Published papers

Background: Nivolumab paved a new way in the treatment of patients with recurrent or metastatic (RM) head and neck squamous cell carcinoma (RM-HNSCC). However, the limited rates of long-term survivors (< 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study aimed to identify a plasma exosome (PEX) mRNA signature, which serves as a companion diagnostic of nivolumab and provides a biological clue to develop effective therapies for a majority of non-survivors. Methods: Pre-treatment plasmas (N = 104) of RM-HNSCC patients were subjected to comprehensive PEX mRNA analyses for prognostic marker discovery and validation. In parallel, paired treatment-naïve tumor and plasma samples (N = 20) were assayed to elucidate biological implications of the PEX mRNA signature. Results: Assays for pre-treatment blood samples (N = 104) demonstrated that a combination of 6 candidate PEX mRNAs plus neutrophil-to-lymphocyte ratio precisely distinguished non-survivors from >2-year survivors (2-year OS; 0% vs 57.7%; P = 0.000124) with a high hazard ratio of 2.878 (95% CI 1.639-5.055; P = 0.0002348). Parallel biological assays demonstrated that in the paired treatment-naïve HNSCC tumor and plasma samples (N = 20), PEX HLA-E mRNA (a non-survivor-predicting marker) was positively corelated with overexpression of HLA-E protein (P = 0.0191) and the dense population of tumor-infiltrating NK cells (P = 0.024) in the corresponding tumor, suggesting that the HLA-E-NKG2A immune checkpoint may inhibit the antitumor effect of PD-1blockade. Conclusion: The PEX mRNA signature could be useful as a companion diagnostic of nivolumab. The combination of an anti-NKG2A antibody (i.e., monalizumab) and nivolumab may serve as a treatment option for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs.

Objectives: To determine the natural history of hearing loss and tumor volume in patients with untreated neurofibromatosis type 2 (NF2)-related schwannomatosis. Moreover, we statistically examined the factors affecting hearing prognosis. Methods: This retrospective cohort study was conducted on 37 ears of 24 patients with NF2-related vestibular schwannomatosis followed up without treatment for more than 1 year. We obtained detailed chronological changes in the PTA and tumor volume in each case over time, and the rate of change per year was obtained. Multivariate analysis was also conducted to investigate factors associated with changes in hearing. Results: The average follow-up period was approximately 9 years, and hearing deteriorated at an average rate of approximately 4 dB/year. The rate of maintaining effective hearing decreased from 30 ears (81%) at the first visit to 19 ears (51%) at the final follow-up. The average rate of change in tumor growth for volume was approximately 686.0 mm3/year. This study revealed that most patients with NF2 experienced deterioration in hearing acuity and tumor growth during the natural course. A correlation was observed between an increase in tumor volume and hearing loss (r = 0.686; p < 0.001). Conclusions: Although the hearing preservation rate in NF2 cases is poor with the current treatment methods, many cases exist in which hearing acuity deteriorates, even during the natural course. Patients with an increased tumor volume during the follow-up period were more likely to experience hearing deterioration. Trial registration number 20140242 (date of registration: 27 October 2014).

Noise-induced hearing loss (NIHL) is a common type of sensorineural hearing loss caused by exposure to high-intensity noise that leads to irreversible cochlear damage. Despite extensive research on cochlear pathophysiology, the precise mechanisms remain unclear, and no established treatment exists. This is due to the challenges in imaging and the inability to perform biopsies in human patients. Consequently, animal models, particularly mice, have been widely used to study NIHL. Clinically, NIHL presents as either a temporary threshold shift, in which hearing recovers, or a permanent threshold shift, which results in an irreversible loss. Histopathological studies have identified the key features of NIHL, including outer hair cell loss, auditory nerve degeneration, and synaptic impairment. Recent findings suggest that oxidative stress and inflammation are major contributors to NIHL, highlighting the potential for therapeutic interventions, such as antioxidants and anti-inflammatory agents. Given the increasing prevalence of NIHL owing to occupational noise exposure and personal audio device use, addressing this issue is a pressing public health challenge. This review summarizes the clinical features, underlying mechanisms, and emerging treatment strategies for NIHL while identifying current knowledge gaps and future research directions.

