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Abstract Type I spiral ganglion neurons are peripheral neurons essential for hearing perception. While they can be subdivided in mice based on characteristic gene expression patterns, detailed examinations of these subtypes in primates and humans are lacking. In this study, we investigated the developmental subtypes of spiral ganglion neurons in the common marmoset (Callithrix jacchus). We confirmed that Type I spiral ganglion can be divided based on the characteristic gene expression patterns of several marker genes. However, some combinations of these genes differ from those in rodents, suggesting common marmoset's suitability for advancing our understanding of human cochlear development. Additionally, identifying the essential time points for subtype specifications and subsequent maturation will aid in studying the primate-specific developmental biology of the inner ear. This could lead to new treatment strategies for hearing loss in humans and be valuable for studying age-related hearing loss, as well as designing regenerative therapies.

Introduction: Goblet cell adenocarcinoma (GCA) of the appendix is an uncommon type of cancer that includes both epithelial and neuroendocrine features, with goblet cells present. These tumors have traditionally been viewed as one of the more aggressive forms of appendiceal cancer, frequently being diagnosed at a metastatic stage. For patients with stage III–IV disease, the 5-year overall survival rate ranges from 14% to 22%. Due to limited data, the diagnosis and management of GCA are challenging. Case Presentation: We present the case of a 55-year-old female who presented with elevated serum carcinoembryonic antigen levels and a left ovarian tumor. Preoperative imaging indicated a normal appendix. During surgery for suspected ovarian carcinoma, frozen section analysis revealed mucinous adenocarcinoma of the ovary, but distinguishing between primary and metastatic lesions was challenging. Meticulous exploration revealed a firm and thickened appendix, prompting appendectomy and subsequent diagnosis of appendiceal GCA with ovarian metastasis. Conclusion: Pathologies of the appendix, like GCA, can mimic ovarian tumors despite a normal-looking appendix, complicating diagnosis. Through this case, we underscored the need for careful intraoperative examination of the appendix in patients with mucinous ovarian neoplasms to avoid misdiagnosis and ensure appropriate treatment.

Abstract Highly accurate real-time cochlear nerve monitoring to preserve cochlear nerve function is essential for simultaneous cochlear implantation and ipsilateral vestibular schwannoma resection. In the present study, we developed a novel real-time monitoring system that combines dorsal cochlear nucleus action potential monitoring with intracochlear stimulating electrodes (Auditory Nerve Test System, ANTS). We used this system for a case with vestibular schwannoma resection via the translabyrinthine approach. The monitoring system developed in this study detected highly reliable evoked potentials from the cochlear nerve every two seconds continuously during tumor resection. Near-total tumor resection was achieved, and cochlear implantation was performed successfully after confirming the preservation of cochlear nerve function in a case. The patient’s hearing was well compensated by cochlear implantation after surgery. Our novel method continuously achieved real-time monitoring of the cochlear nerve every two seconds during vestibular schwannoma resection. The usefulness of this monitoring system for simultaneous tumor resection and cochlear implantation was demonstrated in the present case. The system developed in this study is compatible with continuous facial nerve monitoring. This highly accurate and novel monitoring method will broaden the number of candidates for this type of surgery in the future.

Abstract 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.

Abstract 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

Hearing loss is a significant quality-of-life (QOL) issue in aging populations and is linked to social isolation, dementia, and depression. Early detection and treatment of hearing loss are critically important aspects of preventing cognitive decline and dementia. To date, smartphone, or tablet-based hearing test methods have been proposed to increase the rate of hearing loss detection outside of the hospital. However, simple hearing tests may be performed without adequate soundproofing facilities; therefore, the reliability of such tests in noisy environments is questionable. In this study, we propose a simple hearing test method that uses a soundproof active noise control (ANC) headphone with acoustic-filtering earcups. The ANC headphones provide sufficient soundproofing over a wide frequency range, and the acoustic-filtering earcups provide effective soundproofing around the test frequency. The proposed earcup is equipped with a Helmholtz resonator (HR) array, wherein multiple HRs are densely arrayed in a honeycomb structure. The muffling effect of the HRs effectively attenuated the noise at a specific frequency. This property is useful for high-accuracy hearing tests, in which the noise around the test frequency is sufficiently reduced. The prototype device attained a maximum noise attenuation of 50 dB at approximately 4 kHz and provided hearing tests that were as accurate as those obtained in a soundproof room.

