The Heterogeneous Impact of Prediagnostic Folate Intake for Fluorouracil-Containing Induction Chemotherapy for Head and Neck Cancer.

Fluorouracil (FU) exerts its antitumor activity by inhibiting folate-mediated one-carbon metabolism. Evidence that folate may play a role in the carcinogenic process via folate-mediated one-carbon metabolism has given rise to the hypothesis that pre-diagnostic folate intake may induce heterogeneous chemosensitivity to FU-containing induction chemotherapy (IC) in head and neck cancer. To assess this hypothesis, we conducted a cohort study to investigate whether the association between prediagnostic dietary folate intake and cancer survival differed between treatment regimens with and without FU-containing IC in 504 cases of locally advanced (stage III/IV) HNSCC, using an epidemiologic database combined with clinical data. In total, 240 patients were treated with FU-containing IC followed by definitive treatment, and 264 patients were treated with definitive treatment alone. Definitive treatment is defined as (1) the surgical excision of a tumor with clear margins, with or without neck lymph node dissection; or (2) radiotherapy with or without chemotherapy. In the overall cohort of the FU-containing IC group, a higher folate intake was significantly associated with better overall survival (adjusted hazard ratios (HRs) for the highest compared to the lowest folate tertiles (HRT3-T1) = 0.42, 95%CI, 0.25-0.76, Ptrend = 0.003). Conversely, no apparent association between prediagnostic folate intake and survival was observed with definitive treatment alone (HRT3-T1: 0.83, 95%CI, 0.49-1.42, Ptrend = 0.491)). A consideration of the cumulative dose of FU-containing IC showed that the survival impact of prediagnostic folate intake differed statistically significantly by treatment regimen (Pinteraction = 0.012). In conclusion, an association between prediagnostic folate intake and HNSCC survival significantly differed by FU-containing IC. This finding indicates that in the carcinogenic process, folate status causes HNSCC to be heterogenous in terms of one-carbon metabolism.

Frequency-dependent hearing outcomes with or without preservation of intact ossicular articulations.

Objective: To determine the frequency-specific benefits of ossicular chain preservation compared to performing disarticulations and reconstructions in transmastoid facial nerve decompression surgery in patients with an intact ossicular chain. Methods: A retrospective chart review (January 2007 and June 2018) of patients undergoing transmastoid facial nerve decompression on the intact middle ear for severe facial palsy at a tertiary referral center. Surgery was performed with ossicular chain disarticulation on an as-needed basis using either ossicular chain preservation (without ossicular disarticulation), incudostapedial separation, or incus disarticulation technique. Hearing outcomes were assessed. Results: The 108 patients were included in this study. Among these, 89 patients underwent ossicular chain preservation, 5 underwent incudostapedial separation and 14 underwent incus repositioning. The proportion of patients with a change in the 4-frequency air conduction pure-tone average of less than 10 dB was 91%, 60%, and 50%, respectively, for the three surgical techniques; these were significantly different (Fisher's exact test, p < .001). Frequency-specific analysis showed that air conduction was significantly better following the ossicular chain preservation technique compared with the incus repositioning technique at stimulation frequencies lower than 250 Hz and higher than 2000 Hz, and compared with the incudostapedial separation technique at 4000 Hz. Analysis of biometric measures determined on CT images suggested that the feasibility of the ossicular chain preservation technique correlates with incus body thickness on coronal CT images. Conclusions: Ossicular chain preservation is an effective approach for hearing preservation in transmastoid facial nerve decompression or similar surgical procedures.

Mature dendritic cells enriched in regulatory molecules may control regulatory T cells and the prognosis of head and neck cancer.

We previously reported that regulatory T (Treg) cells expressing CTLA-4 on the cell surface are abundant in head and neck squamous cell carcinoma (HNSCC). The role of expanded Treg cells in the tumor microenvironment of HNSCC remains unclear. In this study, we reveal that the tumor microenvironment of HNSCC is characterized by the high expression of genes related to Treg cells, dendritic cells (DCs), and interleukin (IL)-17-related molecules. Increased expression of IL17A, IL17F, or IL23A contributes to a favorable prognosis of HNSCC. In the tumor microenvironment of HNSCC, IL23A and IL12B are expressed in mature dendritic cells enriched in regulatory molecules (mregDCs). The mregDCs in HNSCC are a migratory and mature phenotype; their signature genes strongly correlate with Treg signature genes in HNSCC. We also observed that IL17A was highly expressed in Th17 cells and exhausted CD8+ T cells in HNSCC. These data suggest that mregDCs in HNSCC may contribute to the prognosis by balancing Treg cells and effector T cells that produce IL-17. Targeting mregDCs may be a novel strategy for developing new immune therapies against HNSCC.

