Severe Type 2 Inflammation Leads to High Platelet-Activating-Factor-Associated Pathology in Chronic Rhinosinusitis with Nasal Polyps-A Hierarchical Cluster Analysis Using Bulk RNA Barcoding and Sequencing.

Platelet-activating factor (PAF) is a phospholipid-derived inflammatory mediator that triggers various inflammatory conditions, including eosinophil activation and recruitment. This study aimed to evaluate the expressions of PAF-metabolism-associated genes, namely genes coding the enzymes involved in PAF synthesis (LPCAT1, LPCAT2, LPCAT3, and LPCAT4), PAF degradation (PAFAH1B2, PAFAH1B3, and PAFAH2), and the gene for the PAF receptor (PTAFR) in subtypes of CRSwNP classified by clinical- or hierarchal-analysis-based classifications. Transcriptomic analysis using bulk RNA barcoding and sequencing (BRB-seq) was performed with CRSwNP, including eosinophilic CRS (ECRS) (n = 9), nonECRS (n = 8), ECRS with aspirin-exacerbated respiratory disease (Asp) (n = 3), and controls with a normal uncinate process mucosa (n = 6). PTAFR was only upregulated in ECRS and nonECRS. In the hierarchical cluster analysis with clusters 1 and 2 reflecting patients with low-to-moderate and high levels of type 2 inflammation, respectively, cluster 1 exhibited a significant downregulation of LPCAT2 and an upregulation of PTAFR expression, while cluster 2 showed an upregulation of LPCAT1, PAFAH1B2, and PTAFR and downregulation of PAFAH2 expression. Understanding this strong PAF-associated pathophysiology in the severe type 2 inflammation group could provide valuable insights into the treatment and management of CRSwNP.

Oncostatin M's Involvement in the Pathogenesis of Chronic Rhinosinusitis: Focus on Type 1 and 2 Inflammation.

OBJECTIVES: The cytokine oncostatin M (OSM) elicits pathogenic effects involving disruption of the epithelial barrier function as a part of immunological response networks. It is unclear how these integrated cytokine signals influence inflammation and other physiological processes in the pathology of chronic rhinosinusitis (CRS). We investigated the expression and distribution of OSM and OSM receptor (OSMR) in CRS patients' sinonasal specimens, and we compared the results with a panel of inflammatory cytokine levels and clinical features. PATIENTS AND METHODS: We classified CRS patients as eosinophilic (ECRS, n = 36) or non-eosinophilic (non-ECRS, n = 35) based on the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis phenotypic criteria and compared their cases with those of 20 control subjects. We also examined OSM's stimulatory effects on cytokine receptor expression levels using the human bronchial epithelium cell line BEAS-2B. RESULTS: RT-PCR showed that the OSM mRNA levels were significantly increased in the CRS patients' ethmoid sinus mucosa. The OSM mRNA levels were positively correlated with those of TNF-α, IL-1ß, IL-13, and OSMR-ß. In BEAS-2B cells, OSM treatment induced significant increases in the OSMRß, IL-1R1, and IL-13Ra mRNA levels. CONCLUSIONS: OSM is involved in the pathogenesis of CRS in both type 1 and type 2 inflammation, suggesting the OSM signaling pathway as a potential therapeutic target for modulating epithelial stromal interactions.

Swallowing Exercise Evaluated Using High-Density Surface Electromyography in Patients with Head and Neck Cancer: Supplementary Analysis of an Exploratory Phase II Trial.

