BACKGROUND:Branchio-oto-renal (BOR) syndrome is characterized by branchiogenic malformation, hearing loss, and renal anomalies, with EYA1, SIX1, and SIX5 known as the causative genes. As BOR syndrome presents with various clinical phenotypes, its characteristics and genotype-phenotype correlations remain unknown. AIMS/OBJECTIVES:In this study, we aimed to clarify the detailed hearing loss phenotypes and genotype-phenotype correlations of BOR syndrome. MATERIAL AND METHODS:In this study, we performed an etiological analysis of 169 BOR syndrome patients from 129 families. We also performed genetic testing for 78 probands. RESULTS:In all, 66.7% of BOR patients carried EYA1 variants, whereas 17.9% carried SIX1 variants. We also clarified the detailed clinical features including the prevalence of major and minor symptoms, asymmetrical hearing loss, type of hearing loss, severity of hearing loss and detailed clinical characteristics of auricular, external ear, and middle ear and inner ear anomalies. In terms of genotype-phenotype correlations, patients with SIX1 variants had no kidney anomalies and fewer middle ear anomalies. CONCLUSIONS AND SIGNIFICANCE:We clarified the detailed hearing loss phenotypes of BOR syndrome patients. Our study results will contribute to a better understanding and clinical management of BOR syndrome patients.

INTRODUCTION:This study aimed to determine the frequency of intubation-related laryngeal granulomas (ILGs) after surgery under general anesthesia and identify risk factors, with a focus on tube type and duration. METHODS:A single-center prospective cohort (November 2012-September 2013) of adults undergoing elective surgery expected to last at least 5 h with intubation was conducted. Fiberoptic laryngoscopy was performed on the day after extubation and at 1 week, 1 month, and 3 months. Candidate variables included tube type (single lumen vs. double lumen [DLT]), intubation duration, Cormack-Lehane grade, intraoperative transesophageal echocardiography (TEE), gastroesophageal reflux disease, body mass index, sex, and age. Associations were evaluated using univariate tests and multivariable logistic regression. RESULTS:Forty patients were analyzed (median age, 73 years; 19 men). Cardiovascular surgery accounted for 25 of 40 cases (62.5%); DLTs were used in 6 of 40 (15.0%) and TEE in 22 of 40 (55.0%). Mucosal changes (erythema/white plaque) were observed on day 1 in 18 of 40 patients (45.0%). ILG was detected at 1 week in 10 of 40 patients (25.0%), including nine after cardiovascular surgery. Eight of 10 cases (80%) resolved spontaneously by 1 month, whereas 2 of 10 (20%) enlarged and required 2 months of inhaled steroid therapy, with complete resolution by 3 months. Univariate analysis revealed that both intubation duration ≥13 h (p = 0.014) and DLT use (p = 0.026) were significantly associated with ILG. In multivariable analysis, intubation duration ≥13 h (adjusted odds ratio [aOR]: 10.697, 95% confidence interval [CI]: 1.639-69.828; p = 0.013) and DLT use (aOR: 14.521, 95% CI: 1.531-137.680; p = 0.020) were independent risk factors. CONCLUSION:In this cohort, ILG was detected in 25% of patients at 1 week post-extubation and typically resolved within 1 month. Prolonged intubation and DLT use were independently associated with increased ILG risk. High-risk patients - particularly those with prolonged intubation or DLT exposure - may benefit from selection of the smallest appropriate DLT when required and targeted laryngoscopy within 1 month. These findings should be interpreted cautiously, given the small sample and single-center design.