Acoustic neuromas associated with sudden sensorineural hearing loss.

BACKGROUND: Several studies have reported sudden sensorineural hearing loss (SHL) as an initial symptom of acoustic neuromas (ANs). AIMS/OBJECTIVES: We aimed to retrospectively evaluate the incidence of SHL and the associated rates of post-treatment improvement in patients diagnosed with ANs. MATERIALS AND METHODS: We analysed the clinical data of 686 patients with ANs and examined tumour size, correlation with hearing loss, number of episodes of SHL, extent of auditory recovery, and associated audiogram patterns. RESULTS: Among 686 enrolled patients with ANs, 232 (86 with intracanalicular and 146 with extrameatal tumours) experienced SHL at some point in their clinical history. The incidence of SHL was not significantly associated with tumour size. Of the 172 patients analysed, 119, 44, and 9 patients experienced one, two, or three or more episodes of SHL, respectively. Confirmed auditory recovery occurred in 61%, 45.3%, and 33.3% of the patients after the first, second, or third or later episodes of SHL, respectively. The audiograms of 78/172 (45.3%) patients showed a typical trough-shaped pattern of hearing loss at medium-level frequencies. CONCLUSIONS AND SIGNIFICANCE: Among patients with ANs, 7.7% experienced two or more episodes of SHL. The recovery rate of SHL decreased with each successive occurrence.

Different voltage dependence of ICaL blockade in nonselective IKr blockers causes their opposite effects on early afterdepolarization in drug-induced arrhythmia.

Several false-positive results in the human ether-à-gogo-related gene test suggest that blockers of the rapid component of delayed rectifier K+ current (IKr) do not necessarily produce drug-induced arrhythmias. Specifically, the occurrence of early afterdepolarization (EAD) differs among IKr blockers, even if the prolonged action potential duration is in the same range. To predict EAD in drug-induced arrhythmias, we proposed a prediction method based on the mechanisms underlying the difference in frequency of EAD among nonselective IKr blockers. The mechanisms were elucidated by examining how different blockade kinetics of L-type Ca2+ current (ICaL) affect the frequency of EAD, using mathematical models of human ventricular myocytes. Addition of voltage-independent ICaL blockade resulted in the suppression of EAD. However, when voltage-dependent ICaL blockade kinetics of amiodarone, bepridil, and terfenadine were incorporated into ICaL in the model, bepridil and terfenadine induced EAD more than the voltage-independent ICaL blockade, while amiodarone suppressed EAD more effectively. Opposite effects were accounted for by the difference in ICaL blockade at negatively polarized potential. EAD occurrence was found to be associated with ICaL blockade measured at -20 mV. These results suggest that voltage dependence of ICaL blockade may be useful in predicting the different risks of nonselective IKr blockers.

Intratympanic steroid therapy for Bell's palsy with poor prognostic results.

In Bell's palsy, electrodiagnosis by electroneurography (ENoG) is widely used to predict a patient's prognosis. The therapeutic options for patients with poor prognostic results remain controversial. Here, we investigated whether early intervention with intratympanic steroid therapy (ITST) is an effective treatment for Bell's palsy patients with poor electrodiagnostic test results (≤ 10% electroneurography value). Patients in the concurrent ITST group (n = 8) received the standard systemic dose of prednisolone (410 mg total) and intratympanic dexamethasone (16.5 mg total) and those in the control group (n = 21) received systemic prednisolone at the standard dose or higher (average dose, 605 ± 27 mg). A year after onset, the recovery rate was higher in the ITST group than in the control group (88% vs 43%, P = 0.044). The average House-Brackmann grade was better in the concurrent ITST group (1.13 ± 0.13 vs 1.71 ± 0.16, P = 0.035). Concurrent ITST improves the facial nerve outcome in patients with poor electroneurography test results, regardless of whether equivalent or lower glucocorticoid doses were administered. This may be ascribed to a neuroprotective effect of ITST due to a higher dose of steroid reaching the lesion due to dexamethasone transfer in the facial nerve.

A Multi-Institutional Study of Older Hearing Aids Beginners-A Prospective Single-Arm Observation on Executive Function and Social Interaction.

