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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Bilobed flap for reconstruction of skin defects after excision of parotid carcinoma: A case report

Sakamoto K., Ozawa H., Shimoda M., Nakaishi M., Sakanushi A., Matsunobu T., Okubo K., Okada T., Sato Y., Shinden S., Ogawa K.

Journal of Nippon Medical School (Journal of Nippon Medical School) 89 ( 6 ) 606 - 611 2022

ISSN 13454676

Objectives: Local flaps, pedicled flaps, and free flaps are used to reconstruct medium-sized skin defects after excision of parotid carcinoma. The bilobed flap is a local flap primarily used by plastic surgeons for small defects of nasal skin. We report a case of parotid carcinoma with skin infiltration successfully treated by skin reconstruction with a bilobed flap. Methods: An 84-year-old man presented with a parotid mass he had noticed 2 months earlier. Parotid carcinoma with skin infiltration was diagnosed and he underwent radical surgery. The skin defect was round (diameter, 6 cm) and was resected and reconstructed with a bilobed flap designed to be caudal to the defect. Results: Postoperative facial nerve palsy improved within 6 months. The postoperative course was otherwise uneventful, and the patient was discharged on postoperative day 7. Pathological examination revealed a sarcomatoid salivary duct carcinoma. Conclusions: Bilobed flaps are useful for reconstructing skin defects with a diameter of 6 cm or less.

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Transcanal endoscopic ear surgery for management of ossicular malformation: clinical outcomes of 17 cases

Yoshida A., Hosoya M., Kanzaki S., Fujioka M., Ozawa H.

Acta Oto-Laryngologica (Acta Oto-Laryngologica) 142 ( 2 ) 154 - 160 2022

ISSN 00016489

Background: In recent years, transcanal endoscopic ear surgery (TEES) is known as an innovative and minimally invasive surgery. Aims: To clarify the usefulness of TEES for the ossicular malformation, we performed a retrospective study. Material and methods: We examined cases of ossicular malformation performed using TEES at our hospital between April 2015 and April 2020. Results: The hearing level results were countable for 16 cases. Post-operative hearing levels were significantly improved. Transient nausea, tongue paralysis, and taste disorders were observed; however, no other complications were observed. In 2015–2018, some of the cases required the assistance of a surgical microscope. In contrast, all the cases were performed by TEES after 2019 using a powered device to curve the canal. Conclusions and significance: TEES requires considerable training, and the sensation of depth is difficult to acquire. However, this less invasive method is also helpful for ossicular malformation cases.

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Survival benefit of HER2-targeted or androgen deprivation therapy in salivary duct carcinoma

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

Therapeutic Advances in Medical Oncology (Therapeutic Advances in Medical Oncology) 14 2022

ISSN 17588340

Background: The efficacy and safety of human epidermal growth factor receptor 2 (HER2)-targeted therapy and androgen deprivation therapy (ADT) for locally advanced or recurrent or metastatic (LA/RM) salivary duct carcinoma (SDC) have been reported in prospective studies. However, the survival benefit of these therapies to conventional therapy remains controversial, and whether HER2-targeted therapy or ADT should be chosen in HER2- and androgen receptor (AR)-positive SDC patients remains unknown. Methods: Overall, 323 LA/RM SDC patients treated at seven institutions between August 1992 and June 2020 were retrospectively enrolled. The primary aim was to analyze the effect of HER2-targeted therapy and ADT on overall survival from the diagnosis of LA/RM disease to death from any cause (OS1). The secondary indicators included the overall response rate (ORR), clinical benefit rate (CBR), overall survival from therapy initiation for LA/RM disease (OS2), progression-free survival (PFS), time to second progression (PFS2), duration of response (DoR), and duration of clinical benefit (DoCB) of HER2-targeted therapy or ADT as first-line therapy for HER2-positive/AR-positive SDC. Results: Patients treated with HER2-targeted therapy or ADT had longer OS1 than those treated without these therapies (Median OS1: historical control, 21.6 months; HER2-targeted therapy, 50.6 months; ADT, 32.8 months; HER2-targeted therapy followed by ADT, 42.4 months; and ADT followed by HER2-targeted therapy, 45.2 months, p < 0.001). Among HER2-positive/AR-positive SDC patients, although HER2-targeted therapy had better ORR, CBR, and PFS than those of ADT as first-line therapy, we found no significant differences between HER2-targeted therapy and ADT regarding OS2, PFS2, DoR, and DoCB. Conclusion: Patients treated with HER2-targeted therapy and ADT showed longer survival in LA/RM SDC. HER2-targeted therapy can be recommended prior to ADT for HER2-positive/AR-positive SDC. It is warranted to establish a biomarker that could predict the efficacy of clinical benefit or better response in ADT.