Background/Objectives: The OTOG gene is responsible for autosomal recessive non-syndromic sensorineural hearing loss and is assigned as DFNB18B. To date, 44 causative OTOG variants have been reported to cause non-syndromic hearing loss. However, the detailed clinical features for OTOG-associated hearing loss remain unclear. Methods: In this study, we analyzed 7065 patients with non-syndromic hearing loss (mean age 26.4 ± 22.9 years, 2988 male, 3855 female, and 222 without gender information) using massively parallel DNA sequencing for 158 target deafness genes. We identified the patients with biallelic OTOG variants and summarized the clinical characteristics. Results: Among the 7065 patients, we identified 14 possibly disease-causing OTOG variants in 26 probands, with 13 of the 14 variants regarded as novel. Patients with OTOG-associated hearing loss mostly showed congenital or childhood-onset hearing loss. They were considered to show non-progressive, mild-to-moderate hearing loss. There were no symptoms that accompanied the hearing loss in OTOG-associated hearing loss patients. Conclusions: We confirmed non-progressive, mild-to-moderate hearing loss as the clinical characteristics of OTOG-associated hearing loss. These findings will contribute to a better understanding of the clinical features of OTOG-associated HL and will be useful in clinical practice.

Background/Objectives: A heterozygous mutation in the WFS1 gene is responsible for autosomal dominant non-syndromic hearing loss (DFNA6/14/38) and Wolfram-like syndrome, which is characterized by bilateral sensorineural hearing loss with optic atrophy and/or diabetes mellitus. However, detailed clinical features for the patients with the heterozygous p.A684V variant remain unknown. Methods: We report the clinical details of 14 cases with a heterozygous p.A684V variant in the WFS1 gene identified from target resequencing analysis of 63 previously reported deafness genes by next-generation sequencing of 15,684 hearing loss patients (mean age 27.5 ± 23.1 years old, 6574 male, 8612 female and 498 for whom information was unavailable). Results: Among the 14 patients from 13 families with the p.A684V variant, nine were sporadic cases. In addition, we confirmed de novo occurrence of this variant in seven families. This result strongly supports the notion that this variant was located on a mutational hotspot. When comparing previously reported cases of autosomal dominant WFS1 gene-associated hearing loss, most of the patients in this study showed severe-to-profound bilateral sensorineural hearing loss (genotype–phenotype correlation). Two patients had optic atrophy, while the others did not have any other complications. Conclusions: The identified heterozygous p.A684V variant appears to be a hotspot mutation and likely to cause severe-to-profound hearing loss in early childhood. Cochlear implantation is considered favorable in cases of hearing impairment due to this variant.

Introduction: Surgical extirpation of a cholesterol granuloma in the petrous apex, located dorsal to the petrous part of the internal carotid artery (ICA), is challenging. Herein, we report a pediatric case of a cholesterol granuloma of the petrous apex treated using the endoscopic contralateral transmaxillary (CTM) approach. Case Presentation: A 13-year-old boy presented with a left-sided headache, slight hypoesthesia in the left V1 area, and severe neuralgia of the left auriculotemporal nerve. Magnetic resonance imaging (MRI) revealed a high-intensity mass without gadolinium enhancement. The patient's headache was unresponsive to various medications. After careful evaluation, an endoscopic CTM approach was selected for the extirpation of the granuloma. Postoperatively, the patient did not experience headache or associated neurological complications. MRI at 46 months revealed no recurrence. Conclusion: The endoscopic CTM approach can be used for excising cholesterol granulomas of the petrous apex located posterior to the petrous part of the ICA without causing severe complications. This approach can be considered useful for pediatric cases in which granulomas are not accessible via the transnasal endoscopic transsphenoidal approach. .

BACKGROUND:The AJCC cutoff value of 2 mm for the extranodal extension (ENE) distance was determined from an analysis of patients with or without adjuvant therapy. The purpose of this study was to find out the ENE distance that reflects prognosis only in patients with head and neck squamous cell carcinoma (SCC) who received adjuvant therapy. METHODS:The ENE distance was defined for 109 patients who underwent surgery for SCC of larynx or hypopharynx as a primary tumor. RESULTS:To standardize patient conditions, only 26 patients who received additional postoperative treatment were analyzed. Receiver operating characteristic analysis of the ENE distance for overall survival (OS) and recurrence-free survival (RFS) yielded a cutoff value of 4250 μm. Multivariate analysis showed that the ENE distance was an independent poor prognostic factor for OS and RFS. CONCLUSION:The optimal ENE distance cutoff for OS and RFS in postoperatively treated patients was 4250 μm.