OBJECTIVES: To obtain new insights into research questions on how executive function and social interaction would be observed to change after the introduction of hearing aids (HAs) in older people with hearing impairment. DESIGN: Multi-institutional prospective single-arm observational study. SETTING AND PARTICIPANTS: Outpatients with complaints of hearing difficulty who visited HA clinics between October 18, 2017, and June 30, 2019, in 7 different university hospitals in Japan. METHODS: The inclusion criteria of the study named Hearing-Aid Introduction for Hearing-Impaired Seniors to Realize a Productive Aging Society-A Study Focusing on Executive Function and Social Activities Study (HA-ProA study) were age ≥60 years and no history of HA use. A series of multi-institution common evaluations including audiometric measurements, the digit symbol substitution test to assess executive functions, convoy model as an index of social relations, and hearing handicap inventory for the elderly (HHIE) were performed before (pre-HA) and after 6 months of the HA introduction (post-HA). RESULTS: Out of 127 enrollments, 94 participants completed a 6-month follow-up, with a mean age of 76.9 years. The digit symbol substitution test score improved significantly from 44.7 at baseline to 46.1 at 6 months (P = .0106). In the convoy model, the social network size indicated by the number of persons in each and whole circles were not significantly different between pre- and post-HA; however, the total count for kin was significantly increased (P = .0344). In the analyses of HHIE, the items regarding the family and relatives showed significant improvement. CONCLUSIONS AND IMPLICATIONS: HA use could benefit older individuals beginning to use HAs in executive function and social interaction, though the results should be interpreted cautiously given methodological limitations such as a single-arm short 6 months observation. Reduction in daily hearing impairment would have a favorable effect on relationships with the family.

Oncolytic activity of naturally attenuated herpes-simplex virus HF10 against an immunocompetent model of oral carcinoma.

Prognosis for advanced oral carcinoma remains poor. Oncolytic virotherapy uses replication-competent viruses to infect and kill only the tumor cells. However, it has been difficult to investigate the oncolytic activity of viruses against oral carcinomas in mouse models. This study established a mouse model of oral cancer and investigated the in vitro and in vivo anti-tumor effects of HF10, a highly attenuated, replication-competent herpes simplex virus (HSV)-1. Mouse tongue cancer was induced by injecting 4-nitroquinoline 1-oxide into the mouse tongue. The murine oral cancer cell line isolated from this tumor, named NMOC1, formed invasive carcinoma within a week when injected into mouse tongue. HF10 successfully infected, replicated, and spread in the cancer cells in vitro. HF10 was able to kill cancer cells isolated from human or mouse tongue tumor. HF10 injection into tongue carcinomas prolonged mouse survival without any side effects or weight loss. Intertumoral injection of GFP-expressing HF10 confirmed that viral spread was confined within the tumors. Immunohistochemical staining showed that HF10 induced infiltration of CD8-positive T cells around HSV-infected cells in the tumor mass, implying increased anti-tumor immunity. We successfully established an oral cancer cell line and showed that HF10 is a promising therapeutic agent for oral cancer.

Clinical characteristics, the diagnostic criteria and management recommendation of otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) proposed by Japan Otological Society.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a form of necrotizing vasculitis with few or no immune deposits. It primarily affects small and medium blood vessels. AAV is classified into three categories, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangitis (EGPA), and two major ANCAs, proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA are involved in their pathogenesis. Intractable otitis media frequently occurs in patients with GPA, MPA or EGPA, although all patients show similar clinical features, regardless of the type of AAV. Furthermore, approximately 15% patients with otitis media caused by AAV do not show ANCA positivity, histopathological evidence, or any other AAV-related lesions at the initial visit; therefore, these patients do not fulfill the ordinary diagnostic criteria for systemic AAV. Thus, we first proposed that this condition could be categorized as "otitis media with AAV (OMAAV)". Subsequently, the Japanese Otological Society (JOS) conducted a nationwide survey between December 2013 and February 2014 and identified 297 patients with OMAAV. The survey revealed that OMAAV is a disease that initially occurs in the middle ear and subsequently spreads to other organs such as the lungs and kidneys, with eventual involvement of all body organs. Severe sequelae such as facial palsy, hypertrophic pachymeningitis, complete deafness, and subarachnoid hemorrhage resulting in death can also occur. In this review, we introduce the clinical features, diagnostic criteria, and treatment strategies recommended by JOS for early diagnosis and treatment of OMAAV.

Facial and hearing outcomes in transmastoid nerve decompression for Bell's palsy, with preservation of the ossicular chain.