Background and Objectives: Muscle strength evaluation using high-density surface electromyography (HD-sEMG) was recently developed for the detailed analysis of the motor unit (MU). Detection of the spatial distribution of sEMG can detect changes in MU recruitment patterns resulting from muscle-strengthening exercises. We conducted a prospective study in 2022 to evaluate the safety and feasibility of transcutaneous electrical sensory stimulation (TESS) therapy using an interferential current device (IFCD) in patients with head and neck squamous cell carcinoma (HNSCC) undergoing chemoradiotherapy (CRT), and reported the safety and feasibility of TESS. We evaluated the efficacy of swallowing exercises in patients with HNSCC undergoing CRT and determined the significance of sEMG in evaluating swallowing function. Materials and Methods: In this supplementary study, the patients performed muscle-strengthening exercises five days a week. The association of the effects of the exercises with body mass index, skeletal muscle mass index, HD-sEMG, tongue muscle strength, and tongue pressure were evaluated. Results: We found significant correlations between the rate of weight loss and skeletal muscle mass index reduction and the rate of change in the recruitment of the MU of the suprahyoid muscle group measured using HD-sEMG. Conclusions: We believe that nutritional supplementation is necessary in addition to muscle strengthening during CRT.

Exhaled Nitric Oxide and Olfactory Dysfunction in Patients with Asthma: Association with Chronic Rhinosinusitis.

Objectives: Olfactory dysfunction is a clinical sign that is important to detect with coexistent upper airway comorbidities in patients with asthma. This study aimed to investigate the etiology of olfactory dysfunction in patients with asthma and the relationship between fractional exhaled nitric oxide (FeNO) levels. Materials and Methods: This study included 47 asthma patients who were evaluated for olfactory dysfunction at Hiroshima University Hospital between 2012 and 2020. The etiologies of olfactory dysfunction were evaluated, and they were classified according to the FeNO levels of patients with asthma. Results: Olfactory dysfunction was observed in 30 patients with asthma, with chronic rhinosinusitis (77%) being the most prevalent etiology. Eosinophilic chronic rhinosinusitis (ECRS) was the most prevalent etiology of olfactory dysfunction in asthma patients with high FeNO levels (≥25 ppb), while non-eosinophilic chronic rhinosinusitis (NCRS) was the most prevalent etiology in asthma patients with low FeNO levels (<25 ppb). Additionally, the prevalence of ECRS was significantly higher in asthma patients with olfactory dysfunction and high FeNO levels (74%) than in those with either high FeNO levels or olfactory dysfunction and those with low FeNO levels and no olfactory dysfunction (12% and 9%, respectively). Conclusions: We found that ECRS was the predominant cause of olfactory dysfunction in patients with high FeNO levels, while NCRS was more common in those with low FeNO levels. The present study showed that both ECRS and NCRS are common etiologies of olfactory dysfunction in patients with asthma. Additionally, this study supports the link between upper and lower airway inflammation in patients with asthma complicated with olfactory dysfunction.

Evaluation of the Safety of Percutaneous Sensory Nerve Stimulation in Patients with Head and Neck Cancer Receiving Chemoradiotherapy.

Chemoradiotherapy (CRT) is the standard treatment for locally advanced head and neck cancer; however, CRT may cause post-treatment dysphagia. Transcutaneous electrical sensory stimulation (TESS), developed in recent years for swallowing rehabilitation, is used at many medical facilities. Although TESS has been used for dysphagia in several fields, its safety and efficacy in patients with head and neck cancer remain to be clarified. Therefore, this study evaluated the safety of TESS in ten patients with head and neck cancers undergoing CRT. Swallowing rehabilitation intervention and TESS implementation were performed for all patients during CRT. Non-blood-toxicity adverse events (AEs), such as dermatitis and mucositis, occurred during CRT; however, the severity was less than grade 3. No patient experienced pain due to TESS. As survival time analysis using the Kaplan-Meier method for interferential current device implementation rates revealed a feasibility of 100% for up to 60 Gy and a feasibility of 78% for up to 70 Gy, TESS may be feasible until 70 Gy. This study confirmed the feasibility and safety of TESS in the head and neck region during CRT. Although the precise mechanism of TESS on dysphagia remains unclear, its continued use has great potential for improving sensory disturbance.

Identification of a novel nonsense NOG mutation in a patient with stapes ankylosis and symphalangism spectrum disorder.