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ-associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ-associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ-associated HL and may be relevant in clinical practice.

要旨 : 新生児聴覚スクリーニング検査 (NHS) の普及により, 難聴児の療育開始が早期化し, 0歳台からの療育が可能になった。一方で, 難聴発見が幼児期後期になる症例も存在する。療育開始までの現状と課題を明らかにする目的で, 2014~2021年度8年間の当施設在籍児を対象に療育開始までの経過を調査し, 療育開始が1歳以降であった症例について検討した。乳幼児健康診査でことばの遅れがみられた際に, NHS リファー群, 未受検群に比しパス群で聴力検査の実施が遅れる傾向がみられた。ことばの遅れが明らかでない軽中等度難聴例では, 保護者が耳鼻咽喉科で聞こえについて相談しても聴力検査が実施されていない症例がみられた。難聴を疑うエピソードがある場合には, 早期に聴力検査を実施し, 難聴の有無を確認することが重要である。

43歳女性。32歳からの伝音難聴で受診，耳硬化症と考えられ，右アブミ骨手術を施行した。10年後に施行した左アブミ骨手術中にガッシャーが出現した。CTで計測した蝸牛水管の内側開口部の径と面積はガッシャー側で6.1mm/21.7mm2，非ガッシャー側で3.8mm/5.3mm2と左蝸牛水管の拡大が考えられた。当科でアブミ骨手術を施行しガッシャーを認めなかった19症例23耳における内側開口部の径の最大値5.0mm，面積の最大値10.6mm2であり，ガッシャー側の径と面積は非ガッシャー症例の最大値よりも大きい値であった。本症例では蝸牛水管の内側開口部の拡大がガッシャーの原因である可能性が示唆された。

腎細胞癌は血行性転移が多いとされているが，鼻副鼻腔への転移は比較的稀とされる。鼻出血を契機に発見された腎細胞癌副鼻腔転移の1例を経験したので報告する。

BACKGROUND:Our previous research showed that a high rate of secondary carcinogenesis is observed during follow-up after transoral surgery in patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal cancers. We speculate that the contributing factors are alcohol drinking, smoking, and aging; however, we could not provide clear evidence. In this study, we aimed to identify the risk factors for secondary carcinogenesis in patients with these cancers, particularly factors associated with drinking and/or smoking.METHODS:The medical records of all-stage laryngeal, oropharyngeal, and hypopharyngeal cancer patients who had undergone definitive treatment were retrospectively analyzed. Assessments included visual and endoscopic observations of the primary site, enhanced cervical CT or US of the primary site and regional lymph nodes, PET-CT, and enhanced whole-body CT. Clinical characteristics were compared in patients with and without secondary carcinogenesis and in patients with hypopharyngeal cancer and patients with other cancers.RESULTS:Hypopharyngeal cancer was an independent risk factor for secondary cancer. The 5-year incidence rate of secondary cancer was 25.5%, 28.6%, and 41.2% in laryngeal, oropharyngeal, and hypopharyngeal cancers, respectively. Radiotherapy was defined as an independent risk factor in hypopharyngeal cancer patients with secondary cancers. No direct correlation was found between secondary carcinogenesis and alcohol consumption, smoking, or aging.CONCLUSIONS:Patients with hypopharyngeal cancer require close follow-up as they are at high risk of developing secondary cancer, possibly because out-of-field radiation exposure may induce systemic secondary carcinogenesis in hypopharyngeal cancer patients with genetic abnormality induced by alcohol consumption.

