Details of a Researcher - Ozawa, Hiroyuki

Papers - Ozawa, Hiroyuki

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Development of cochlear spiral ligament fibrocytes of the common marmoset, a nonhuman model animal

Hosoya M., Iwabu K., Kitama T., Nishiyama T., Oishi N., Okano H., Ozawa H.

Scientific Reports (Scientific Reports) 13 ( 1 ) 2023.12

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.

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Correlation between genotype and phenotype with special attention to hearing in 14 Japanese cases of NF2-related schwannomatosis

Oishi N., Noguchi M., Fujioka M., Nara K., Wasano K., Mutai H., Kawakita R., Tamura R., Karatsu K., Morimoto Y., Toda M., Ozawa H., Matsunaga T.

Scientific Reports (Scientific Reports) 13 ( 1 ) 2023.12

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.

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Apoptosis of type I spiral ganglion neuron cells in Otof-mutant mice

Tsuzuki N., Namba K., Saegusa C., Mutai H., Nishiyama T., Oishi N., Matsunaga T., Fujioka M., Ozawa H.

Neuroscience Letters (Neuroscience Letters) 803 2023.04

ISSN 03043940

Otof, which encodes otoferlin, knockout mice are considered model mice for auditory neuropathy spectrum disorder, which is characterized by an absent auditory brainstem response (ABR) despite preserved distortion product otoacoustic emission (DPOAE). Although otoferlin-deficient mice lack neurotransmitter release at the inner hair cell (IHC) synapse, it remains unclear how the Otof mutation affects spiral ganglions. Thus, we used Otof-mutant mice carrying the Otoftm1a(KOMP)Wtsi allele (Otoftm1a) and analyzed spiral ganglion neurons (SGNs) in Otoftm1a/tm1a mice by immunolabeling type Ⅰ SGNs (SGN-Ⅰ) and type II SGNs (SGN-II). We also examined apoptotic cells in SGNs. Four-week-old Otoftm1a/tm1a mice had an absent ABR but normal DPOAEs. The number of SGNs was significantly lower in Otoftm1a/tm1a mice on postnatal day 7 (P7), P14, and P28 compared with that of wild-type mice. Moreover, significantly more apoptotic SGNs were observed in Otoftm1a/tm1a mice than in wild-type mice on P7, P14, and P28. SGN-IIs were not significantly reduced in Otoftm1a/tm1a mice on P7, P14, and P28. No apoptotic SGN-IIs were observed under our experimental conditions. In summary, Otoftm1a/tm1a mice showed a reduction in SGNs accompanied by apoptosis of SGN-Ⅰs even before the onset of hearing. We speculate that the reduction in SGNs with apoptosis is a secondary defect caused by a lack of otoferlin in IHCs. Appropriate glutamatergic synaptic inputs may be important for the survival of SGNs.

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Molecular basis of carotid body tumor and associated clinical features in Japan identified by genomic, immunohistochemical, and clinical analyses

Yoshihama K., Mutai H., Sekimizu M., Ito F., Saito S., Nakamura S., Mikoshiba T., Nagai R., Takebayashi A., Miya F., Kosaki K., Ozawa H., Matsunaga T.

Clinical Genetics (Clinical Genetics) 103 ( 4 ) 466 - 471 2023.04

ISSN 00099163

Carotid body tumor (CBT) is classified as a paraganglioma (PGL). Here, we report the genetic background, protein expression pattern, and clinical findings of 30 Japanese CBT cases. Germline pathogenic or likely pathogenic (P/LP) variants of genes encoding succinate dehydrogenase subunits (SDHs) were detected in 15 of 30 cases (50%). The SDHB variants were the most frequently detected, followed by SDHA and SDHD variants. One case with SDHAF2 variant was bilateral CBT, and other two multiple PGL cases were not detected P/LP variants. The three cases with germline variants that could be tested did not have somatic P/LP variants of the same genes. Immunohistochemical analysis showed negative SDHB signals in CBT tissues in five cases with germline P/LP variants of SDHB, SDHD, or SDHA. In addition, SDHB signals in CBT tissues were negative in four of nine cases without germline P/LP variants of SDHs. These findings suggest the involvement of unidentified molecular mechanisms affecting SDHs.

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Generation of two induced pluripotent stem cell lines from individuals without auditory disorders

Okura S., Ishii H., Suzuki A., Saegusa C., Fujiki K., Sugano K., Suzuki N., Saeki T., Matsuzaki S., Ozawa H., Fujioka M., Hosoya M., Okano H.