Multiple bone disorders due to mutations in the human noggin (NOG) causes a variety of phenotypes. Hearing impairment due to stapes ankylosis secondary to bony degeneration is also a feature of these syndromes. We describe the case of an individual in a Japanese family with conductive hearing loss due to stapes ankylosis and hyperopia and dactylosymphysis. We revealed a novel NOG mutation, NM_005450.6:c.222 C > A / p.Tyr74*, and confirmed genetic significance.

Functional Alteration and Differential Expression of the Bitter Taste Receptor T2R38 in Human Paranasal Sinus in Patients with Chronic Rhinosinusitis.

The bitter taste receptors (T2Rs) expressed in human sinonasal mucosae are known to elicit innate immune responses involving the release of nitric oxide (NO). We investigated the expression and distribution of two T2Rs, T2R14 and T2R38, in patients with chronic rhinosinusitis (CRS) and correlated the results with fractional exhaled NO (FeNO) levels and genotype of the T2R38 gene (TAS2R38). Using the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) phenotypic criteria, we identified CRS patients as either eosinophilic (ECRS, n = 36) or non-eosinophilic (non-ECRS, n = 56) patients and compared these groups with 51 non-CRS subjects. Mucosal specimens from the ethmoid sinus, nasal polyps, and inferior turbinate were collected from all subjects, together with blood samples, for RT-PCR analysis, immunostaining, and single nucleotide polymorphism (SNP) typing. We observed significant downregulation of T2R38 mRNA levels in the ethmoid mucosa of non-ECRS patients and in the nasal polyps of ECRS patients. No significant differences in T2R14 or T2R38 mRNA levels were found among the inferior turbinate mucosae of the three groups. Positive T2R38 immunoreactivity was localized mainly in epithelial ciliated cells, whereas secretary goblet cells generally showed lack of staining. The patients in the non-ECRS group showed significantly lower oral and nasal FeNO levels compared with the control group. There was a trend towards higher CRS prevalence in the PAV/AVI and AVI/AVI genotype groups as compared to the PAV/PAV group. Our findings reveal complex but important roles of T2R38 function in ciliated cells associated with specific CRS phenotypes, suggesting the T2R38 pathway as a potential therapeutic target for promotion of endogenous defense mechanisms.

Severe multiple simultaneous immune-related adverse events in a patient with head and neck cancer.

Nivolumab, an immune checkpoint inhibitor (ICI) against the programmed death-1 pathway, has been used for the treatment of recurrent metastatic head and neck cancer. However, the management of immune-related adverse events (irAEs), a unique side effect of ICI therapy, can be problematic. Although severe irAEs have been reported to result from multi-ICI therapy, we report a case of multiple severe irAEs caused by single-agent nivolumab treatment. Nivolumab was administered to treat a case of hypopharyngeal cancer recurrence. However, when first-line chemotherapy of nivolumab was replaced with a second chemotherapeutic agent because of insufficient effectiveness, the patient showed anorexia, dermatitis, and mucositis; upper gastrointestinal endoscopy yielded a diagnosis of irAEs. Additional examinations revealed simultaneous multiple irAEs, including hypothyroidism, dermatitis, eyelid conjunctivitis, tracheal mucositis, upper gastrointestinal ulcer, and type 1 diabetes. Since all symptoms improved after steroid treatment, the patient was treated with subsequent chemotherapy. However, he died from uncontrolled cancer recurrence. Thus, even a single ICI agent can cause life-threatening irAEs. Moreover, the management of irAEs requires early recognition and close multidisciplinary collaboration in accordance with the countermeasure manual.

Determining Invasion Depth in Superficial Pharyngeal Carcinoma by Transoral Ultrasonography.