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Effects of hearing aids in patients with unilateral tinnitus with acquired ipsilateral sensorineural hearing loss

Ueno M., Shinden S., Oishi N., Suzuki N., Suzuki D., Ogawa K., Ozawa H.

Ear, Nose and Throat Journal (Ear, Nose and Throat Journal) 2022

ISSN 01455613

Objectives: To evaluate the effectiveness of sound therapy using hearing aids in patients experiencing tinnitus with acquired unilateral sensorineural hearing loss. Methods: A total of 97 patients with unilateral tinnitus with acquired ipsilateral sensorineural hearing loss were included. Evaluation involved self-report questionnaires administered at entry, 3 months after treatment, and 1 year after treatment. Results: The mean Tinnitus Handicap Inventory score before treatment decreased significantly (p < 0.01) at 3 months (50.0 ± 24.5-12.7 ± 16.2), and 1 year (53.3 ± 25.5-8.79 ± 13.9), after treatment. Moreover, the visual analog scale score decreased significantly at 3 months (loudness, 69.6 ± 21.9-29.1 ± 27.2; annoyance, 71.1 ± 24.7-22.7 ± 25.5) and 1 year (loudness, 69.8 ± 22.0-21.1 ± 26.1; annoyance, 72.7 ± 25.6-19.4 ± 27.6). Approximately 80-90% of patients noticed improvements in tinnitus annoyance and loudness, as determined by their responses to the questionnaires of subjective symptom improvement. Conclusions: Hearing aids are remarkably effective for patients with unilateral tinnitus with acquired ipsilateral sensorineural hearing loss.

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Early-Phase Adverse Effects and Management of Liposomal Amikacin Inhalation for Refractory Mycobacterium avium Complex Lung Disease in Real-World Settings

Morita A., Namkoong H., Yagi K., Asakura T., Hosoya M., Tanaka H., Lee H., Ogawa T., Kusumoto T., Azekawa S., Nakagawara K., Kamata H., Ishii M., Fukunaga K., Ozawa H., Hasegawa N.

Infection and Drug Resistance (Infection and Drug Resistance) 15 4001 - 4011 2022

Purpose: Amikacin liposome inhalation suspension (ALIS), which efficiently allows amikacin to reach the pulmonary periphery for effect while minimising systemic adverse effects, was recently approved for treating Mycobacterium avium complex (MAC) infections. The international Phase 3 open-label clinical trials showed promising results, contributing to sputum culture conversion, but few studies have examined the efficacy and adverse effects of ALIS using real-world data. We identified the clinical outcome and adverse effects of ALIS in the early phase of treatment, for more effective and safe use in clinical practice. Patients and Methods: The study population consisted of patients with MAC lung disease (MAC-LD), introduced to ALIS therapy after July 2021 at Keio University Hospital due to poor response to multidrug therapy. The sputum smear/culture results, symptoms, adverse effects, and the serum amikacin concentrations of the early phase of ALIS inhalation therapy were examined. Results: A total of 11 patients (9 women; median age 64.6 years) were included in this study. The median disease duration of MAC-LD was 13.7 years, and all patients exhibited a positive culture at the beginning of ALIS inhalation. Three of the six patients (50.0%) who were initially sputum-smear-positive were confirmed to have become sputum-smear-negative within one month, including one culture conversion. ALIS inhalation therapy caused some adverse effects in nine patients (81.8%); however, no serious systemic adverse effects were observed. The most common adverse effect was hoarseness (72.7%), which mostly occurred around 1 week after initiation. The medians of peak serum amikacin concentrations were 1.4 and 2.3 μg/mL for the first and third inhalations, respectively. Trough serum concentrations just before the third inhalation were <1.2 μg/mL in all patients. Conclusion: ALIS therapy might be a treatment option for patients with refractory MAC infection with long disease duration and a poor response to guideline-based therapy.