Abstract Atherosclerosis is reported to be a risk factor for the severity of idiopathic sudden sensorineural hearing loss (ISSNHL). We evaluated the hypothesis that atherosclerosis affects the hearing thresholds of both the affected and healthy sides of ISSNHL patients. We conducted multivariate analyses on retrospectively collected data of patients with ISSNHL (N = 762) to evaluate the relationship between known factors linked to atherosclerosis and hearing thresholds on affected and healthy sides and whether these factors are prognostic for hearing recovery. Older ages, vertigo or dizziness, diabetes mellitus, and congestive heart failure were significantly related to higher hearing thresholds on the affected side. Older ages, male, and vascular disease were significantly related to higher hearing thresholds on the healthy side. Vertigo or dizziness, severe hearing loss and hearing loss at high frequencies on the affected side, higher hearing thresholds on the healthy side, regular anticoagulant medication, and delayed steroid treatment were significantly related to lack of recovery. Since several atherosclerosis-related factors are associated with higher hearing thresholds on both affected and healthy sides in ISSNHL and higher hearing thresholds on the healthy side predict poorer prognosis, diagnosis, and predicting prognosis of ISSNHL may benefit from rigorous evaluation of patients’ cardiovascular comorbidities and hearing levels on both the healthy and affected sides.

Abstract In situ follicular B cell neoplasm, previously known as follicular lymphoma in situ, is a neoplastic proliferation of follicular lymphoma‐like B cells confined to the germinal centers. Herein, we report a case of a woman in her 70s who initially presented with several enlarged abdominal lymph nodes. Seven months later during follow‐up, a solitary pulmonary nodule was detected. As it was close to the hilum, lobectomy was performed. The intraoperative frozen section showed fibrosis and a collection of lymphocytes and macrophages. Therefore, the lymph nodes were sampled. Station 4 and 10 lymph nodes exhibited similar tumor cells and were immunohistochemically positive for CD10 and BCL2. Thus, the patient was diagnosed with in situ follicular neoplasm and is currently under observation. In situ follicular neoplasm is typically a slowly progressive neoplasm; however, it can present as a rapidly enlarging pulmonary nodule complicated by pulmonary aspergillosis.

Abstract 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.

IntroductionMacrophages are essential immune cells in the cochlea that contribute to inflammation, tissue repair, and homeostasis. They also play an important role in local cochlear immunity. The developmental immigration and maturation of macrophages in the cochlea have been investigated and are considered essential for normal hearing acquisition. Most of our current knowledge regarding cochlear development is based on rodent models because of the ethical challenges of using human fetal samples for research. However, inter-species differences between rodents and humans have been reported. In this study, we used a primate animal model to investigate the distributions of macrophages in the developing cochlea. The common marmoset (Callithrix jacchus), a small monkey species that inhabits the New World, was used as the model.MethodsWe investigated the distribution of macrophages in the developing cochlea of the common marmoset by performing immunohistochemical analyses of cochlear tissue from common marmoset embryos at different development stages.ResultsWe revealed detailed distribution changes in the macrophages of a primate animal model cochlea. This observation indicates that most of the changes in the general distribution of macrophages were well preserved between rodents and this primate. The distribution changes observed in the common marmoset were also compatible with observations in the human fetus; although, observations in the human fetus are limited. Our observations in this study also revealed several differences between common marmosets and rodents.ConclusionThe time course of immunological development and maturations established in this study will aid in the study of the primate-specific developmental biology of the inner ear. These observations may eventually lead to new therapeutic strategies for hearing loss in humans. In addition, understanding the immunological steady-state of the cochlea may help in the study of age- and genetic-induced hearing loss and in the design of regenerative therapies.

Abstract The cause of idiopathic sudden sensorineural hearing loss (idiopathic SSNHL)—diagnosed after excluding other causes of hearing loss, such as SSNHL associated with vestibular schwannoma (VS)—is unknown. The presumed pathogenesis of idiopathic SSNHL includes circulatory disorders (e.g., cochlear infarction). We tested the hypothesis that patients with SSNHL who are at high stroke risk will have a lower rate of VS compared to those with low stroke risk. The rationale is that the primary cause of SSNHL in patients with high stroke risk might be a circulatory disturbance. We conducted a retrospective study in six hospitals. Our sampling of SSNHL patients included those diagnosed with idiopathic SSNHL and VS-associated SSNHL. SSNHL patients who had a head MRI were stratified by severity of hearing loss and evaluated for differences in the detection rate of VS between the high-scoring CHADS2 (CHADS2-H-), an index of stroke risk, and low-scoring CHADS2 (CHADS2-L-) groups. We identified 916 patients who met the inclusion criteria. For severe hearing loss, the CHADS2-H group had a significantly lower rate of VS than the CHADS2-L group (OR 0 [95% CI 0.00–0.612]; P = 0.007). These results indirectly support the hypothesis that a primary cause of severe idiopathic SSNHL in those at high risk of stroke might be a circulatory disorder.