OBJECTIVES: Facial nerve decompression is a salvage treatment for Bell's palsy patients for whom a poor prognosis is anticipated with standard medical treatment. The transmastoid approach is a frequently performed approach, but it remains unknown if this surgery is effective when the ossicular chain is preserved. This study aimed to determine the efficacy of facial nerve decompression using the transmastoid approach in Bell's palsy. DESIGN, SETTING AND PARTICIPANTS: This retrospective study included patients who had undergone transmastoid facial nerve decompression with ossicular chain preservation and patients who met the criteria for surgery, but received only medical treatment between January 2007 and May 2019, at a single centre. MAIN OUTCOME MEASURES: Attainment of House-Brackmann grade I at 12 months after onset of facial palsy. RESULTS: The recovery rate to House-Brackmann grade I in the decompression group in the early phase (≤18 days after onset) was higher than that of the medical treatment group, although the difference was not significant (70% vs 47%, P = .160). However, within this early surgery group, a subgroup of cases with ≥95% facial nerve degeneration demonstrated a significant improvement in recovery rate (73% vs 30%, P = .018). Among surgeries performed in the late phase (≥19 days), only a subgroup with ≥95% facial nerve degeneration was available for analysis, and the difference in recovery rate was not significant compared with medical treatment alone (26% vs 30%, P = 1.00). Post-surgical hearing evaluation demonstrated that average hearing deterioration was 1.3 dB which was non-significant, suggesting this procedure does not cause hearing loss. CONCLUSIONS: Transmastoid facial nerve decompression with ossicular chain preservation in the early phase after symptom-onset is an effective salvage treatment for severe Bell's palsy with ≥95% facial nerve degeneration.

Effect of muscle strengthening on peripheral facial palsy: A randomized controlled trial.

OBJECTIVE: To evaluate the effect of muscle strengthening intervention in peripheral facial palsy (PFP). METHODS: A randomized controlled trial was conducted at five hospitals. Fifty-one subjects with PFP who showed a response of less than 20% on electroneurography (ENoG) were enrolled. Subjects in a muscle-strengthening-intervention group (MS Group) underwent a selective muscle contraction intervention (SMCI). Subjects in another group not receiving muscle strengthening intervention (Non-MS Group). Both groups underwent three interventions: Prohibition of maximum effort movements, Stretching of the affected facial muscles, and Mirror biofeedback therapy. The outcomes were measured by the Sunnybrook Facial Grading System (FGS) at 6 months after onset (primary endpoint) and at 12 months after onset (secondary endpoint). The subjects in the MS Group and Non-MS Group were further divided into subgroups showing ENoG responses of 10% or less and ENoG responses of over 10%, as a sub-analysis. RESULTS: No significant differences between the MS Group and Non-MS Group at either the primary endpoint or secondary endpoint. Among the subjects in the treatment group with an ENoG response of over 10% at the primary endpoint, the FGS Composite Score and FGS Voluntary Movement score were both significantly higher in the MS Group than in Non-MS Group. Although the MS Group had a significantly lower FGS Resting Symmetry Score, there was no significant difference between the two groups in the FGS Synkinesis Score. CONCLUSIONS: SMCI improved paralysis in subjects exhibiting an ENoG response of over 10% within the 6 months from onset without any deterioration of synkinesis.

Data for temporal facial nerve recovery in Ramsay Hunt syndrome following intratympanic steroid therapy.

This article contains data related to the research article entitled "Concurrent treatment with intratympanic dexamethasone improves facial nerve recovery in Ramsay Hunt syndrome" (Akira Inagaki, Toshiya Minakata, Schiyo Katsumi, Shingo Murakami) [1]. This data article reports the protocol for a clinical trial investigating the benefit of intratympanic steroid therapy on facial recovery in Ramsay Hunt syndrome and temporal facial recovery. The data included in this article are as follows: inclusion and exclusion criteria, the treatment protocol of steroids and antiviral therapies, facial recovery as assessed by the House-Brackmann scale in all enrolled patients, House-Brackmann scores in patients with a poor electrophysiological result, and House-Brackmann scores after propensity score matching. This article will be useful for related investigations or clinical practices in the future by serving as a model and benchmark.

Concurrent treatment with intratympanic dexamethasone improves facial nerve recovery in Ramsay Hunt syndrome.

OBJECTIVE: To determine whether early intervention with intratympanic steroid injections, known as concurrent intratympanic steroid therapy (ITST), is an effective supplement to systemic steroid therapy for moderately-severe to severe Ramsay Hunt syndrome. METHODS: Forty-six patients with Ramsay Hunt syndrome (House-Brackmann grade IV or higher) who received either concurrent ITST with standard systemic steroid therapy (ITST group, n = 12) or standard systemic therapy alone (control group, n = 34) with antivirals starting within 7 days of onset. Patients in the concurrent ITST group received the standard systemic dose of prednisolone (410 mg in total) and intratympanic dexamethasone (16.5 mg in total) over 10 consecutive days. Patients in the control group received systemic prednisolone at the standard dose or higher (average dose, 581 ± 25 mg). RESULTS: The recovery rate was higher in the concurrent ITST group than in the control group (93% vs 47%, P = .013). The adjusted odds ratio was 22.2 (95% confidence interval 1.32-373.58, P = .031). CONCLUSIONS: The recovery rate was higher after concurrent systemic and intratympanic steroid therapy than after standard systemic steroid therapy, regardless of whether the steroid used had lower or equivalent glucocorticoid potency. This finding suggests that concurrent intratympanic steroid therapy is a beneficial supplement in patients with Ramsay Hunt syndrome.

Oncolytic activity of HF10 in head and neck squamous cell carcinomas.

Recent developments in therapeutic strategies have improved the prognosis of head and neck squamous cell carcinoma (HNSCC). Nevertheless, 5-year survival rate remains only 40%, necessitating new therapeutic agents. Oncolytic virotherapy entails use of replication-competent viruses to selectively kill cancer cells. We aimed to explore the potential of HF10 as an oncolytic virus against human or mouse HNSCC cell lines, and primary-cultured HNSCC cells. HF10 replicated well in all the HNSCC cells, in which it induced cytopathic effects and cell killing. Next, we investigated the oncolytic effects of HF10 in ear tumor models with human or mouse tumor cells. We detected HF10-infected cells within the ear tumors based on their expression of green fluorescent protein. HF10 injection suppressed ear tumor growth and prolonged overall survival. In the syngeneic model, HF10 infection induced tumor necrosis with infiltration of CD8-positive cells. Moreover, the splenocytes of HF10-treated mice released antitumor cytokines, IL-2, IL-12, IFN-alpha, IFN-beta, IFN-gamma, and TNF-alpha, after stimulation with tumor cells in vitro. The HF10-treated mice that survived their original tumor burdens rejected tumor cells upon re-challenge. These results suggested that HF10 killed HNSCC cells and induced antitumoral immunity, thereby establishing it as a promising agent for the treatment of HNSCC patients.

Clinical practice guidelines for diagnosis and treatment of chronic tinnitus in Japan.

Clinical practice guidelines in Japan for tinnitus were published in May 2019. Effective treatment of tinnitus contributes to quality of life and may improve depression, anxiety, and cognitive function. The highest priority of treatment recommended by this guideline involves educational counseling, including an explanation of the mechanisms of tinnitus. Understanding tinnitus pathology has also been reported to be a therapeutically effective educational counseling strategy. Further, explaining how sound therapy such as tinnitus retraining therapy (TRT) works is effective. Psychological and cognitive behavioral therapies may be an option. Here, the hearing aid is coupled with a sound generator in order to administer sound therapy for patients with more-severe symptoms. In Japan, it can be difficult to perform psychotherapy alongside otorhinolaryngology, and exemplary sound therapy is more likely to be carried out. In any case, the purpose of treatment is not to eliminate tinnitus, but rather reduce distress that manifests in response to tinnitus by promoting sensory adaptation. Clinically, the most important subject is not the loudness of tinnitus, but the severity of tinnitus distress. TRT consists of educational counseling and sound therapy. The tinnitus handicap inventory (THI) is used to measure the distress level for tinnitus and to determine treatment priorities. Rehabilitation of tinnitus is important because anxiety and depression are often observed in patients with severe tinnitus. Additionally, drug administration should be avoided. As a surgical treatment, a cochlear implant can affect tinnitus symptoms. It is essential to establish a treatment policy according to the disease condition and degree of distress.

Clinical and Radiological Characteristics of Malignant Tumors Located to the Cerebellopontine Angle and/or Internal Acoustic Meatus.

OBJECTIVE: Metastatic lesions to the internal auditory meatus (IAM) and/or the cerebellopontine angle (CPA) are rare and may appear like a vestibular schwannoma (VS). We herein raise the issue of the diagnosis and treatment of nine malignant cases of the CPA and IAM among three referral centers in France and Japan. The aim of this study was 1) to report malignant lesions of the CPA, their diagnosis and treatment, 2) to review the literature, 3) to propose criteria of suspicion for malignant tumors of the CPA. METHODS: Nine patients who had malignant lesions of the CPA and/or IAM for whom the final diagnosis was made by surgery, lumbar puncture, or PET scan were included. The main outcomes measured were: rapid onset of symptoms, association of cochlea-vestibular symptoms with facial palsy, and MRI analysis. RESULTS: Among the nine patients with malignant tumor of the CPA, 8 of them (89%) had a facial palsy associated with cochlea-vestibular symptoms. Rapid growth of the tumor was observed in 77% (7/9) of the cases in a mean time interval of 4.6 months. The initial diagnosis evoked was VS in 44% of the cases (4/9). Atypical MRI aspect was seen in 67% of the cases (6/9) with bilateral tumors in 55% of cases (5/9). CONCLUSION: Although rare, malignant tumors of the CPA and/or IAM should be evoked in case of association of cochleovestibular symptoms and facial palsy, rapid onset and atypical MRI aspect.

Concurrent Treatment With Intratympanic Dexamethasone for Moderate-Severe Through Severe Bell's Palsy.

OBJECTIVE: To determine whether early intervention with intratympanic steroid injection, known as concurrent intratympanic steroid therapy, is effective as a supplement to systemic steroid therapy for treating moderate-severe to severe Bell's palsy. DESIGN: An open-label historical control trial. SETTING: Tertiary referral center. PARTICIPANTS: A total of 35 Bell's palsy patients presenting with House-Brackmann grade IV or higher were treated with intratympanic steroid therapy concurrent with standard systemic treatment and compared with 108 patients treated with standard systemic therapy alone started within 7 days of onset. INTERVENTIONS: In the concurrent intratympanic steroid therapy group, patients received both 410 mg of prednisolone (standard dose) and 1.65 mg of intratympanic dexamethasone for 10 consecutive days. Patients in the control group received the standard dose, or more, of systemic prednisolone. Both groups were additionally treated with valacyclovir. MAIN OUTCOMES AND MEASURES: The primary outcome measure was restoration of a House-Brackmann score of grade I. RESULTS: The rate of recovery to House-Brackmann Grade I was higher for the concurrent intratympanic steroid therapy group than for the control group (94% vs 73%, p = 0.008). The adjusted odds ratio was 5.47 (95% confidence interval: 1.18-25.21, p = 0.029). CONCLUSIONS: The recovery rate was higher for concurrent intratympanic steroid therapy treatment than for standard-of-care control treatment, regardless of whether steroid with lower or equivalent glucocorticoid action was administered. This result suggests that concurrent treatment with intratympanic steroid therapy is a potentially beneficial supplement to systemic steroid administration.

Calcium-Sensing Receptor Is Functionally Expressed in the Cochlear Perilymphatic Compartment and Essential for Hearing.

Maintaining Ca2+ homeostasis in lymphatic fluids is necessary for proper hearing. Despite its significance, the mechanisms that maintain the cochlear lymphatic Ca2+ concentrations within a certain range are not fully clarified. We investigated the functional expression of calcium-sensing receptor (CaSR), which plays a pivotal role in sensing extracellular Ca2+ concentrations for feedback regulations. Western blotting for CaSR revealed an approximately 130-kDa protein expression in cochlear tissue extracts and immunohistochemical analysis revealed its expression specifically in type I fibrocytes in the spiral ligament, fibrocytes in the supralimbal and limbal regions, the epithelium of the osseous spiral lamina, and the smooth muscle cells of the spiral modiolar arteries. Ca2+ imaging demonstrated that extracellular Ca2+ increased the levels of intracellular Ca2+ in CaSR-expressing fibrocytes in the spiral ligament, and that this was suppressed by the CaSR inhibitor, NPS2143. Furthermore, hearing thresholds were moderately elevated by intracochlear application of the CaSR inhibitors NPS2143 and Calhex231, across a range of frequencies (8-32 kHz). These results demonstrate the functional expression of CaSR in the cochlear perilymphatic compartment. In addition, the elevated hearing thresholds that are achieved by inhibiting CaSR suggest this is a required mechanism for normal hearing, presumably by sensing perilymphatic Ca2+ to stabilize Ca2+ concentrations within a certain range. These results provide novel insight into the mechanisms regulating Ca2+ homeostasis in the cochlea and provide a new perspective on cochlear physiology.