OBJECTIVES: To examine the clinical usefulness of transoral ultrasonography (US) in determining the invasion depth of superficial pharyngeal carcinoma (SPC). Determining the invasion depth of SPC is crucial for transoral surgery including determining treatment strategy. This study aimed to examine the usefulness of transoral US in determining the invasion depth of SPC. METHODS: Forty-six patients with 51 lesions who underwent both magnifying endoscopy with narrow-band imaging (ME-NBI) and transoral US were included. The primary outcomes were the sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of ME-NBI and transoral US findings for pathological tumor depth in SPCs. RESULTS: The accuracy (82.4%), sensitivity (85.2%), PPV (82.1%), and NPV (82.6%) rates of US for subepithelial propria (SEP) were higher than those of ME-NBI and macroscopic classification, indicating that transoral US is superior to ME-NBI in determining the invasion depth. All cases where the SEP was clearly invaded (SEP deep) could be diagnosed as SEP by transoral US. CONCLUSIONS: Transoral US may be useful in determining the invasion depth of SPCs. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2192-2197, 2023.

Effectiveness of Expanded Instantaneous Input Dynamic Range Adjustment on Speech Perception.

Instantaneous input dynamic range (IIDR), as defined by Cochlear Ltd. (Sydney, Australia), refers to the acoustic level of short-term input dynamic range (IDR). Our aim was to evaluate the efficacy of expanding IIDR to improve speech understanding. We enrolled 11 unilateral Cochlear Ltd. patients with post-lingual hearing loss. The two types of IIDR settings (T-SPL/C-SPL of 25/65 dB (default IIDR) and 25/80 dB (wide IIDR)) were blindly assigned, and only one IIDR setting selected according to their preference was used for at least three months. Each IIDR group was evaluated with both default and wide IIDR conditions using the recorded word and sentence test materials of the Japanese CD speech discrimination scoring system (CI-2004 test) in quiet and noise with a signal-to-noise ratio (SNR) of +10 dB, presented at 65/80 dB SPL. Wide IIDR significantly improved speech perception in all tests, except for sentences in quiet conditions at a presentation level of 65 dB. Improvements during loud conversations in noisy environments were obtained without any adaptation period. Wide IIDR should become a new individual configuration setting method in Cochlear Ltd. devices to improve hearing in loud conversations and noisy environments.

Deep Association between Transglutaminase 1 and Tissue Eosinophil Infiltration Leading to Nasal Polyp Formation and/or Maintenance with Fibrin Polymerization in Chronic Rhinosinusitis with Nasal Polyps.

Transglutaminase (TGM) isoform catalyze the cross-linking reaction of identical or different substrate proteins. Eosinophil has been recognized in chronic rhinosinusitis with nasal polyps (CRSwNP) forming tissue eosinophil in nasal polyp (NP), and TGM isoforms are suggested to be associated with a critical role in asthma and other allergic conditions. The aim of this study was to reveal the association of specific TGM isoform with both the tissue eosinophil infiltration deeply concerning with the intractable severity of CRSwNP and the fibrin polymerization ability of TGM isoform associated with the tissue eosinophil infiltration, which lead to NP formation and/or maintenance in CRSwNP. NP tissues (CRSwNP group) and uncinate process (UP) (control group) were collected from patients with CRSwNP and control subjects. We examined: (1) the expression level of TGM isoforms by using a real-time polymerase chain reaction (PCR) and the comparison to the issue eosinophil count in the CRSwNP group, (2) the location of specific TGM isoform in the mucosal tissue using immunohistochemistry, (3) the inflammatory cell showing the colocalization of specific TGM isoform in Laser Scanning Confocal Microscopy (LSCM) imaging, and (4) the fibrin polymerase activity of specific TGM isoform using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). A certain level of TGM 1, 2, 3, 5 expression was present in both the CRSwNP group and the control group. Only TGM 1 expression showed a positive significant correlation with the tissue eosinophil count in the CRSwNP group. The localization of TGM 1 in NP (CRSwNP) laid mainly in a submucosal layer as inflammatory cells and was at the cytoplasm in the tissue eosinophil. Fibrin polymerase activity of TGM 1 showed the same polymerase ability of factor XIIIA. TGM 1 might influence the NP formation and/or maintenance in CRSwNP related to the tissue eosinophil infiltration, which formed fibrin mesh composing NP stroma.

Swallowing function after transoral surgery for laryngopharyngeal cancer.