Tumoral lesions of the temporal bone include benign or malignant tumors and congenital or inflammatory lesions. Temporal bone lesions are difficult to approach. Therefore, making a preoperative diagnosis and considering whether the lesions require treatment are necessary; if they require treatment, then the type of treatment requires consideration. These tumors cannot be observed directly and must be diagnosed based on symptoms and imaging findings. However, the differentiation of temporal bone lesions is difficult because they are rare and large in variety. In this pictorial review, we divided temporal bone lesions by location such as along the facial nerve, along the internal jugular vein, around the endolymphatic sac, in the internal auditory canal/cerebellopontine angle, petrous apex, middle ear, and mastoid, focusing on the imaging findings of temporal bone lesions. Then, we created a diagnostic flowchart that suggested that the systematic separation of imaging findings is useful for differentiation. Although it is necessary to make comprehensive judgments based on the clinical symptoms, patient background, and imaging findings to diagnose temporal bone mass lesions, capturing imaging features can be a useful differentiation method.

Abstract Background Inflammatory pseudotumors (IPTs) are rare, idiopathic, and inflammatory lesions that are histopathologically benign. Here, we present three cases of labyrinthine destruction caused by an IPT. Methods The first patient was a 74‐year‐old male with a mass lesion extending from the inner ear to the external ear canal. The second patient was a 62‐year‐old female with a foliated polycystic lesion in the petrous bone on the dorsal side of the left internal auditory canal. The third patient was a 68‐year‐old female with a mass extending from the inner ear to the middle ear, destroying the semicircular canal and cochlea. Results In two cases, we performed surgical resection successfully with no recurrence. In the other case, the lesion showed shrinkage after chemotherapy for colorectal cancer incidentally found during the examination process. Conclusion Surgical technique and indication for IPT should be based on the location and function of the lesion. In addition, there is room to consider pharmacotherapy as a treatment option for IPT of the temporal bone. Level of Evidence 4.

Abstract Metastatic intrathyroid thymic carcinoma (ITTC) is a rare cancer with no effective drugs for controlling. This case report has shown genomic and immune microenvironment profiles in metastatic ITTC and emphasized an immunosuppression via a PD‐1/PD‐L1 pathway, possibly strengthening the rationale for immune checkpoint blockade as a novel treatment.

Abstract Background Salivary gland choristoma (SGCh) is a rare benign tumor reported in several unusual sites, such as the gastrointestinal tract, the optic nerve, and the internal auditory canal, but never reported in the inner ear. Case presentation An 8-year-old girl with a history of left profound congenital hearing loss presented to us with ipsilateral progressive severe facial nerve palsy (House-Brackmann Grade VI). The left tympanic membrane was swollen with a pulsatile tumor. Radiological investigations revealed a multilocular tumor in the inner ear extending into the middle ear and internal auditory canal (IAC). We performed a partial resection of the tumor by transmastoid approach to preserve the anatomical structure of the facial nerve. The tumor was pathologically diagnosed as SGCh. Two years after surgery, her facial function recovered to House-Brackmann Grade II and the residual tumor did not show regrowth on MRI. Conclusions Although the natural course of this rare tumor is unknown, a partial resection is an acceptable treatment procedure when functional recovery of the facial nerve is anticipated. Graphical abstract

Abstract Clinical features of sudden sensorineural hearing loss (SSNHL) associated with vestibular schwannoma (VS) are not fully understood. Determining a treatment plan and explaining it to patients requires clinicians to clearly understand the clinical features related to the tumor, including SSNHL. To identify the full range of clinical features of VS-associated SSNHL, especially recovery of hearing following multiple episodes of SSNHL and what factors predict recovery and recurrence. A multicenter retrospective chart review was conducted in seven tertiary care hospitals between April 1, 2011, and March 31, 2020. We collected and analyzed dose of administered steroid, pure-tone audiometry results, and brain MRIs of patients diagnosed with VS-associated SSNHL. Seventy-seven patients were included. They experienced 109 episodes of audiogram-confirmed SSNHL. The highest proportion of complete recoveries occurred in patients with U-shaped audiograms. The recovery rates for the first, second, and third and subsequent episodes of SSNHL were 53.5%, 28.0%, and 9.1%, respectively. Recovery rate decreased significantly with increasing number of SSNHL episodes (P =0 .0011; Cochran-Armitage test). After the first episode of SSNHL, the recurrence-free rate was 69.9% over 1 year and 57.7% over 2 years; the median recurrence time was 32 months. Logarithmic approximation revealed that there is a 25% probability that SSNHL would recur within a year. SSNHL in patients with VS is likely to recur within one year in 25% of cases. Also, recovery rate decreases as a patient experiences increasing episodes of SSNHL.