Stem Cell Research (Stem Cell Research) 67 2023.03

ISSN 18735061

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Vestibular Schwannoma Surgery with Endoscope-Assisted Retrolabyrinthine Approach under Modified Reinforced Continuous Intraoperative Monitoring for Hearing Preservation: Experience of 33 Cases in a Single Center

Hosoya M., Nishiyama T., Wakabayashi T., Shimanuki M.N., Miyazaki H., Ozawa H., Oishi N.

Diagnostics (Diagnostics) 13 ( 2 ) 2023.01

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.

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Effectiveness of vocal fold medialization surgery on the swallowing function of patients with unilateral vocal fold paralysis

Kono T., Tomisato S., Ozawa H.

Laryngoscope Investigative Otolaryngology (Laryngoscope Investigative Otolaryngology) 2023

Objectives: Vocal fold medialization surgery is generally considered a phonosurgical procedure for improvement of vocal function in patients with glottic insufficiency. However, the literature describing this procedure for the management of dysphagia is limited. This study aims to assess the effects of medialization surgery on swallowing function in patients with unilateral vocal fold paralysis (UVFP). Methods: We enrolled 32 patients with UVFP undergoing vocal fold medialization surgery (medialization laryngoplasty combined with arytenoid adduction [ML + AA], 12 cases; injection laryngoplasty [IL], 20 cases). We assessed the aerodynamic vocal function including maximum phonation time and mean flow rate to evaluate glottal closure status. The Hyodo score determined by flexible endoscopic evaluation and Functional Oral Intake Scale (FOIS) were evaluated pre- and postoperatively. Results: Almost 60% of patients with UVFP had dysphagia, and one-third were at high risk for aspiration. Aerodynamic parameters effectively improved after IL and ML + AA. With regard to swallowing, both the FOIS and total Hyodo score were significantly improved postoperatively. We found a particularly significant improvement in pharyngeal clearance. However, patients with high vagal nerve paralysis and postoperative insufficient glottal closure showed poor swallowing benefits after the interventions. In patients with recurrent laryngeal nerve palsy, there were no significant differences in postoperative swallowing function between the ML + AA and IL groups. Conclusion: Vocal fold medialization surgery was effective in improving swallowing function in most cases with UVFP, except for those with high vagal paralysis and insufficient postoperative glottal closure. Both IL and ML + AA showed an equivalent effect on swallowing improvement. Level of evidence: 3b.

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Prognostic value and clinicopathological roles of the tumor immune microenvironment in salivary duct carcinoma

Hirai H., Nakaguro M., Tada Y., Saigusa N., Kawakita D., Honma Y., Kano S., Tsukahara K., Ozawa H., Okada T., Okami K., Yamazaki K., Sato Y., Urano M., Kajiwara M., Utsumi Y., Shimura T., Fushimi C., Shimizu A., Kondo T., Imanishi Y., Sakai A., Sato Y., Togashi T., Hanazawa T., Matsuki T., Yamazaki K., Nagao T.

Virchows Archiv (Virchows Archiv) 2023

ISSN 09456317

Salivary duct carcinoma (SDC) is an aggressive type of salivary gland carcinoma. Recently, immunotherapies targeting immune checkpoints, including PD1, PD-L1, CTLA4, and LAG3, have had a considerable prognostic impact on various malignant tumors. The implementation of such immune checkpoint inhibitor (ICI) therapies has also been attempted in cases of salivary gland carcinoma. The tumor immune microenvironment (TIME) is implicated in tumorigenesis and tumor progression and is closely associated with the response to ICI therapies. However, the TIME in SDC has not been fully explored. We examined the immunohistochemical expression of CD8, FOXP3, PD1, PD-L1, CTLA4, LAG3, and mismatch repair (MMR) proteins, tumor-infiltrating lymphocytes (TILs), and microsatellite instability (MSI) status in 175 cases of SDC. The associations between these TIME-related markers and the clinicopathological factors and prognosis were evaluated. An elevated expression of CD8, FOXP3, PD1, CTLA4, and LAG3 was associated with more aggressive histological features and an advanced N and/or M classification, elevated Ki-67 index, and poor prognosis. Furthermore, cases with a high PD-L1 expression exhibited more aggressive histological features and adverse clinical outcomes than those with a low expression. Alternatively, there was no significant correlation between TILs and clinicopathological factors. No SDC cases with an MSI-high status or MMR deficiency were found. The coexistence of both an immunostimulatory and immunosuppressive TIME in aggressive SDC might play a role in the presence of T-cell exhaustion. The contribution of multiple immune escape pathways, including regulatory T cells and immune checkpoints, may provide a rationale for ICI therapy, including combined PD1/CTLA4 blockade therapy.

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Mapping of Notch signaling in the developing organ of Corti in common marmosets

Hosoya M., Fujioka M., Okano H., Ozawa H.

Frontiers in Neuroanatomy (Frontiers in Neuroanatomy) 17 2023

Introduction: The well-regulated development of the sensory epithelium is essential for hearing. This process involves the specification of a pro-sensory epithelium containing common progenitors that differentiate into hair and supporting cells. Notch signaling is one of the most critical pathways during these processes, and its modification is thought to be a feasible approach for treating hearing loss. Despite interspecies differences between rodents and primates or humans, most of our current knowledge regarding cochlear development has been obtained from rodent models. Methods: We therefore examined and mapped the expression patterns of Notch signal components in the developing cochlea of the common marmoset (Callithrix jacchus), a small monkey species native to the New World, a primate model animal. Results: In contrast to the preserved expression patterns of the Notch signaling components in the hair cell differentiation between primates and rodents, we unveiled relatively large interspecies differences during the maturation of supporting cells. Discussion: This improved knowledge of Notch signaling during primate cochlear development will facilitate the development of future regenerative therapies.

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Association between atherosclerosis, hearing recovery, and hearing in the healthy ear in idiopathic sudden sensorineural hearing loss: a retrospective chart analysis

Tsuzuki N., Wasano K., Oishi N., Hentona K., Shimanuki M., Nishiyama T., Hiraga Y., Ueno M., Suzuki N., Shinden S., Ogawa K., Ozawa H.

Scientific Reports (Scientific Reports) 12 ( 1 ) 2022.12

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.

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Identification of novel prognostic and predictive biomarkers in salivary duct carcinoma via comprehensive molecular profiling

Kohsaka S., Tada Y., Ando M., Nakaguro M., Shirai Y., Ueno T., Kojima S., Hirai H., Saigusa N., Kano S., Tsukahara K., Togashi T., Ozawa H., Kondo T., Okami K., Takahashi H., Kawakita D., Fushimi C., Suzuki T., Shimizu A., Okamoto I., Okada T., Sato Y., Imanishi Y., Watanabe Y., Sakai A., Ebisumoto K., Sato Y., Urano M., Honma Y., Yamazaki K., Ueki Y., Hanazawa T., Saito Y., Shimura T., Nagao T., Mano H.

npj Precision Oncology (npj Precision Oncology) 6 ( 1 ) 2022.12

Molecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73–13.1, p = 7.8 × 10−6). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies.

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Early development of the cochlea of the common marmoset, a non-human primate model

Hosoya M., Fujioka M., Okahara J., Yoshimatsu S., Okano H., Ozawa H.

Neural Development (Neural Development) 17 ( 1 ) 2022.12

Background: Fine-tuned cochlear development is essential for hearing. Owing to the difficulty in using early human fetal samples, most of our knowledge regarding cochlear development has been obtained from rodents. However, several inter-species differences in cochlear development between rodents and humans have been reported. To bridge these differences, we investigated early otic development of a non-human primate model animal, the common marmoset (Callithrix jacchus). Methods: We examined 20 genes involved in early cochlear development and described the critical developmental steps for morphogenesis, which have been reported to vary between rodents and marmosets. Results: The results revealed that several critical genes involved in prosensory epithelium specifications showed higher inter-species differences, suggesting that the molecular process for hair cell lineage acquisition in primates differs considerably from that of rodents. We also observed that the tempo of cochlear development was three times slower in the primate than in rodents. Conclusions: Our data provide new insights into early cochlear development in primates and humans and imply that the procedures used for manipulating rodent cochlear sensory cells cannot be directly used for the research of primate cells due to the intrinsic inter-species differences in the cell fate determination program.

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Development of the stria vascularis in the common marmoset, a primate model

Hosoya M., Kitama T., Iwabu K., Nishiyama T., Oishi N., Okano H., Ozawa H.

Scientific Reports (Scientific Reports) 12 ( 1 ) 2022.12

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.

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Comparison of Cartilage Conduction Hearing Aid, Bone Anchored Hearing Aid, and ADHEAR: Case Series of 6 Patients with Conductive and Mixed Hearing Loss

Kitama T., Nishiyama T., Iwabu K., Wakabayashi T., Shimanuki M.N., Hosoya M., Oishi N., Ozawa H.

Applied Sciences (Switzerland) (Applied Sciences (Switzerland)) 12 ( 23 ) 2022.12

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.