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Diagnosis and Management of Carotid Body Tumors

Ozawa H.

Practica Oto-Rhino-Laryngologica (Practica Oto-Rhino-Laryngologica) 115 ( 4 ) 259 - 264 2022

ISSN 00326313

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.

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Cricotracheostomy in a patient with severe kyphosis: A case report

Kasahara K., Nishiyama T., Shigetomi S., Ikari Y., Matsui Y., Ozawa H.

Ear, Nose and Throat Journal (Ear, Nose and Throat Journal) 2022

ISSN 01455613

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.

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Pterygovaginal artery as a target of embolization before endoscopic skull base surgery

Yoshida K., Akiyama T., Raz E., Kamamoto D., Ozawa H., Toda M.

Neuroradiology Journal (Neuroradiology Journal) 34 ( 6 ) 676 - 682 2021.12

ISSN 19714009

Background: The pterygovaginal artery (PtVA), a recurrent branch of the internal maxillary artery (IMA), can be a feeder of skull base tumors. Preoperative embolization can help endoscopic resection of hypervascular lesions, which is performed under a narrow surgical space with restricted instrumental maneuverability. Methods: We performed preoperative embolization in five cases with hypervascular skull base lesions supplied by the PtVA, four of which were resected via endoscopic endonasal approach. In two cases, selective PtVA embolization through the distal IMA was successfully conducted. Results: In all the cases, intraoperative bleeding during endoscopic resection was easily controlled. The medial and lateral origins of the PtVA from the IMA were demonstrated by cone-beam CT images reconstructed from three-dimensional rotational angiography, and anastomoses around the eustachian tube and soft palate were visualized by superselective angiography. Conclusions: The PtVA embolization can be an effective strategy before endoscopic skull base tumor resection. When embolizing through the PtVA, clinicians should be aware of its anatomical variations and dangerous anastomoses. Understanding the surrounding angioarchitecture by angiographic techniques helps ensure safe embolization.

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Neuronal development in the cochlea of a nonhuman primate model, the common marmoset

Hosoya M., Fujioka M., Murayama A.Y., Ozawa H., Okano H., Ogawa K.

Developmental Neurobiology (Developmental Neurobiology) 81 ( 8 ) 905 - 938 2021.11

ISSN 19328451

Precise cochlear neuronal development is vital to hearing ability. Understanding the developmental process of the spiral ganglion is useful for studying hearing loss aimed at aging or regenerative therapy. Although interspecies differences have been reported between rodents and humans, to date, most of our knowledge about the development of cochlear neuronal development has been obtained from rodent models because of the difficulty in using human fetal samples in this field. In this study, we investigated cochlear neuronal development in a small New World monkey species, the common marmoset (Callithrix jacchus). We examined more than 25 genes involved in the neuronal development of the cochlea and described the critical developmental steps of these neurons. We also revealed similarities and differences between previously reported rodent models and this primate animal model. Our results clarified that this animal model of cochlear neuronal development is more similar to humans than rodents and is suitable as an alternative for the analysis of human cochlear development. The time course established in this report will be a useful tool for studying primate-specific neuronal biology of the inner ear, which could eventually lead to new treatment strategies for human hearing loss.

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Angio-anatomical study of the pterygovaginal artery based on cone-beam computed tomography

Yoshida K., Akiyama T., Raz E., Kamamoto D., Ozawa H., Toda M.