Objective: Intraoperative systems for monitoring facial nerve function, in which temporal electrical stimulation is applied to the facial nerve through electrodes, are used in many surgeries requiring facial nerve preservation; however, continuous stimulation or quantitative evaluation of facial nerve function is difficult with this approach. We examined the usefulness of a continuous and quantitative facial nerve-monitoring system for temporal bone lesions by using our experience to modify the existing methods used for cases involving vestibular schwannomas. Study design: Retrospective observational study. Setting: Department of Otorhinolaryngology-Head and Neck Surgery at our hospital. Methods: We modified the electrode placement and examined the usefulness of the modified system under several conditions. The study population consisted of patients who were operated on for temporal bone lesions at our department and underwent continuous nerve monitoring using the modified system. Case details, electrode-placement sites, and facial nerve function data before and after the surgery were obtained and retrospectively evaluated. Results: Electrodes were placed safely during surgery in all cases. No obvious deterioration in facial nerve function was observed, except in one case. Conclusion: The advantages of this system include its ability to perform quantitative intraoperative evaluations and prevent unexpected nerve damage in cases where the facial nerve shows complicated pathways. This monitoring system is useful, even in complex temporal bone surgeries.

Background: Transoral laser microsurgery is a well-established treatment for early glottic cancer. However, managing patients with close/positive margins remains debated. This study analyzes the relationship between resection margins and oncologic outcomes. Methods: Patients with early glottic cancer who underwent transoral laser microsurgery were included. We compared clinical characteristics, recurrence-free survival, laryngeal preservation, and disease-specific survival between negative and close/positive margin groups. Results: Among 107 patients, 49 (45.8%) had close/positive margins. The recurrence-free survival rate was significantly lower in the close/positive margin group. Anterior commissure involvement was a significant risk factor for recurrence. The median recurrence time for the close/positive margin group was 18.5 months, similar to the negative margin group. Laryngeal preservation and disease-specific survival were similar between groups with > 95%. Conclusions: Patients with close/positive margins in early glottic cancer showed similar disease-specific survival and laryngeal preservation rates as negative margins; despite lower recurrence-free survival, suggesting a follow-up approach is sufficient.

Background/Objectives: This study aimed to investigate the optimal sound presentation level for sound localization testing to assess the effect of hearing interventions in individuals with unilateral conductive hearing loss (UCHL). Methods: Nine participants with normal hearing were tested, and simulated two-stage UCHL was created using earmuffs and earplugs. We created two types of masking conditions: (1) only an earplug inserted, and (2) an earplug inserted with an earmuff worn. A sound localization test was performed for each condition. The sound presentation levels were 40, 45, 50, 55, 60, 65, and 70 dB SPL, and the results were evaluated using root mean square and d-values. Results: Both values showed little difference in masking Condition 2, regardless of the sound presentation level, whereas in masking Condition 1, the values were at their minimum at 55 dB SPL. In addition, comparing the differences between masking Conditions 1 and 2 for each sound presentation level, the greatest difference was observed at 55 dB SPL for both values. Conclusions: The optimal sound presentation level for sound localization testing to assess hearing intervention effects in UCHL was 55 dB. This result may be attributed to the effect of input from the non-masked ear, accounting for interaural attenuation; the effect was considered minimal at 55 dB SPL.

PURPOSEThe humanized antivascular endothelial growth factor (VEGF) antibody bevacizumab (Bev) is efficacious for the treatment of NF2-related schwannomatosis (NF2), previously known as neurofibromatosis type 2. This study evaluated the safety and efficacy of a VEGF receptor (VEGFR) vaccine containing VEGFR1 and VEGFR2 peptides in patients with NF2 with progressive schwannomas (jRCTs031180184).MATERIALS AND METHODSVEGFR1 and VEGFR2 peptides were injected subcutaneously into infra-axillary and inguinal regions, once a week for 4 weeks and then once a month for 4 months. The primary end point was safety. Secondary end points included tolerability, hearing response, imaging response, and immunologic response.RESULTSSixteen patients with NF2 with progressive schwannomas completed treatment and were assessed. No severe vaccine-related adverse events occurred. Among the 13 patients with assessable hearing, word recognition score improved in five patients at 6 months and two at 12 months. Progression of average hearing level of pure tone was 0.168 dB/mo during the year of treatment period, whereas long-term progression was 0.364 dB/mo. Among all 16 patients, a partial response was observed in more than one schwannoma in four (including one in which Bev had not been effective), minor response in 5, and stable disease in 4. Both VEGFR1-specific and VEGFR2-specific cytotoxic T lymphocytes (CTLs) were induced in 11 patients. Two years after vaccination, a radiologic response was achieved in nine of 20 assessable schwannomas.CONCLUSIONThis study demonstrated the safety and preliminary efficacy of VEGFR peptide vaccination in patients with NF2. Memory-induced CTLs after VEGFR vaccination may persistently suppress tumor progression.