BACKGROUND/AIM:This study aimed to identify key molecules associated with the survival of patients with hypopharyngeal squamous cell carcinoma (HpSCC) by combining in silico and in vitro analyses.MATERIALS AND METHODS:Differentially expressed genes (DEGs) were screened using the Gene Expression Omnibus database. For DEGs, we performed functional enrichment and protein-protein interaction network analyses to identify potential biological functions and hub genes. Functional analysis of HpSCC cell lines verified the critical roles of the hub genes.RESULTS:DEGs were associated with the extracellular matrix. Among the hub genes, high expression of prolyl 4-hydroxylase subunit alpha 1 (P4HA1) was significantly associated with shorter survival. In addition, P4HA1 knockdown inhibited cell migration and colonization. Suppression of cell proliferation was demonstrated using P4HA1-selective inhibitors.CONCLUSION:P4HA1 may be a useful therapeutic target for the treatment of HpSCC.

Paranasal sinus osteoma is the most frequently encountered benign tumor in the nasal and sinus areas. Frontal sinus osteoma is the most common sinus osteoma (80%), and is usually asymptomatic. A 35-year-old woman was admitted to our hospital complaining of right forehead prominence and pain, and was diagnosed as having a right frontal sinus osteoma and frontal sinusitis. Extranasal frontal sinusectomy was performed. There was no recurrence of the lesion after surgery. Surgery is indicated in cases of frontal sinus osteoma when the condition is symptomatic. The surgical methods include extra-nasal frontal sinus surgery and endoscopic sinus surgery. Endoscopic sinus surgery is superior in terms of yielding better aesthetic outcomes, being minimally invasive, and allowing a shortened hospital stay. The indications for endoscopic sinus surgery have been expanding with the development of endoscopic surgery techniques, however, the precise indications have not been clearly defined until date. In regard to reconstruction of the frontal bone following extranasal frontal sinusectomy, it is necessary to select the most appropriate material for individual patients based on an understanding of the characteristics of different materials available.

We report the case of a patient with otitis media and ANCA-associated vasculitis (OMAAV), who presented with rapidly progressive bilateral deafness. A 64-year-old woman visited an ENT clinic with the chief complaint of right ear pain. She was diagnosed as having right acute otitis media and left otitis media with effusion, and treated with antibiotics and myringotomies. Twenty-seven days later, she was transported to our hospital by ambulance with headache, fever, vertigo and hearing loss, and pure tone audiometry revealed bilateral deafness. The right eardrum was normal, whereas the left tympanic membrane was perforated, and discharge was observed from the left middle ear cavity. Blood tests showed elevated levels of inflammatory markers, positive serology for MPO-ANCA and a negative test for serum PR3-ANCA. Contrast-enhanced MRI showed findings consistent with hypertrophic pachymeningitis and no enhancement of the inner ear. The hypertrophic pachymeningitis improved with steroid pulse therapy, but the hearing did not improve. During tapering of the prednisolone dose, the patient underwent cochlear implantation and speech hearing was restored. Because of the rapid progression of her bilateral deafness, it was difficult to diagnose OMAAV prior to the occurrence of deafness. Although prolonged treatment is generally required for OMAAV, early cochlear implantation could improve the effect by shorting the hearing loss period.

Background We previously identified hypopharyngeal cancer as an independent risk factor for the incidence of newly diagnosed secondary cancers after the treatment of early-stage laryngeal, oropharyngeal, and hypopharyngeal cancers. We subsequently used a different patient cohort to validate the usefulness of this factor during the follow-up period in these patients. Methods Patients who underwent transoral surgery (TOS) as a definitive treatment between April 1, 2016, and September 30, 2020, were included. The incidence of secondary cancer was evaluated in hypopharyngeal and other cancers. Overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS) outcomes were evaluated. Statistical analyses based on the risk factors were also performed. Results Incidence of new secondary cancer was 30% in hypopharyngeal cancer patients as compared to 11% in other cancer patients, and the risk was 3.60-fold (95% confidence interval 1.07-12.10) higher after definitive treatment for initial head and neck cancers. The 3-year OS, RFS, and DFS rates were 98%, 86%, and 67%, respectively. Conclusions Among patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma, who were initially treated with TOS, hypopharyngeal cancer patients had a higher risk of newly diagnosed secondary cancers as observed during the follow-up period.