Neuroradiology (Neuroradiology) 63 ( 8 ) 1325 - 1333 2021.08

ISSN 00283940

Purpose: To investigate the anatomical characteristics and clinical implications of the pterygovaginal artery (PtVA), a recurrent branch from the distal internal maxillary artery (IMA), which courses through the pterygovaginal canal that connects the pterygopalatine fossa and nasopharynx. Methods: Eighty-two patients with 90 sides of cone-beam computed tomography (CBCT) reconstructed from rotational angiography of the external or common carotid artery with a field of view covering the pterygopalatine fossa were retrospectively reviewed. The origin from the IMA, branching type, distribution, and anastomoses was evaluated. The underlying lesions were 36 hypervascular lesions with possible supply from PtVA (17 cavernous sinus arteriovenous fistulas (AVFs), 6 anterior condylar AVFs, and 13 nasopharyngeal, parasellar, or paraclival tumors) and 46 other diseases. Results: PtVA was identified in 75 sides (83%). It originated from the pterygopalatine segment of the IMA in 45 sides (60%) and from the pterygoid segment in 30 sides (40%). It arose independently (77%), sharing the common trunk with the Vidian artery (15%) or with other branches. It ran posteromedially through the pterygovaginal canal to supply the mucosa over the nasopharyngeal roof, the choanae, and the pharyngeal ostium of the eustachian tube. It anastomosed with the ascending pharyngeal artery (n=37), the accessory meningeal artery (n=7), and the mandibular artery from the petrous internal carotid artery (n=2). It served as a feeder of osseous AVFs and skull base tumors. Conclusion: PtVA was often identified by CBCT even in normal anatomy. Its detailed angio-anatomy could be evaluated in the presence of parasellar or paraclival hypervascular lesions.

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Endoscopic Endonasal Management of Pterygopalatine Fossa Tumors

Ozawa H., Sekimizu M., Saito S., Nakamura S., Mikoshiba T., Toda M., Ogawa K.

Journal of Craniofacial Surgery (Journal of Craniofacial Surgery) 32 ( 5 ) E454 - E457 2021.07

ISSN 10492275

Surgical removal of pterygopalatine fossa (PPF) tumors with endoscopic endonasal approach is still challenging. The present study aimed to evaluate our endoscopic endonasal management of PPF tumors based on the tumor pathology and purpose of the surgery. This comprised both a single nostril approach for biopsy and a binostril approach for complete resection of benign and noninfiltrating tumors. Based on this strategy, 12 patients underwent endoscopic endonasal surgery for PPF tumors between 2013 and 2018. The patients' data were analyzed retrospectively to demonstrate the significance of our treatment scheme. The surgery was terminated only after taking a biopsy specimen in 6 patients. Other 6 patients underwent gross total resection or bulk tumor reduction. Final pathological diagnosis was malignant in 6 cases and benign in the remaining 6. Post-operative treatment was needed in 7 patients. Four operations for the 6 patients who underwent either debulking or radical surgery were performed by the binostril approach; while 5 surgeries for the 6 biopsy patients were performed by the single nostril approach. Postoperative complications were tolerable. Endoscopic resection should be adopted preferentially for benign tumors that can be removed in a piecemeal fashion. However, as most malignant tumors were impossible to resect with a negative margin, priority should be given to tumor biopsy using an endoscopic approach, which is less invasive than an open approach, and an appropriate treatment customized to the pathological diagnosis should be administered.

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Cyclooxygenase‑2 expression is associated with chemoresistance through cancer stemness property in hypopharyngeal carcinoma

Saito S., Ozawa H., Imanishi Y., Sekimizu M., Watanabe Y., Fumihiro I.T.O., Ikari Y., Nakahara N., Kameyama K., Ogawa K.

Oncology Letters (Oncology Letters) 22 ( 1 ) 2021.07

ISSN 17921074

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.

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Dynamic spatiotemporal expression changes in connexins of the developing primate’s cochlea

Hosoya M., Fujioka M., Murayama A.Y., Ogawa K., Okano H., Ozawa H.

Genes (Genes) 12 ( 7 ) 2021.07

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.

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Endoscopic Endonasal Transinfraturbinate Approach With Nasoseptal Window for Removal of the Pterygopalatine Fossa Tumor

Yamada H., Toda M., Abiko T., Ozawa H., Ogawa K., Yoshida K.

Journal of Craniofacial Surgery (Journal of Craniofacial Surgery) 32 ( 2 ) 716 - 718 2021.03

ISSN 10492275

AbstractRecent advances in endoscopic intranasal technology have allowed for a safe approach to the pterygopalatine fossa lesion. However, we consider that there is still scope of improvement to approach a broader area with better operability and minimal invasiveness. A 51-year-old man underwent endoscopic endonasal surgery due to the recurrence of chordoma at the left pterygopalatine fossa. To access the lower and lateral part of the pterygopalatine fossa, we performed endoscopic endonasal transmaxillary removal via an inferior turbinate incision. During surgery, a wide operative field and good operability could be secured by inserting an endoscope from the right nostril through a window of the nasal septum. Subtotal removal of the tumor was achieved without any complication during the surgery. Endoscopic endonasal transinfraturbinate approach with nasoseptal window was effective in the removal of the pterygopalatine fossa tumor because it is less invasive and provides a good surgical view with better operability.

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Prognostic Value of the Lymphocyte-to-Monocyte Ratio in Patients with Parotid Gland Carcinoma

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

Laryngoscope (Laryngoscope) 131 ( 3 ) E864 - E869 2021.03

ISSN 0023852X

Objective: Previous studies have evaluated various markers as prognostic predictors in patients with many types of cancers. However, the influence of such factors on the outcomes of patients with parotid gland carcinoma (PGC) is unknown. This study investigated the roles of alternative markers in the prognoses of patients with PGC. Methods: Overall, 101 patients who underwent curative treatment for PGC were retrospectively evaluated, and their 5-year overall and disease-free survival rates were calculated. The prognostic values of clinical and pathologic factors were determined. Results: The 5-year overall and disease-free survival rates were 73.1% and 62.8%, respectively. Multivariate analysis revealed that a low lymphocyte-to-monocyte ratio (LMR), high T classification, high N classification, and perineural invasion were independent predictors of poor prognosis. Conclusions: Thus, we identified LMR as an independent prognostic factor for patients with PGC. Patients with low LMRs who are amenable to treatment may require adjuvant treatment to improve their prognoses. Level of Evidence: 4 Laryngoscope, 131:E864–E869, 2021.

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Transoral Removal of Tumors of the Dorsal Aspect of the Soft Palate: A Technical Note

Nakamura S., Ozawa H., Sekimizu M., Ikari Y., Nakahara N., Saito S., Yoshihama K., Nishiyama Y., Ogawa K.

Laryngoscope (Laryngoscope) 131 ( 9 ) 2011 - 2014 2021

ISSN 0023852X

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A case of sinonasal teratocarcinosarcoma

Ikari Y., Ozawa H., Mikoshiba T., Saito S., Nakahara N., Ito F., Sekimizu M., Kawaida M., Kameyama K., Toda M., Ogawa K.

Practica Oto-Rhino-Laryngologica (Practica Oto-Rhino-Laryngologica) 114 ( 3 ) 203 - 209 2021

ISSN 00326313

Teratocarcinosarcoma is a rare, highly malignant tumor, that occurs mainly in the nasal cavity and paranasal sinuses. The prognosis is poor because the tumor invades the surrounding tissues even from an early stage. We report a case of sinonasal teratocarcinosarcoma that was treated by transnasal endoscopic skull base surgery and radiotherapy. The patient was a 65-year-old man who presented with a 2-month history of recurrent left epistaxis. Examination revealed a mass in the left nasal cavity. Computed tomography (CT) revealed a tumor extending from the left ethmoid sinus to the sphenoid sinus, and bone destruction of the anterior skull base. Magnetic resonance imaging (MRI) revealed intracranial extension of the tumor, but no apparent invasion of the brain parenchyma. Biopsy findings led to the suspicion of olfactory neuroblastoma. Since an olfactory neuroblastoma was suspected by biopsy and the possibility of invasion of the brain parenchyma was low, we performed endoscopic endonasal skull base surgery. The tumor was resected with the bone of the skull base and the dura. The skull base was reconstructed with the skull periosteum, fascia lata, and a nasal septum flap. Postoperative histopathological examination revealed the diagnosis of teratocarcinosarcoma. Therefore, after the surgery, the patient received radiotherapy. One year and ten months after the radiotherapy, metastasis to the left cervical lymph nodes was found, and neck dissection was performed. A follow-up examination at 4 years after the radiotherapy showed no evidence of local recurrence or distant metastases to other organs. It was difficult to confirm the histological diagnosis before surgery, and the diagnosis could be confirmed only by histopathology of the resected tumor specimen. The main treatment modality for teratocarcinosarcoma is surgical excision. However, teratocarcinoma is a highly malignant tumor, and radiotherapy and chemotherapy may be useful in addition to surgery, to obtain a better prognosis.

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Trapezius muscle branch of the spinal accessory nerve without penetrating the sternocleidomastoid muscle as a pitfall in neck dissection: prevalence in a Japanese institution and a protocol for the prevention of iatrogenic injury

Sakamoto K., Ozawa H., Shimanuki M., Kida A., Kitama T., Iwabu K., Nakaishi M., Sakanushi A., Matsunobu T., Okubo K., Sato Y., Shinden S., Ogawa K.

Acta Oto-Laryngologica (Acta Oto-Laryngologica) 141 ( 8 ) 825 - 829 2021

ISSN 00016489

Background: The spinal accessory nerve (SAN) has several anatomical variations, which may be a pitfall in neck dissection (ND). These include the trapezius muscle branch (TB), which stems from the common trunk before entering the sternocleidomastoid muscle (SCM). Aims/Objectives: To investigate the prevalence of this variation and suggest a protocol for preventing unexpected injury of the TB in ND. Materials and methods: We conducted a retrospective cohort study for 93 patients who had undergone neck dissection (117 sides) without resection of the SCM nor SAN. We recorded the division of the TB after and before penetration of the SCM by the common trunk (penetrating type TB [PTB]) and non-penetrating type TB [NPTB], respectively). Results: Among NDs, PTB and NPTB were observed in 61 (52%) and 56 (48%) sides, respectively. In the subgroup of 24 cases with bilateral ND, PTB/PTB, NPTB/NPTB, and NPTB/PTB were observed in eight (33%), nine (38%), and seven (29%) cases, respectively. The prevalence of PTB/NPTB did not differ according to age, sex, or laterality. Conclusions and significance: NPTB is a common anatomical variation. The presence or absence of a branch from the common trunk must be initially checked to avoid unexpected damage to the TB.

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Risk factor for cerebrospinal fluid leak after endoscopic endonasal skull base surgery: a single-center experience

Ozawa H., Sekimizu M., Saito S., Nakamura S., Mikoshiba T., Watanabe Y., Ikari Y., Toda M., Ogawa K.

Acta Oto-Laryngologica (Acta Oto-Laryngologica) 141 ( 6 ) 621 - 625 2021

ISSN 00016489

Background: One of the major complications in endoscopic endonasal skull base surgery (EESBS) is postoperative cerebrospinal fluid (CSF) leaks. Recently, EESBS has been applied to various skull base diseases as well as more complicated cases influenced by previous treatment with or without various comorbidities. Aims/objectives: This study aimed to assess the factors that influence the results of postoperative CSF leak after EESBS with mixed patient backgrounds. Materials and methods: We conducted a retrospective analysis of the clinical records of patients undergoing EESBS in our institution from 2012 to 2017. Results: Out of a total of 230 cases of EESBS, 11 (4.8%) suffered from postoperative CSF leakage. The rate of CSF leakage for pituitary adenoma, Rathke’s cleft cyst, chordoma, and meningioma was 3.5%, 0%, 3.6% and 8.0%, respectively. Multiple variate analysis revealed that repeated surgery (p =.008) and intraoperative CSF leak (p =.044) were significant risk factors for postoperative CSF leakage. Conclusions and significance: The rate of postoperative CSF leakage in this study was comparable to previous reports, and repeated surgery may increase postoperative CSF leakage. The surgical strategy for tumor removal as well as skull base reconstruction should be given careful consideration according to tumor pathology and the patient’s condition.

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Effectiveness of hearing aids in treating patients with chronic tinnitus with average hearing levels of <30 dBHL and no inconvenience due to hearing loss

Suzuki N., Shinden S., Oishi N., Ueno M., Suzuki D., Ogawa K., Ozawa H.

Acta Oto-Laryngologica (Acta Oto-Laryngologica) 141 ( 8 ) 773 - 779 2021

ISSN 00016489

Background: The effectiveness of hearing aids for tinnitus patients without hearing loss in conversation-comprehension range and inconvenience in daily communication is unknown. Objective: We aimed to evaluate their therapeutic effect. Materials and methods: We included 91 patients with average hearing levels <30 dBHL. To determine the effects, self-reported questionnaires were used. Data were collected at the entry and 3 months (n = 91) and 1 year (n = 70) after treatment initiation. Results: All scores (mean ± standard deviation) decreased significantly (p < 0.0001) from before treatment to 3 months and 1 year after treatment: tinnitus handicap inventory score: from 56 ± 21 to 17 ± 17 and 13 ± 15; visual analogue scale (VAS) score for tinnitus loudness: from 71 ± 20 to 31 ± 26 and 28 ± 29; VAS score for tinnitus annoyance: 79 ± 20 to 27 ± 25 and 26 ± 30, respectively. Approximately 90% of patients noticed improvements in tinnitus annoyance and loudness, as determined by the questionnaires regarding subjective symptom improvement. Conclusions: Hearing aids may be useful for tinnitus patients without hearing loss and inconvenience in daily communication. Significance: Our findings provide a treatment option for tinnitus patients with an average hearing level of <30 dBHL.

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A Retrospective Analysis of 22 Cases with Carcinomas of the External Auditory Canal

Suzuki N., Oishi N., Ozawa H., Kanzaki S., Fujioka M., Nishiyama T., Noguchi M., Hosoya M., Sekimizu M., Saito S., Ogawa K.

Journal of Otolaryngology of Japan (Journal of Otolaryngology of Japan) 124 ( 3 ) 197 - 204 2021

ISSN 00306622

Carcinoma of the external auditory canal is a rare tumor, accounting for about 1% of all head and neck cancers. Although no treatment method has been established yet, surgical treatment is the primary treatment method in cases where resection is possible. At our institution, we adopt surgical treatment, mainly lateral temporal bone resection （LTBR）, for cases with T1―T3 disease, and chemoradiation therapy（CCRT）for cases with T4 disease, as the treatment of first choice. We have adopted cartilage conduction hearing aids（CC―HAs）in some cases following LTBR. We examined the short―term outcomes, at two years, in the patients treated at our department. This study was a retrospective case review of 22 ears with carcinoma of the external auditory canal in 21 patients who underwent initial treatment at our institution between January 2012 and June 2018. The observation period was 2 to 81 months（median 26 months）. The tumors were analyzed using the modified Pittsburgh tumor staging system. The tumor T stage was T1 in four ears, T2 in nine ears, T3 in six ears, and T4 in three ears. CCRT was performed in three ears with T4 disease and one ear with T2 disease, heavy ion radiotherapy was performed in one ear with T2 disease, and surgery（LTBR in 16 ears and partial external auditory meatus resection in one ear）was performed for all the other cases. The surgical margin after LTBR was positive in three out of six cases with T3 disease and negative in all of the cases with T1 and T2 disease. The positive surgical margin was mainly found in the medial wall of the tympanic cavity or cartilaginous portion of the external acoustic meatus. The overall 2―year survival rate was 87.4%; the rate was 100% in the T1 cases, 87.5% in the T2 cases, 75.0% in the T3 cases, and 100% in the T4 cases. Four out of five patients who tried CC―HAs continued to use them after the LTBR. The indication for LTBR should be carefully judged in cases with T3 disease. The appropriate indication for LTBR in cases with T3 disease are: 1）a small amount of soft tissue shadow beyond the tympanum in the preoperative CT, and/ or 2）a clear boundary between the tumor and the soft tissue around the external acoustic meatus in the preoperative enhanced MRI. In cases with T3 disease not fulfilling these criteria, CCRT should be selected as the treatment of first choice. However, considering the side effects after CCRT, including sensorineural hearing loss and persistent otorrhea in some cases, LTBR with postoperative CC―HAs is one of the optimal treatment options that would allow the remaining hearing ability to be utilized.

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A Case Report of a Middle Ear Mass Originated From Cartilage-like Tissue Treated With Transcanal Endoscopic Ear Surgery

Suda S., Kitamura M., Kawaida M., Fujioka M., Ozawa H.

Ear, Nose and Throat Journal (Ear, Nose and Throat Journal) 2021

ISSN 01455613

Middle ear tumors are relatively rare, and among them, the diagnoses of middle ear lesions originating from cartilage-like tissue are even rarer. Use of transcanal endoscopic ear surgery (TEES) has increased in recent years because of its advantages, such as clear visual field and minimally invasive procedure. Here, we report a middle ear mass originating from cartilage-like tissue treated with TEES. A 62-year-old woman presented with progressive right-sided hearing loss. A white mass was revealed through the tympanic membrane, and pure-tone audiometry detected a mean 50.0 dB conductive hearing loss. Computed tomography showed a mass in the tympanic cavity. TEES was performed for diagnosis and treatment. A white translucent tumor was observed intraoperatively, and it was completely resected. Histopathological examination confirmed the diagnosis of a mass originating from degenerated cartilage-like tissue. To the best of our knowledge, this is the first study of a middle ear mass originating from cartilage-like tissue treated with TEES. TEES with its clear visual field and precise techniques was beneficial in treating the middle ear lesions circumscribed in the tympanic cavity.

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The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

Hirai H., Tada Y., Nakaguro M., Kawakita D., Sato Y., Shimura T., Tsukahara K., Kano S., Ozawa H., Okami K., Sato Y., Fushimi C., Shimizu A., Okamoto I., Takase S., Okada T., Sato H., Imanishi Y., Otsuka K., Watanabe Y., Sakai A., Ebisumoto K., Togashi T., Ueki Y., Ota H., Saigusa N., Takahashi H., Ando M., Urano M., Hanazawa T., Nagao T.

Virchows Archiv (Virchows Archiv) 477 ( 2 ) 291 - 299 2020.08

ISSN 09456317

Salivary duct carcinoma (SDC) is an aggressive, uncommon tumor histologically comparable to high-grade mammary ductal carcinoma. SDCs are usually androgen receptor (AR)–positive and often HER2-positive. Recently, therapies targeting these molecules for SDC have attracted attention. Lipid metabolism changes have been described in association with biological behavior in various cancers, although no such relationship has yet been reported for SDC. We therefore analyzed the clinicopathological relevance of the immunohistochemical expression of adipophilin (ADP) and fatty acid synthase (FASN), representative lipid metabolism–related proteins, in 147 SDCs. ADP and FASN were variably immunoreactive in most SDCs (both 99.3%), and the ADP and FASN expression was negatively correlated (P = 0.014). ADP-positive (≥ 5%) SDCs more frequently exhibited a prominent nuclear pleomorphism and high-Ki-67 labeling index than those ADP-negative (P = 0.013 and 0.011, respectively). In contrast, a high FASN score, calculated by the staining proportion and intensity, (≥ 120) was correlated with the high expression of AR and FOXA1 (P < 0.001 and = 0.003, respectively). The ADP and FASN expression differed significantly among the subtypes based on biomarker immunoprofiling, as assessed by the AR, HER2, and Ki-67 status (P = 0.017 and 0.003, respectively). A multivariate analysis showed that ADP-positive expression was associated with a shorter overall and progression-free survival (P = 0.018 and 0.003, respectively). ADP was associated with an aggressive histopathology and unfavorable prognosis, and FASN may biologically interact with the AR signaling pathway in SDC. ADP may, therefore, be a new prognostic indicator and therapeutic target in SDC.

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Endoscopic endonasal removal of a pediatric paranasal ossifying fibroma using preoperative embolization

Saito S., Ozawa H., Ikari Y., Nakahara N., Ito F., Sekimizu M., Kameyama K., Akiyama T., Toda M., Ogawa K.

Otolaryngology Case Reports (Otolaryngology Case Reports) 14 2020.03

Background: Ossifying fibroma arising in the sinonasal tract is rare. Its treatment includes complete resection; however, this can be challenging to perform due to the well-vascularized nature of the fibroma. Some surgical techniques can control intraoperative hemorrhage; however, to date, no reports have assessed the use of preoperative embolization. Methods: We report a case of a child with ossifying fibroma arising from the ethmoid sinus, which was resected by endoscopic surgery using preoperative transarterial embolization. Conclusions: Embolization was effective in decreasing intraoperative hemorrhage. No complications related to the procedure or operation were encountered. