferate in postnatal mammals, SNHL was thought to be an intractable disease. The maintenance of hair cell and supporting cell numbers after cochlear injury is therefore important for the treatment of sensorineural hearing loss. To achieve such treatment, protection and/or regeneration of hair cells is necessary. Progress in cochlear injury research, developmental biology, and regenerative medicine has led to the discovery of cochlear hair cells being protected or regenerated not only by direct reaction of hair cells themselves but also by that of supporting cells. Insulin-like growth factor 1 (IGF1) is considered a novel and potent treatment for SNHL based on the findings of various in vivo and in vitro experiments and clinical trials. The application of IGF1 maintains hair cell number of postnatal mammalian cochleae after various kinds of ototoxicity including aminoglycoside treatment, noise exposure, and ischemia. The positive effects of IGF1 on hair cell damage have been confirmed with in vivo animal experiments; hearing recovery in patients with sudden sensorineural hearing loss refractory to systemic glucocorticoid treatment has also been shown to occur following IGF1 treatment. The mechanisms of IGF1-induced maintenance of hair cell number have been investigated using a cochlear explant culture system, which demonstrated that IGF1 acts on supporting cells, leading to the inhibition of hair cell apoptosis and the proliferation of supporting cells. Netrin1 has furthermore been identified as one of the effectors whose expression is increased by IGF1 treatment.

Transcription factors are believed to play key roles in determining cell fate in inner ear development. Olig genes, which are basic helix-loop-helix transcription factors, have been reported to play important roles in the development of the central nervous system. However, members of this family have not previously been implicated in inner ear development, despite the similarity between otocyst and neural tube development. Olig1 begins to be expressed at the ventral domain of the otocyst at embryonic day (E) 9.5, and Olig1 expression in the epithelium of the developing inner ear persists to E15.5. Olig2 expression is localized to the cochleovestibular ganglia from E12.5 through E14.5. Olig3 has a diffuse expression pattern in the developing inner ear from E12.5 through the postnatal stage. Furthermore, at early stages of inner ear development, the Olig1 expression domain overlaps a region that is positive for Sox2 and Jagged1. This observation indicates that Olig1 may play an important role in the specification of the prosensory domain in the developing inner ear. As Olig genes are expressed in the mouse developing inner ear in a temporospatially distinct fashion, they may play substantial roles in the regulation of mammalian inner ear development.

35歳男性。左頸部の腫脹から近医を経て著者らの施設にある血管内科を受診、確定診断のため頸部リンパ節生検目的で耳鼻咽喉科へ紹介となった。所見では左上頸部に約3cm大のリンパ節腫脹がみられ、造影CTでは左レベルII～IIIに腫大した著明な造影効果を伴うリンパ節と少し離れた左レベルIIIに1cm大の造影効果を伴うリンパ節が認められた。しかし、左副咽頭間隙には石灰化を伴う約3cm大の造影効果を認めない腫瘤も認められた。一方、FDG-PETでは左頸部リンパ節に局所集積が認められるも、副咽頭間隙腫瘍には全く集積が認められなかった。以上より、本症例は悪性リンパ腫が疑われ、左レベルIIIの1cm大リンパ節の生検を行なったところ、病理組織学的に腺癌の転移であった。以後、原発巣検索のため胸部CTをはじめ上下部消化管内視鏡、甲状腺エコーが施行されたが異常所見は確認できず、次いで原発腫瘍を副咽頭間隙腫瘍である可能性を考え、造影MRIにより検討したが、副咽頭間隙腫瘍とリンパ節は明らかに性質が異なったものと考えられた。以後、術前診断は困難と判断して、原発巣は副咽頭間隙腫瘍または甲状腺微小癌の2つの可能性にしぼり、左頸部郭清術+左副咽頭間隙腫瘍摘出術+甲状腺左葉切除術を施行、あわせて術後、左頸部全域に60Gy/30fr、腫瘍床にboost10Gy/5frの総線量70Gy/35frの放射線照射が施行された。その結果、術後2年経過現在、再発は認められていない。

BACKGROUND: Notch signaling plays a crucial role in the fate determination of cochlear progenitor cells, hair cells, and supporting cells in the developing cochlea. Recent studies have demonstrated the temporal activation of Notch signaling in damaged mature cochleae, and have demonstrated the induction of new hair cells by pharmacologically inhibiting Notch signaling. The present study aimed to illustrate the feasibility of pharmacologically inhibiting Notch signaling by using a gamma-secretase inhibitor for treating sensorineural hearing loss. RESULTS: The effect of the sustained local delivery of MDL28170, a gamma-secretase inhibitor, on hearing and hair cell induction was tested in a guinea pig model with noise-induced hearing loss. MDL28170 was directly delivered into the cochlear fluids via a micro-osmotic pump. Drug application was initiated 7 days after noise exposure. Measurements of auditory brainstem responses revealed better hearing in the MDL28170-treated animals than in the vehicle controls. Histological analysis demonstrated a higher number of outer hair cells in the MDL28170-treated cochleae than the vehicle-treated cochleae. CONCLUSION: These findings strongly suggest that local sustained delivery of a gamma-secretase inhibitor into the cochlea could be a novel strategy for treating acute hearing loss that is refractory to conventional treatment.

68歳男性。半年ほど前から咳嗽と喀痰に続き、喘鳴や労作時呼吸困難感が出現、近医の総合病院にて気管支喘息の診断にて呼吸器内科入院となったが、気管支鏡検査で声門下気管後方に腫瘍を認め、生検にて扁平上皮癌と診断され、著者らの施設へ緊急転院となった。転院時、酸素投与なしでSpO2は96%であったが、呼吸苦が著明で喘鳴を伴っていた。また、頸部単純CTでは腫瘍の長径は約5cm大で、気管膜様部原発の腫瘍は上方が輪状軟骨、下方が第3気管輪レベルまで広がっていた。以上より、気管癌と診断され、入院翌日に緊急手術が行われたが、術中所見では気管内挿管は困難と判断され、経皮的心肺補助装置(PCPS)を使用して気管切開を行い、気管膜様部に存在の腫瘍を直視下に切り下ろし、頸部襟状切開を加えて右頸部郭清術を行った。そして、甲状腺を全摘したところ、両側の気管傍リンパ節腫大は上縦隔まで連続しており、気管を上方に牽引することでリンパ節を持ち上げ郭清した。また更に舌骨上筋群を切断して喉頭全摘を行い、腫瘍を直視下に確認、気管を第7気管輪で切断し、摘出した。その結果、術後は化学放射線療法も施行されたが、患者はリンパ節・肺転移を来し、術後15ヵ月で死亡となった。

82歳女性。嚥下時の違和感を主訴に近医の耳鼻咽喉科を受診、左下咽頭梨状陥凹に腫瘍を指摘され、著者らの施設へ紹介来院となった。初診時、喉頭ファイバーでは左下咽頭梨状陥凹に表面平滑な腫瘍が認められ、下咽頭癌の可能性が考えられた。そこで、咽頭ファイバー下に腫瘍からの生検が行われたが悪性所見は得られなかった。一方、造影CTでは左下咽頭梨状陥凹に著明な造影効果を持つ最大径約3cm大の、内部に石灰化を認めない腫瘍が確認された。更にMRIでは同部にT1強調像で低信号、T2強調像で高信号の境界不明瞭な腫瘍が認められたが、PETでの同部位の集積は軽度であった。以上、これらの所見から本症例は悪性腫瘍の可能性が否定できないため直達喉頭鏡下生検を施行したところ、表面粘膜は正常で粘膜下腫瘍と判断された。また、前回同様に炎症性細胞の浸潤のみで確定診断には至らず、良性腫瘍と考えられた。以後、頸部外切開による腫瘍摘出術を施行した結果、摘出標本の病理組織学的所見では黄紋筋組織内に大小の血管が混在して増生しており、筋肉内血管腫の混在型と診断され、臨床所見から後輪状披裂筋に発生した筋肉内血管腫と診断された。尚、患者は術後14日目に退院となり、目下、術後12ヵ月経過で再発は認められていない。