Abstract Background Gorham-Stout disease is a rare bone disorder. Here, we present a case of Gorham-Stout disease diagnosed during follow-up of a patient with cholesteatoma; the disease affected the temporal bone and other sites of the skull. To the best of our knowledge, this is the first report of Gorham-Stout disease diagnosed with recurrent cerebrospinal leakage after surgery to treat cholesteatoma. Case presentation A 25-year-old male patient re-presented to our department for the first time in 7 years with otorrhea in the right ear and recurrent meningitis. The patient had a history of multiple surgeries for cholesteatoma and suffered from recurrent cerebrospinal fluid leakage, which initially was thought to be caused by recurrence of cholesteatoma. Therefore, skull base reconstruction was planned. However, the underlying cause was identified eventually as defects in the temporal bone caused by massive osteolysis due to Gorham-Stout disease. Skull base reconstruction was abandoned because the osteolysis was considered to be progressive. Conservative treatment with infectious control was implemented as an alternative. Conclusion This case describes unusual temporal bone osteolysis after cholesteatoma surgery and the importance of considering the possibility of multiple concurrent diseases in such individuals. The distinguishing features of this case are the fact that the temporal bone had disappeared, and deconstruction was complicated by infection and inflammation caused by cholesteatoma, surgical invasion, and Gorham-Stout disease. Appropriate diagnosis saved the patient from ineffective multiple surgeries for cerebrospinal fluid leakage or cholesteatoma, and improved his quality of life.

Abstract Purpose This study aims to examine the availability of subscales in the Tinnitus Handicap Inventory (THI) originally proposed by Newman and the possibility of other useful subscales. We also examine whether each item of the THI could be used to better understand the status of patients with tinnitus. Methods This study included 1332 patients who answered the THI on their first visit. Confirmatory factor analysis was conducted to the 25 items of the THI to confirm the usefulness of the emotional, functional, and catastrophic subscales. Exploratory factor analysis was performed to discover the availability of other suitable subscales in addition to the proposed subscales. The proportion of patients who chose “yes” in each item of the THI was also examined to understand the status of patients with tinnitus. Results In the confirmatory factor analysis, the emotional, functional, and catastrophic subscales did not fit the model. In the exploratory factor analysis, data were extremely biased to one factor. Examination of each item of the THI showed the tendency of worsening of comorbid symptoms when tinnitus handicap became worse. Conclusions As a result of the factor analysis, only the total score, not any subscale, would be clinically useful in the THI. Examination of each item of the THI was helpful to understand the status of patients with tinnitus and comorbid symptoms of tinnitus. It is necessary to consider treatment by taking these comorbid symptoms into account.

Abstract Background We reported that tinnitus patients showed reduced levels of auditory functional connectivity (FC) in comparison with normal hearing control subjects, and that we succeeded in objective diagnosis of tinnitus with 86% sensitivity and 74% specificity by focusing only on auditory‐related FC. However, the age‐related change of auditory FC is not clarified. In this study, we examine age‐related change of the auditory FC using the database of Human Connectome Project (HCP) and compared with our database of tinnitus patients. Method From the HCP database HCP Lifespan Pilot project, we studied five age groups, 8 to 9 years old, 14 to 15, 25 to 35, 45 to 55, and 65 to 75. We also applied our tinnitus patients' resting‐state functional magnetic resonance imaging (fMRI) database, which is divided into three generations; 20 to 40 years old, 40 to 60, and 60 to 80 to compare with the HCP database. The resting state fMRI analyses were performed using the CONN toolbox version 18. As auditory‐related regions, Heschl's gyrus, planum temporale, planum polare, operculum, insular cortex, and superior temporal gyrus were set as the regions of interest from our previous reports. Result Auditory FC is strongest among adolescents and reduces with age. But the auditory FC of tinnitus patients were significantly less than those of HCP data in each generation. Conclusion Although auditory FC decreases with age, tinnitus patients have less auditory FC compared with age‐matched controls. The age‐matched cutoff values are necessary for an objective diagnosis of tinnitus with resting state fMRI.