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Potential Usefulness of Tracking Head Movement via a Wearable Device for Equilibrium Function Testing at Home

Yamanobe Y., Fujioka M., Ohashi M., Ozawa H.

Journal of Medical Systems (Journal of Medical Systems) 46 ( 11 ) 2022.11

ISSN 01485598

Many studies have reported the use of wearable devices to acquire biological data for the diagnosis and treatment of various diseases. Balance dysfunction, however, is difficult to evaluate in real time because the equilibrium function is conventionally examined using a stabilometer installed on the ground. Here, we used a wearable accelerometer that measures head motion to evaluate balance and examined whether it performs comparably to a conventional stabilometer. We constructed a simplified physical head-feet model that simultaneously records “head” motion measured using an attached wearable accelerometer and center-of-gravity motion at the “feet”, which is measured using an attached stabilometer. Total trajectory length (r = 0.818, p -false discovery rate [FDR] = 0.004) and outer peripheral area (r = 0.691, p -FDR = 0.026) values measured using the wearable device and stabilometer were significantly positively correlated. Root mean square area values were not significantly correlated with wearable device stabilometry but were comparable. These results indicate that wearable, widely available, non-medical devices may be used to assess balance outside the hospital setting, and new approaches for testing balance function should be considered.

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Utility of computed tomography findings as a predictor of carotid artery invasion by metastatic lymph nodes in head and neck squamous cell carcinoma

Mikoshiba T., Sakamoto K., Shinden S., Shimanuki M., Nakayama R., Okada T., Ozawa H.

European Archives of Oto-Rhino-Laryngology (European Archives of Oto-Rhino-Laryngology) 279 ( 9 ) 4561 - 4568 2022.09

ISSN 09374477

Purpose: Carotid artery invasion by metastatic lymph nodes in head and neck squamous cell carcinoma (HNSCC) is one of the diagnostic criteria for unresectable tumors. However, to date, the diagnostic criteria for carotid artery invasion have not been well documented. This study investigated the utility of computed tomography (CT) findings as a predictor of carotid artery invasion by metastatic lymph nodes in HNSCC. Methods: Twenty-eight patients who had metastatic lymph nodes of HNSCC attached to the carotid artery as seen on CT images before neck dissection from January 2011 to November 2017 were included. Five imaging parameters (angle of contact [AC], length of contact [LC], haziness of the carotid artery wall [HW], size of the lymph node, and involvement of the bifurcation of the carotid artery [IB]) were assessed using CT to predict carotid artery invasion. Furthermore, the utility of the combination of these five parameters was evaluated. Results: There were significant differences in AC, LC, and IB between patients with and without carotid artery invasion. There were significant differences in all combinations of the two image findings between patients with and without carotid artery invasion. In particular, the combinations of LC and HW, and LC and IB could clearly predict carotid artery invasion. Conclusion: AC, LC, and IB were useful predictors of carotid artery invasion of metastatic lymph nodes in HNSCC. This study is the first to report that IB is a useful predictor of carotid artery invasion in HNSCC.

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Long-Term Outcomes of Endoscopic Cyst Fenestration for Rathke Cleft Cyst

Yamada H., Ueda R., Ozawa H., Toda M.

World Neurosurgery (World Neurosurgery) 161 e282 - e288 2022.05

ISSN 18788750

Objective: We sought to elucidate the long-term surgical outcomes and incidence of recurrence and reoperation of endoscopic endonasal cyst fenestration for Rathke cleft cyst (RCC). Methods: A retrospective review of the chart and operation record of RCC surgical cases between January 2008 and August 2021 at our institution was conducted. Patient characteristics, intraoperative findings, and postoperative follow-up outcomes were evaluated. Results: A total of 27 patients were analyzed, with a median postoperative follow-up period of 52 months (range, 1–150 months). Preoperative symptoms were visual dysfunction (59%), headache (41%), and pituitary dysfunction (22%). Endoscopic cyst fenestration was performed in all patients. Ten (37%) patients had intraoperative cerebrospinal fluid leakage. Among them, the only patient in whom sellar floor reconstruction was not performed experienced a repair operation due to postoperative cerebrospinal fluid leakage. No patients experienced postoperative hypopituitarism. Preoperative headache, visual dysfunction, and pituitary hormone disorder improved in 73%, 75%, and 67% of patients, respectively. Although postoperative cyst regrowth was observed in 8 patients (30%), no patient experienced worsening or novel symptoms and none required reoperation. Conclusions: Patients with a symptomatic RCC can be effectively treated with endoscopic endonasal cyst fenestration. Reversal of the presenting symptoms resulted, including headache, visual dysfunction, and pituitary hormone dysfunction, in the majority of patients. In our series, appropriate reconstruction of the sellar floor reduced the risk of postoperative cerebrospinal fluid leakage without impacting cyst regrowth. This simple technique appears to effectively disrupt cyst progression in most cases, even after a relatively long-term follow-up period.

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The Role of the EZH2 and H3K27me3 Expression as a Predictor of Clinical Outcomes in Salivary Duct Carcinoma Patients: A Large-Series Study With Emphasis on the Relevance to the Combined Androgen Blockade and HER2-Targeted Therapy

Saigusa N., Hirai H., Tada Y., Kawakita D., Nakaguro M., Tsukahara K., Kano S., Ozawa H., Kondo T., Okami K., Togashi T., Sato Y., Urano M., Kajiwara M., Shimura T., Fushimi C., Shimizu A., Okamoto I., Okada T., Suzuki T., Imanishi Y., Watanabe Y., Sakai A., Ebisumoto K., Sato Y., Honma Y., Yamazaki K., Ueki Y., Hanazawa T., Saito Y., Takahashi H., Ando M., Kohsaka S., Matsuki T., Nagao T.

Frontiers in Oncology (Frontiers in Oncology) 11 2022.02

Objective: Salivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only de novo but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy. Materials and Methods: The EZH2 and H3K27me3 immunohistochemical expression and EZH2 Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases). Results: EZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. EZH2 Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups. Conclusions: A high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.

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Pretherapeutic Predictive Factors for Histological High-Grade Parotid Gland Carcinoma

Mikoshiba T., Ozawa H., Watanabe Y., Kawaida M., Sekimizu M., Saito S., Yoshihama K., Nakamura S., Nagai R., Imanishi Y., Kameyama K., Ogawa K.

Laryngoscope (Laryngoscope) 132 ( 1 ) 96 - 102 2022.01

ISSN 0023852X

Objective: The histological grade of parotid gland carcinoma (PGC) is an important prognostic factor; however, the diagnosis prior to treatment has been challenging to make. This study aimed to investigate whether the pretreatment clinical findings, including hematological inflammatory, nutritional, and immune markers, could predict the histological grade of PGC. Study Design: Retrospective study. Methods: We retrospectively enrolled 111 patients with PGC and evaluated the correlation between histological grade and pretreatment clinical findings such as age, sex, tumor staging, facial nerve paralysis, pain or tenderness, adhesion to the surrounding tissues or tumor immobility, and hematological markers. Results: Sixty patients (54%) were diagnosed with histological high-grade PGC. Univariate analysis revealed that age, T classification, N classification, TNM stage, facial nerve paralysis, adhesion/immobility, C-reactive protein (CRP), and CRP-to-albumin ratio (CAR) were significant predictors of PGC histological grade. On multivariate analysis, high T classification (T3, 4), high N classification (≥1), and elevated CRP (≥0.22 mg/dL) were independent predictors of high-grade PGC. Conclusions: Pretreatment T classification, N classification, and CRP are significant predictors of the histological grading of PGC. Our results are useful for treatment planning and obtaining appropriate informed consent from the patients before treatment. Level of Evidence: 4 Laryngoscope, 132:96–102, 2022.

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Analysis of conductive olfactory dysfunction using computational fluid dynamics

Asama Y., Furutani A., Fujioka M., Ozawa H., Takei S., Shibata S., Ogawa K.

PLoS ONE (PLoS ONE) 17 ( 1 January ) 2022.01

Conductive olfactory dysfunction (COD) is caused by an obstruction in the nasal cavity and is characterized by changeable olfaction. COD can occur even when the olfactory cleft is anatomically normal, and therefore, the cause in these cases remains unclear. Herein, we used computational fluid dynamics to examine olfactory cleft airflow with a retrospective cohort study utilizing the cone beam computed tomography scan data of COD patients. By measuring nasal–nasopharynx pressure at maximum flow, we established a cut-off value at which nasal breathing can be differentiated from combined mouth breathing in COD patients. We found that increased nasal resistance led to mouth breathing and that the velocity and flow rate in the olfactory cleft at maximum flow were significantly reduced in COD patients with nasal breathing only compared to healthy olfactory subjects. In addition, we performed a detailed analysis of common morphological abnormalities associated with concha bullosa. Our study provides novel insights into the causes of COD, and therefore, it has important implications for surgical planning of COD, sleep apnea research, assessment of adenoid hyperplasia in children, and sports respiratory physiology.

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