Transoral surgery (TOS) has been widely used to treat laryngopharyngeal cancers. Although TOS is a minimally invasive procedure, postoperative complications, such as postoperative dysphagia, may occur, which can lead to a poor quality of life for patients undergoing TOS. This study aimed to investigate factors that may affect swallowing function in patients who underwent TOS for laryngopharyngeal cancers. Swallowing function of 84 patients who underwent endoscopic resection for oropharyngeal, hypopharyngeal, and supraglottic lesions was evaluated by the Functional Outcome Swallowing Scale, and predictors for postoperative dysphagia were identified. Multivariate analysis identified the following factors as independent predictors for postoperative dysphagia: Eastern Cooperative Oncology Group Performance Status (ECOG PS, p = 0.008), prior neck radiation therapy (p = 0.008), and operative time (p = 0.021). This study suggests that patients with poor ECOG PS or those who received prior neck radiation therapy should be fully assessed for preoperative swallowing function. In the future, we would like to clarify the criteria for preoperative swallowing evaluation to create a system that can identify patients suitable for TOS.

Distinct Gene Set Enrichment Profiles in Eosinophilic and Non-Eosinophilic Chronic Rhinosinusitis with Nasal Polyps by Bulk RNA Barcoding and Sequencing.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory disease with a high symptom burden, including nasal congestion and smell disorders. This study performed a detailed transcriptomic analysis in CRSwNP classified as eosinophilic CRS (ECRS), nonECRS according to the Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis (JESREC) criteria, and a group of ECRS with comorbid aspirin intolerant asthma (Asp). Gene expression profiles of nasal polyps and the uncinate process in CRSwNP patients and normal subjects (controls) were generated by bulk RNA barcoding and sequencing (BRB-seq). A differentially expressed genes (DEGs) analysis was performed using DESeq2 software in iDEP to clarify any relationship between gene expression and disease backgrounds. A total of 3004 genes were identified by DEGs analysis to be associated with ECRS vs control, nonECRS vs control, and Asp vs control. A pathway analysis showed distinct profiles between the groups. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) showed distinct phenotype-specific pathways of expressed genes. In the specific pathway of "cytokine-cytokine receptor interaction", the differentially expressed genes were widely distributed. This study indicates that transcriptome analysis using BRB-seq may be a valuable tool to explore the pathogenesis of type 2 inflammation in CRSwNP.

A Case of Primary Osteosarcoma of the Mandible That Responded to Preoperative Chemotherapy: p16 as a Potential Prognostic Factor.

We report a case of mandibular osteosarcoma in a Japanese woman in her 70s who was p16-positive. Despite the rapid growth of the tumor, the patient responded well to chemotherapy and was then able to undergo surgery. Head and neck osteosarcoma (HNOS) is a very rare cancer, and although the importance of surgery has been pointed out, the effectiveness of chemotherapy is unclear. Resection margin negativity and response to chemotherapy have been reported as prognostic factors; another report assessed the effectiveness of the immunohistochemical expression of p16 protein as a predictor of response to chemotherapy.

Pneumococcal conjugate vaccines reduce myringotomy with tympanostomy tube insertion in young children in Japan.

OBJECTIVE: Pneumococcal conjugate vaccines (PCVs) have been reported to reduce the incidence of myringotomy with tympanostomy tube insertion (MTTI) in children. However, little information is available focusing specific ages. We examined the prophylactic efficacy of PCVs on the onset of complex otitis media (ComOM) that requires MTTI. METHOD: From 2011, the public support for PCV7 started with the usual four-dose schedule and an emergency schedule for 2- to 4-year-old children in Japan. PCV7 was replaced with PCV13 in 2013. We reviewed the nationwide database obtained from the JMDC Claims Database (https://www.jmdc.co.jp/en/) to examine the MTTI incidence during the era before and after PCV introduction (from 2008 to 2010 and from 2011 to 2017, respectively). Subjects were analyzed by stratified age groups (from 0 to 8 years old) and in subdivided groups of 6 months (from 0 to 35 months old). We compared the MTTI incidence between the groups for each age as well as between those for each calendar year. RESULTS: A significant reduction in the MTTI incidence was detected in the 1-year-old children of the PCV era compared to those of the pre-PCV era. The reduction rates were more prominent in the 12-17 months group as compared to the 18-23 months group (PCV7 p = .005 and PCV13 p = .011, PCV7 p = .014 and PCV13 p = .153, respectively). The significant difference in the 1-year-old children continued in six of seven calendar years from 2011 to 2017, whereas no significant reduction was detected in children >3 years old. CONCLUSIONS: The introduction of both PCV7 and PCV13 reduced MTTI incidences in children around 1 year old, and the effects were more prominent during the early half-periods. Our results support etiological evidence that pneumococcal infection in children aged 1 year and younger might play roles in the pathogenesis of ComOM that requires MTTI.

Co-Expression and Localization of Angiotensin-Converting Enzyme-2 (ACE2) and the Transmembrane Serine Protease 2 (TMPRSS2) in Paranasal Ciliated Epithelium of Patients with Chronic Rhinosinusitis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses angiotensin-converting enzyme-2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) as a primary receptor for invasion. Cell entry by the virus requires the co-expression of these molecules in the host cells. OBJECTIVE: We investigated ACE2 and TMPRSS2 expression and localization in paranasal epithelium of eosinophilic chronic rhinosinusitis (ECRS) patients (n = 38), non-ECRS (n = 31), and healthy controls (n = 25). CRS inflammatory patterns are characterized by the type of cytokines; we investigated whether inflammatory endotypes are associated with cell-entry molecules, as this could be linked to susceptibility to SARS-CoV-2 infection. METHODS: The ACE2, TMPRSS2, and other inflammatory cytokine mRNA levels were assessed by quantitative RT-PCR. The localizations of ACE2- and TMPRSS2-positive cells were examined with immunofluorescent double-staining using laser scanning confocal microscopy (LSCM). RESULTS: The non-ECRS patients showed significantly increased ACE2 and TMPRSS2 mRNA expressions compared to the ECRS patients. The CRS patients' ACE2 and TMPRSS2 mRNA levels were positively correlated with IFN-γ (r = 0.3227 and r = 0.3264, respectively) and TNF-α (r = 0.4008, r = 0.3962, respectively). ACE2 and TMPRSS2 were negatively correlated with tissue eosinophils (r = -0.3308, r = -0.3112, respectively), but not with IL-13. ACE2 mRNA levels were positively correlated with TMPRSS2 (r = 0.7478). ACE2 and TMPRSS2 immunoreactivities were localized mainly in the epithelial ciliated cells, as confirmed by co-staining with TMPRSS2 and acetylated α-tubulin, a cilia organelle marker. Using LSCM imaging, we observed higher expressions of these molecules in the non-ECRS patients versus the ECRS patients. CONCLUSION: ECRS patients with type 2 inflammation showed decreased ACE2 and TMPRSS2 expressions in their sinus mucosa. ACE2 and TMPRSS2 regulation seems to be positively related to IFN-γ and TNF-α production in CRS patients; ACE2 and TMPRSS2 were co-expressed in the ciliated epithelium of their paranasal mucosa, implicating the paranasal epithelium as a portal for initial infection and transmission.

A long survival patient of anaplastic thyroid carcinoma treated with lenvatinib.

Anaplastic thyroid carcinoma (ATC) accounts for 1-2% of all malignant thyroid tumors. There are only a small number of patients with ATC and most of them die within 6 months after diagnosis, making it difficult to establish a standard treatment strategy. Although multimodal therapy, including radical surgery, radiotherapy, and chemotherapy, has been introduced, the survival rate remains poor. The use of molecular-targeted drugs for cancer therapy has become widely popular. Lenvatinib, a new molecular-targeted anticancer drug, is a multi-targeted receptor tyrosine kinase inhibitor (TKI). We report a rare case of a patient with ATC (T4N0M0) who responded extremely well to the administration of lenvatinib after radical surgery. Although ATC is one of the most fatal neoplasms, lenvatinib is a promising drug.

Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.