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.

We had previously identified the following risk factors for insufficient control of early T-stage head and neck cancer by transoral surgery (TOS): (1) tumor thickness > 7 mm on enhanced computed tomography (CT), and (2) poor differentiation in pathological examination. We subsequently used a different patient cohort to validate the usefulness of these factors in determining the need for adaptation of TOS. A prospective observational study Patients who received TOS as a definitive treatment between April 1, 2016 and September 30, 2020 were included. Primary control rates (by single TOS and TOS alone) in relation to the above-mentioned risk factors were calculated. Overall (O), recurrence-free (RF), and disease-free (DF) survival (S) outcomes were evaluated. A combination analysis based on the number of risk factors was also performed. Patients with tumor thickness > 7 mm had a 2.88-fold [95% confidence interval (CI) 1.01–8.51] higher risk of incomplete primary resection by single TOS, while patients who showed poor differentiation on pathological assessments had a 13.14-fold (95% CI 3.66–47.14) higher risk of insufficient primary control by TOS alone. The 3 year OS, RFS, and DFS rates were 99%, 83%, and 63%, respectively. Patients with both risk factors had a 93.00-fold (95% CI 4.99–1732.00) higher risk of incomplete primary control by TOS alone. Among patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma, primary control by TOS alone may not be achieved in patients with both risk factors, that is, tumor thickness > 7 mm as measured by enhanced CT and poor differentiation on pathological examination.

To generate a reliable preclinical model system exhibiting the molecular features of salivary adenoid cystic carcinoma (ACC) whose biology is still unclear due to the paucity of stable cell cultures. To develop new in vitro and in vivo models of ACC, the techniques of organoid culture and patient-derived tumor xenograft (PDX), which have attracted attention in other malignancies in recent years, were applied. Tumor specimens from surgically resected salivary ACC were proceeded for the preparation of PDX and organoid culture. The orthotopic transplantation of patient-derived or PDX-derived organoids was demonstrated into submandibular glands of NSG mice and those histology was evaluated. PDX-derived organoid cells were evaluated for the presence of MYB-mediated fusion genes and proceeded for in vitro drug sensitivity assay. Human ACC-derived organoids were successfully generated in three-dimensional culture and confirmed the ability of these cells to form tumors by orthotopic injection. Short-term organoid cell cultures from two individual ACC PDX tumors were also established that maintain the characteristic MYBL1 translocation and histological features of the original parent and PDX tumors. Finally, the establishment of drug sensitivity tests on these short-term cultured cells was confirmed using three different agents. This is the first to report an approach for the generation of human ACC-derived organoids as in vitro and in vivo cancer models, providing insights into understanding of the ACC biology and creating personalized therapy design for patients with ACC.

Our prospective study of patients with early T-stage head and neck cancer indicated a high incidence of newly diagnosed secondary malignancies during the follow-up period. We aimed to determine the incidence rate and risk factors of secondary malignancies in early-stage head and neck cancer patients. We sub-analyzed the patient data of a previous study focusing on secondary cancer incidence. The endpoints were statistical analyses of risk factors and survival and incidence rates. The incidence rate of secondary cancer was 37%, the crude incidence of second primary cancers was 10.6 per 100 person-years, and the 5 year secondary cancer-free survival rate was 63%. The hypopharynx as the primary site was an independent significant predictive factor (odds ratio 3.96, 95% confidence interval 1.07–14.6, p = 0.039). Early stages of laryngeal, oropharyngeal, and hypopharyngeal cancer had a risk of secondary cancer, especially hypopharyngeal cancer. Attention to the secondary cancer has to be paid during the follow-up period after controlling the early-stage disease. These findings highlight the need for awareness of the incidence of secondary cancer in cases of early-stage primary head and neck cancer.