Surgery for vestibular schwannoma includes various techniques such as the middle cranial fossa, suboccipital, translabyrinthine, and retrolabyrinthine approaches. The retrolabyrinthine approach does not impair the labyrinth and allows postoperative hearing preservation. Previously, we reported an endoscope-assisted retrolabyrinthine approach under reinforced continuous intraoperative monitoring for preservation of hearing and facial nerve function. However, the hearing preservation rate was relatively low in patients with long-wave V latency in the auditory brainstem response or poor otoacoustic emission response under this approach. Thus, the hearing preservation rate in such patients remains to be improved. To overcome this limitation, we modified the previous approach. In 26 of the 33 consecutive cases (79%) over the last three years, preservation of hearing equivalent to that before surgery or improved hearing was achieved. Postoperative deafness was observed in only two of the 33 cases (6%). According to previous reports, the rate of hearing preservation using the retrolabyrinthine approach is approximately 30–50%. Therefore, we have achieved a higher hearing preservation rate than that previously reported using the endoscopy-assisted retrolabyrinthine approach under reinforced continuous intraoperative monitoring. These improvements in our department are considered to be helpful for hearing preservation.

The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has shown efficacy for the treatment of neurofibromatosis type 2 (NF2). Here, the authors show that VEGFRs peptide vaccination can improve hearing and reduce tumor volume in NF2 patients, including in previously bevacizumab resistant tumors.

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.

We experienced a very rare case, which we believe to be sporadic schwannomatosis, in which a 49-year-old female patient presented with conductive hearing loss due to a subcutaneous tumor in the right external auditory canal and the symptoms were completely ameliorated by surgery. The patient had surgical histories of multiple cervical spinal cord schwannoma removal. At the age of 47, she was referred to our department due to a growing tumor in the right external auditory canal. At the initial visit, a smooth surface tumor was found in the right external auditory canal, and pure tone audiometry confirmed the conductive hearing loss of the right ear. Also, several tender masses with severe pain were observed around the right auricle. Contrast-enhanced MRI images revealed multiple well-defined masses in the right external ear canal, and above, behind, and below the right auricle. Furthermore, a small vestibular schwannoma localized in the left internal ear canal was found. We performed a surgical resection of the tumor in the right external auditory canal and the subcutaneous tumors around the right ear. Histopathological examination showed that all tumors were schwannomas with no malignant findings. After the surgery, the right air-bone gap completely disappeared, and so did the severe pain around the auricle. Her clinical course suggests that the schwannomas were a part of systematic schwannomatosis. This is the first case report of schwannomatosis of which the schwannoma was located in the external auditory canal.

There are no established indications for facial nerve schwannoma treatment, including surgery, radiation and follow-up observation, and it is difficult to determine treatment policy uniformly. The treatment policy was examined from each treatment course. Data of patients with facial nerve schwannomas at our hospital from 1987 to 2018 were retrospectively examined. Their age, sex, clinical symptoms, tumor localization, treatment policies and outcomes were reviewed. In total, 22 patients underwent surgery and 1 patient underwent radiotherapy; 22 patients were followed up without treatment. After total resection, there were no tumor recurrences, and most patients had grade 3 or 4 postoperative facial paralysis. After subtotal resection, tumor regrowth was observed in four patients and reoperation was required in two patients. Facial nerve function was maintained in four patients and was decreased in two patients. During follow-up, six patients showed tumor growth. Only one patient had worsening facial nerve paralysis; four patients underwent facial nerve decompression owing to facial nerve paralysis during follow-up. If the tumor compresses the brain or it is prone to growth, surgery may be indicated, and when the preoperative facial nerve function is grade ≤ 3, consideration should be given to preserving facial nerve function and subtotal resection should be indicated. If the preoperative facial nerve function is grade ≥ 3, total resection with nerve grafting is an option to prevent regrowth. If there is no brain compression or tumor growth, the follow-up is a good indication, and decompression should be considered in facial nerve paralysis cases.

Vestibular schwannoma is a clinically benign schwannoma that arises from the vestibulocochlear nerve that causes sensorineural hearing loss. This tumor is clinically and oncologically regarded as a benign tumor as it does not metastasize or invade surrounding tissues. Despite being a benign tumor, its management is difficult and controversial due to the potential serious complications, such as irreversible sensorineural hearing loss, of current interventions. Therefore, preventing hearing loss due to the natural course of the disease and complications of surgery is a challenging issue for an otologist. Improvements have been reported recently in the treatment of vestibular schwannomas. These include advances in intraoperative monitoring systems for vestibular schwannoma surgery where the risk of hearing loss as a complication is decreased. Precise genomic analysis of the tumor would be helpful in determining the characteristics of the tumor for each patient, leading to a better hearing prognosis. These procedures are expected to help improve the treatment of vestibular schwannomas. This review summarizes recent advances in vestibular schwannoma management and treatment, especially in hearing preservation. In addition, recent advances in the understanding of the molecular mechanisms underlying vestibular schwannomas and how these advances can be applied in clinical practice are outlined and discussed, respectively. Moreover, the future directions from the bedside to the bench side are presented from the perspective of otologists.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.

Abstract Background There have been many reports on the treatment effect of cochlear implantation and hearing aids in the treatment of tinnitus in patients with severe hearing loss. However, as far as we are aware, there are no reports of investigation of treatment approaches for the tinnitus of deaf patients whose communication is solely carried out in sign language due to a long duration of deafness. Case presentation We experienced a case of severe tinnitus with bilateral deafness for more than 50 years. The patient is a 69-year-old woman who communicates with her family solely in sign language. Family stress triggered the onset of tinnitus, accompanied by sleep disorder and palpitations. At the initial visit, she suffered from severe tinnitus (THI 94) as well as strong tendencies toward depression and anxiety. Because neither the patient nor her family was willing to use cochlear implantation, the administration of an antidepressant and a sleep-inducing agent was started, which resulted in improvement of the psychological conditions. Tinnitus distress, synchronized with the heartbeat, was relieved by the addition of autogenic training. At four and half years after the initial visit, the THI score had dropped to 0, and the subjective tinnitus and palpitation had almost disappeared, with only a low dose of antidepressant necessary. Conclusion A deaf patient with severe tinnitus was successfully treated with drug and psychotherapy.

Abstract Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive (EpCAM+) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted EpCAM+ and EpCAM− HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted EpCAM+ cells than in EpCAM− cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted EpCAM+ and EpCAM− cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs.

BACKGROUND: Cancer stem cells (CSCs) are considered a pivotal target for the eradication of hepatocellular carcinoma (HCC). Recently, we reported that the CSC markers epithelial cell adhesion molecule (EpCAM) and CD90 are expressed independently in primary HCCs and cell lines, and CD90+ cells share features of metastatic vascular endothelial cells and express the vascular endothelial marker CD105, a co-receptor of transforming growth factor-beta. METHODS: The EpCAM+ cell lines HuH1 and HuH7 were treated with 5-fluorouracil (5-FU) or epirubicin in vitro. Gene and protein expression levels were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and fluorescence-activated cell sorting, respectively. The expression of CD105 in primary HCC was evaluated by immunohistochemistry. The relationship of CD105 expression status and HCC prognosis was evaluated using 85 surgically resected HCC tissues by Kaplan–Meier survival analysis. RESULTS: 5-FU or epirubicin treatment resulted in the generation of CD90+ and CD105+ cells in vitro in HuH1 and HuH7 cells, which originally contain no CD90+ or CD105+ cells. This phenomenon was validated by qRT-PCR analysis with activation of the epithelial-mesenchymal transition (EMT) program regulators Snail family zinc finger 1 (SNAI1) and SNAI2. Immunohistochemical analysis indicated that CD105+ cells were morphologically identical to vascular endothelial cells in untreated primary HCCs. However, surgically resected specimens after transcatheter arterial chemoembolization clearly indicated that CD105+ cancer cells survived at the peripheral edge of the tumor. Kaplan–Meier survival analysis indicated that HCCs expressing CD105 showed poor prognosis after surgery with statistical significance. CONCLUSIONS: Taken together, our data highlight the role of CD105+ HCC cells with activation of the EMT program generated de novo after cytotoxic therapy on the prognosis of HCC patients.

Objective: Quality of life (QoL) and subjective symptoms are predominantly used to evaluate treatment outcome of patients with vestibular schwannoma (VS). However, for patients undergoing conservative treatment—the most frequently used intervention—the association between QoL and subjective symptoms is unclear. Moreover, it is unknown whether VS-related tinnitus could be associated with the audiological and psychological status of the patient. Our overall aim is to provide objective evidence of this association to better guide treatment of VS.Methods: In a prospective study, we analyzed factors that influence VS-related tinnitus and QoL in 72 patients receiving conservative management of unilateral sporadic VS. This was done through questionnaires that assessed QoL, anxiety, depression, and audiological examinations. We used the SF-36 Short Form to assess QoL; the Tinnitus Handicap Inventory, Dizziness Handicap Inventory, Facial Clinimetric Evaluation Scale, Visual Analog Scale for hearing impairment to assess symptoms subjectively; and pure tone audiometry, the speech discrimination for hearing measurements. For psychological status, we used the Hospital Anxiety and Depression Scale. For analyses, we used Pearson correlation analysis and multiple regression between variables and QoL.Results: Correlation and regression analyses revealed that the severity of tinnitus distress had the largest negative impact on QoL in all domains of SF-36. The severity of tinnitus was significantly associated with subjective hearing impairment and the degree of depression and anxiety. Hearing thresholds had no statistical association with severity of tinnitus.Conclusions: To our knowledge, this is the first study to investigate VS-related tinnitus with respect to both patients' hearing status and psychological condition. Our results suggest that tinnitus distress strongly affects VS patients' QoL and that its characteristics are similar to primary tinnitus. An intervention for VS-related tinnitus, therefore, should assess to what extent tinnitus bothers patients, and it should reduce any unpleasant emotions that may exacerbate symptoms. This approach should improve their QoL.

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The presence of distant metastasis is associated with an adverse outcome in papillary thyroid cancer. We performed a meta-analysis to investigate the role of molecular markers as predictors for distant metastasis in papillary thyroid cancer. Four electronic databases including PubMed, Web of Science, Scopus, and Virtual Health Library were searched, and odds ratio and its 95% confidence interval concerning the association of BRAF , RAS , and TERT promoter mutations and RET/PTC rearrangements with distant metastasis were calculated using random-effects model. In total, 42 studies with 11,109 papillary thyroid cancers were included for meta-analyses. Overall, the presence of TERT promoter (odds ratio = 5.95; 95% confidence interval = 2.95–11.99), RAS mutations (odds ratio = 2.5; 95% confidence interval = 1.00–6.22), and RET/PTC rearrangements (odds ratio = 1.92; 95% confidence interval = 1.03–3.56) were found to be associated with a significantly increased risk for distant metastasis. BRAF mutations were not associated with an elevated risk for distant metastasis (odds ratio = 0.79; 95% confidence interval = 0.54–1.16). In conclusion, our study demonstrated the promising value of few molecular biomarkers, especially TERT promoter mutations in predicting distant metastasis in papillary thyroid cancers, while BRAF mutations showed no association with distant metastasis. Our study affirms the value of selected mutations for tumor risk stratification and assessment of patients’ prognosis.

The Tinnitus Sample Case History Questionnaire was determined as a standardized questionnaire for obtaining patient case histories and for characterizing patients into subgroups at the Tinnitus Research Initiative in 2006. In this study, we developed a Japanese version of this questionnaire for evaluating the clinical characteristics of patients with tinnitus. The Japanese version of the questionnaire will be available for evaluating treatments for tinnitus and for comparing data on tinnitus in research centers.To evaluate the clinical characteristics of patients with tinnitus in Japan using a newly developed Japanese version of Tinnitus Sample Case History Questionnaire.This was a prospective study based on patient records.University hospitals, general hospitals, and clinics.We collected patient data using a Japanese translated version of the Tinnitus Sample Case History Questionnaire. In total, 584 patients who visited our institutions in Japan between August 2012 and March 2014 were included (280 males and 304 females; age 13-92 years; mean age, 60.8). We examined patients after dividing them into two groups according to the presence or absence of hyperacusis. The collected results were compared with those from the Tinnitus Research Initiative database.Compared with the TRI database, there were significantly more elderly female patients and fewer patients with trauma-associated tinnitus. There was a statistically lower ratio of patients with hyperacusis. We found that patients with tinnitus in addition to hyperacusis had greater tinnitus severity and exhibited higher rates of various complications.The Japanese version of the Tinnitus Sample Case History Questionnaire developed in this study can be a useful tool for evaluating patients with tinnitus in Japan. The results of this multicenter study reflect the characteristics of patients with tinnitus who require medical care in Japan. Our data provides a preliminary basis for an international comparison of tinnitus epidemiology.

The spatiotemporal distribution of drugs in the inner ear cannot be precisely evaluated because of its small area and complex structure. In the present study, we used hyaluronic acid (HA)-dispersed luciferin to image transgenic mice and to determine the effect of HA on controlled drug delivery to the cochlea. GFAP-luc mice, which express luciferase in cochlear spiral ganglion cells, were subcutaneously administered HA-luciferin (HA-sc) or luciferin dissolved in saline (NS-sc) or intraperitoneally administered luciferin dissolved in saline (NS-ip). The bioluminescence of luciferin was monitored in vivo in real time. The peak time and half-life of fluorescence emission were significantly increased in HA-sc-treated mice compared with those in NS-sc- and NS-ip-treated mice; however, significant differences were not observed in peak photon counts. We detected differences in the pharmacokinetics of luciferin in the inner ear, including its sustained release, in the presence of HA. The results indicate the clinical potential of using HA for controlled drug delivery to the cochlea.

The cancer stem cell (CSC) hypothesis was first proposed over 40 years ago. Advances in CSC isolation were first achieved in hematological malignancies, with the first CSC demonstrated in acute myeloid leukemia. However, using similar strategies and technologies, and taking advantage of available surface markers, CSCs have been more recently demonstrated in a growing range of epithelial and other solid organ malignancies, suggesting that the majority of malignancies are dependent on such a compartment.Primary liver cancer consists predominantly of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). It is believed that hepatic progenitor cells (HPCs) could be the origin of some HCCs and ICCs. Furthermore, stem cell activators such as Wnt/β-catenin, TGF-β, Notch and Hedgehog signaling pathways also expedite tumorigenesis, and these pathways could serve as molecular targets to assist in designing cancer prevention strategies. Recent studies indicate that additional factors such as EpCAM, Lin28 or miR-181 may also contribute to HCC progression by targeting HCC CSCs. Various therapeutic drugs that directly modulate CSCs have been examined in vivo and in vitro. However, CSCs clearly have a complex pathogenesis, with a considerable crosstalk and redundancy in signaling pathways, and hence targeting single molecules or pathways may have a limited benefit for treatment. Many of the key signaling molecules are shared by both CSCs and normal stem cells, which add further challenges for designing molecularly targeted strategies specific to CSCs but sparing normal stem cells to avoid side effects. In addition to the direct control of CSCs, many other factors that are needed for the maintenance of CSCs, such as angiogenesis, vasculogenesis, invasion and migration, hypoxia, immune evasion, multiple drug resistance, and radioresistance, should be taken into consideration when designing therapeutic strategies for HCC.Here we provide a brief review of molecular signaling in liver CSCs and present insights into new therapeutic strategies for targeting liver CSCs.

We encountered a patient with primary cervical leiomyoma with remarkable calcification and ossification. A 68-year-old man presenting with induration and swelling of the left submandibular region was found to have nodular lesions with calcifications in the left submandibular region and the upper mediastinum on CT. Fine needle aspiration biopsies (FNAB) of the left submandibular lesion revealed no malignancy. Resection was performed for definitive diagnosis and treatment. The resected specimen contained a solid tumor, which was markedly calcified and ossified on the cut surface. Histopathological examination showed proliferating spindle cells in a tangled and crossed arrangement. Immunohistochemically, the spindle cells were stained intensely with α-SMA and h-caldesmon, consistent with smooth muscle cells. These findings led to a definitive diagnosis of leiomyoma with calcification and ossification. This is extremely rare and the preoperative differentiation from other tumors of the head and neck was very difficult. By resection of the submandibular tumor, both definitive diagnosis of leiomyoma by histopathological and immunohistochemical analyses and treatment could be carried out. However, as the tumor in the upper mediastinum was most likely to be leiomyoma with calcification, he did not wish to undergo its biopsy and resection immediately. We have continued the follow-up.

Agricultural systems using advanced information and communication (ICT) technology can produce high-quality crops in a stable environment while decreasing the need for manual labor. The system collects a wide variety of environmental data and provides the precise cultivation control needed to produce high value-added crops; however, there are the problems of packet transmission errors in wireless sensor networks or system failure due to having the equipment in a hot and humid environment. In this paper, we propose a reliable wireless control system for hydroponic tomato cultivation using the 400 MHz wireless band and the IEEE 802.15.6 standard. The 400 MHz band, which is lower than the 2.4 GHz band, has good obstacle diffraction, and zero-data-loss communication is realized using the guaranteed time-slot method supported by the IEEE 802.15.6 standard. In addition, this system has fault tolerance and a self-healing function to recover from faults such as packet transmission failures due to deterioration of the wireless communication quality. In our basic experiments, the 400 MHz band wireless communication was not affected by the plants’ growth, and the packet error rate was less than that of the 2.4 GHz band. In summary, we achieved a real-time hydroponic liquid supply control with no data loss by applying a 400 MHz band WSN to hydroponic tomato cultivation.

A vestibular schwannoma is a benign tumor; however, the schwannoma itself and interventions can cause sensorineural hearing loss. Most vestibular schwannomas are unilateral tumors that affect hearing only on one side. Attention has focused on improving the quality of life for patients with unilateral hearing loss and therapeutic interventions to address this issue have been emphasized. Herein, we encountered a patient who was a candidate for hearing preservation surgery based on preoperative findings and had nonserviceable hearing after the surgery, according to the Gardner–Robertson classification. Postoperatively, the patient had decreased listening comprehension and ability to localize sound sources. He was fitted with bilateral hearing aids, and his ability to localize sound sources improved. Although the patient had postoperative nonserviceable hearing on the affected side and age-related hearing loss on the unaffected side, hearing aids in both ears were useful for his daily life. Therefore, the patient was able to maintain a binaural hearing effect and the ability to localize the sound source improved. This report emphasizes the importance of hearing preservation with vestibular schwannomas, and the demand for hearing loss rehabilitation as a postoperative complication can increase, even if hearing loss is nonserviceable. [ABSTRACT FROM AUTHOR]