Objective: To assess pretreatment factors including preoperative vestibular function tests evaluated using cVEMP and caloric tests, which correlate with the development of prolonged dizziness after vestibular schwannoma resection. Study Design: Retrospective cohort study. Setting: Academic tertiary referral centers. Patients: Patients with vestibular schwannoma who underwent surgery and completed preoperative vestibular function tests and questionnaires. Intervention: Diagnostic. Main Outcome Measures: Participants were divided into prolonged dizziness and nonprolonged dizziness groups according to their postoperative DHI scores. The rates of abnormal results of preoperative vestibular function tests (caloric test, cVEMP), including other factors such as preoperative HADS scores, were compared. Furthermore, univariate logistic regression analysis was performed with the DHI score at 3 months as the dependent variable. Results: Of the whole 45 participants, 14 (31%) developed prolonged dizziness postoperatively. The proportion of participants with abnormal cVEMP results was significantly lower in the prolonged dizziness group (7.1%) than in the nonprolonged dizziness group (42%). Other factors did not show any significant differences. Univariate analysis showed that only the cVEMP results correlated with the postoperative DHI score (OR = 9.39, 95% CI [1.56, 181.3], p < 0.05). About 70% of patients with prolonged dizziness continued to exhibit high DHI scores at 6 months after surgery; however, about half of them recovered by 1 year. Conclusion: Vestibular schwannoma patients with normal preoperative cVEMP results tended to develop prolonged dizziness after resection compared to those with abnormal results. Preoperative cVEMP results enable physicians to predict whether vestibular schwannoma patients undergoing resection would likely develop prolonged dizziness postoperatively.

Acute low-tone sensorineural hearing loss (ALHL), first reported in 1988, is a disease characterized by hearing loss, tinnitus, and other auditory symptoms, and is recognized as an independent disease entity from sudden hearing loss. Although the severity of hearing loss was defined for the first time in 2015 by the “Research Group on Intractable Hearing Impairment” of the Ministry of Health, Labour and Welfare, few studies have examined the treatment outcomes by the severity of hearing loss. We determined the overall cure rate (cure/all cases) in 336 ALHL cases treated over an 11-year period from 2011 to 2021, and also the cure rates by the severity of the hearing loss and steroid use. The overall cure rate was 64.0%, 75.0% in cases with Grade 1 severity, 74.3% in cases with Grade 2 severity, 57.4% in cases with Grade 3 severity, and 34.7% in cases with Grade 4 severity. The cure rate in the Grade 3/Grade 4 cases was significantly lower than that in the Grade 1/Grade 2 cases. There was no significant difference in the cure rate by steroid use. It is well known that the cure rate of sudden hearing loss depends on the hearing level at the time of the initial diagnosis, and the cure rate of ALHL can also be predicted by the sum of the hearing levels of the three lowest frequencies at the time of the initial diagnosis. Although this study did not demonstrate the efficacy of steroid use, it is possible that the study design biased the sample population. ALHL is associated with a higher incidence of recurrence than sudden hearing loss, but steroids also have a variety of side effects. Therefore, the appropriateness of steroid use in the treatment of ALHL should be determined based on a comprehensive assessment of comorbidities, patient age, and disease severity.

The extent of hearing loss requiring hearing aid (HA) to prevent cognitive decline is unclear; we assessed this post-midlife along with the relationship between hearing thresholds and cognitive function in those who had never used HA (non-users) or used HAs for >3 years (long-term users). This study comprised 117 individuals ≥55 years with an average hearing threshold of ≥25 dB HL in their better ear and 55 of the non-users and 62 of the long-term users. The Mini-Mental State Examination, the Symbol Digit Modalities Test (SDMT), and pure-tone and sound-field audiometry were assessed. Mean ± SD hearing levels of the non-user and long-term user group were 40.83 ± 8.16 and 51.13 ± 14.80 dB HL. Non-users showed a significant association (P = 0.01) between the hearing thresholds and SDMT scores, with a cutoff value of above 38.75 dB HL identified as affecting cognitive function. There were no significant associations for long-term users.

Paragangliomas (PGLs) are rare neuroendocrine tumors that arise from the paraganglionic tissues and are associated with the autonomic nervous system. Although traditionally classified conjointly, head and neck PGLs (HNPGLs) and PGLs located outside the head and neck (PGLOs) exhibit distinct embryological origins, genetic predispositions, functional profiles, clinical behavior, and therapeutic strategies. HNPGLs are typically nonfunctional and arise from parasympathetic tissues, whereas PGLOs often originate from sympathetic tissues, are frequently functional, and secrete catecholamines. Recent advances in molecular genetics, particularly those involving SDHx mutations, have revealed genotype–phenotype correlations that further differentiate these tumor groups. Despite overlapping histopathological features, the natural history, risk of malignancy, and surveillance strategies differ substantially. Although surgical resection remains the mainstay of treatment for both HNPGLs and PGLOs, the indications, risks, and outcomes vary according to tumor location and genetic context. This review aims to provide a comprehensive clinical comparison between HNPGLs and PGLOs, outlining their unique anatomical, genetic, and clinical characteristics. We emphasize the importance of site-specific management strategies that consider both functional status and prognosis. Based on these distinctions, we propose a revised diagnostic and therapeutic framework that surpasses a uniform classification and emphasizes precision medicine for the management of PGLs. This approach could reduce treatment-related morbidity, optimize long-term outcomes, and guide genetic counseling and surveillance in affected individuals and their families.

Cyclooxygenase‑2 (COX‑2) is one of the two isoforms of COX, an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins. COX‑2 is associated with the progression in various types of cancer, and its expres‑ sion has been associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC). Furthermore, COX‑2 expression has been associated with resistance to anticancer drugs. However, the precise mechanism of COX‑2 for chemoresistance in HNSCC has not been fully elucidated. The present study aimed to investigate the effect of COX‑2 on cancer stem cell (CSC) property and to reveal its effect on chemoresistance using in vitro and clinicopathological assays in HNSCC cells and tissues. The current study analyzed the immunohistochemical expression levels of COX‑2 and clinicopathological factors using matched samples of pretreatment biopsy and surgical specimens from patients with hypopharyngeal carcinoma who underwent tumor resec‑ tion with preoperative chemotherapy, including docetaxel. Additionally, the chemoresistance to docetaxel with or without a COX‑2 inhibitor (celecoxib) was examined in HNSCC cell lines by MTS assays. To evaluate the association of COX‑2 expression with stemness property, the expression levels of CSC‑associated genes after exposure to celecoxib were assessed by reverse transcription‑quantitative PCR. A sphere formation assay was also performed using ultra‑low attachment dishes and microscopic imaging. The immunohistochemical analysis of biopsy specimens revealed a negative association between COX‑2 expression in biopsy specimens and the pathological effect of induction chemotherapy in surgical specimens. The cell survival rate under exposure to docetaxel was decreased by the addition of celecoxib. COX‑2 inhibition led to downregulation of CSC‑associated gene expression and sphere formation. The present findings suggested that COX‑2 expression may be associated with chemoresistance through the cancer stemness property, and inhibition of COX‑2 may enhance chemo‑sensitivity in HNSCC. Therefore, COX‑2 may be an attractive target for the treatment of HNSCC.

Cartilage conduction hearing aids (CC-HA), bone anchored hearing aids (Baha), and ADHEAR are good choices to improve hearing in patients who cannot use air conduction hearing aids because of aural atresia or continuous otorrhea. As there are many overlaps in the characteristics of these devices, we conducted a comparative trial of CC-HA, Baha, and ADHEAR. We provided patients with the opportunity to select their devices. The data of 6 patients who underwent comparative trials in our department between October 2021 and August 2022 were retrospectively examined. The gains of Baha and CC-HA outweighed those of ADHEAR. Regarding the sound localization test, there was no significant tendency for any of the hearing devices. Regarding the Glasgow Benefit Inventory, there was no clear tendency among the three devices in the quality of life evaluation. The most satisfactory model was the one subjectively chosen by the patient, regardless of the gain and score of the sound source localization test. Therefore, we believe that it is necessary to provide an opportunity for comparative trials and a consultation with each patient in the process of selecting a device.

NF2-related schwannomatosis (NF2) is an autosomal dominant genetic disorder caused by variants in the NF2 gene. Approximately 50% of NF2 patients inherit pathogenic variants, and the remainder acquire de novo variants. NF2 is characterized by development of bilateral vestibular schwannomas. The genetic background of Japanese NF2 cases has not been fully investigated, and the present report performed a genetic analysis of 14 Japanese NF2 cases and examined genotype–phenotype correlations. DNA samples collected from peripheral blood were analyzed by next-generation sequencing, multiplex ligation-dependent probe amplification analysis, and in vitro electrophoresis. Ten cases had pathogenic or likely pathogenic variants in the NF2 gene, with seven truncating variants and three non-truncating variants. The age of onset in all seven cases with truncating variants was < 20 years. The age of onset significantly differed among cases with truncating NF2 variants, non-truncating NF2 variants, and no NF2 variants. However, the clinical course of tumor growth and hearing deterioration were not predicted only by germline pathogenic NF2 variants. The rate of truncating variants was higher in the present study than that of previous reports. Genotype–phenotype correlations in the age of onset were present in the analyzed Japanese NF2 cases.

Cricotracheostomy is a useful surgical procedure for opening the airway in cases where conventional tracheotomy is difficult. This is a safe and easy technique involving removal of the anterior portion of the cricoid cartilage. Herein, we report the case of a patient with difficulty in neck extension due to severe kyphosis, who underwent cricotracheostomy. A 65-year-old woman developed dyspnea and was transported to our hospital. SpO2 was 60% (room air) and endotracheal intubation was performed. She was managed on ventilator. However, weaning off the ventilator was difficult, and endotracheal intubation was prolonged. Subsequently, the patient was referred to us for a tracheostomy. The patient was unable to maintain the supine position due to severe kyphosis, and computed tomography revealed that the brachiocephalic artery was running just below the thyroid gland. Therefore, conventional tracheostomy was difficult to perform, and we performed cricotracheostomy instead. After the cricotracheostomy, there were no tracheal problems, such as tracheal stenosis and stomal hemorrhage. Cricotracheostomy can be performed in cases where multiple anatomical difficulties may be faced in the tracheostomy site, as in this case. Furthermore, cricotracheostomy is beneficial for long-term airway management because it causes fewer complications compared to conventional tracheotomy.

Spiral ligament fibrocytes generate potassium gradients, which hair cells require to convert mechanical sound waves into electrical palsy. Together with the stria vascularis, they regulate endolymph electrolyte homeostasis. Developing spiral ligament fibrocytes and generating endocochlear potential with an appropriate endolymph ion composition are essential for hearing. Understanding spiral ligament fibrocyte development is useful for studying age-related and genetic hearing loss, as well as for regenerative therapy and cochlear immunology. Despite interspecies differences, most studies of cochlear development have been conducted in rodent models due to the difficulty of using human fetal samples. This study investigated the cochlear development of spiral ligament fibrocytes in a small New World monkey species, the common marmoset (Callithrix jacchus). We examined the developmental expression of specific genes in spiral ligament fibrocytes, including those essential for the generation of endolymphatic potential. Our results showed that this animal model of spiral ligament fibrocyte development is similar to that of humans and is a suitable alternative for the analysis of human cochlear development. The time course established in this study will be useful for studying the primate-specific developmental biology of the inner ear, which may lead to novel treatment strategies for human hearing loss.

Stria vascularis is a structure that generates potassium gradients in the cochlea, which is vital for hair cells to convert mechanical sound waves into electrical pulses. The precise development of the stria vascularis and subsequent generation of endocochlear potential are thus essential for hearing. Understanding the development of the stria vascularis is valuable for studying hearing loss caused by aging or genetics and designing regenerative therapy. Although inter-species differences have been reported between rodents and humans, most of our current knowledge regarding cochlear development has been obtained from rodent models because of the difficulty in using human fetal samples in this field of research. Therefore, we investigated the development of the cochlear stria vascularis in the common marmoset (Callithrix jacchus), a small monkey species native to the New World. Our study confirms that stria vascularis development in the common marmoset is similar to that in humans and is suitable for furthering our understanding of human cochlear development. The time course established in this report will aid in studying the primate-specific developmental biology of the inner ear, which could eventually lead to new treatment strategies for hearing loss in humans.

With the widespread application of genetic testing in recent years, the pathogenesis of carotid body tumors has been clarified. At present, tumor resection is the only curative treatment, with the high risk of perioperative complications, such as intraoperative hemorrhage, inferior cerebral nerve dysfunction, and cerebral infarction. A multidisciplinary team approach is essential for planning safe surgical resection. In addition, treatment options are limited for cases with unresectable disease, such as those with invasion of adjacent structures and/or distant metastasis. New treatment methods are developing. In the near future, new therapies targeting factors contributing to tumor development, such as SDHx, and tumor progression are expected to be developed.

Connexins are gap junction components that are essential for acquiring normal hearing ability. Up to 50% of congenital, autosomal‐recessive, non‐syndromic deafness can be attributed to variants in GJB2, the gene that encodes connexin 26. Gene therapies modifying the expression of connexins are a feasible treatment option for some patients with genetic hearing losses. However, the expression patterns of these proteins in the human fetus are not fully understood due to ethical concerns. Recently, the common marmoset was used as a primate animal model for the human fetus. In this study, we examined the expression patterns of connexin 26 and connexin 30 in the developing cochlea of this primate. Primate‐specific spatiotemporal expression changes were revealed, which suggest the existence of primate‐specific control of connexin expression patterns and specific functions of these gap junction proteins. Moreover, our results indicate that treatments for connexin-related hearing loss established in rodent models may not be appropriate for human patients, un-derscoring the importance of testing these treatments in primate models before applying them in human clinical trials.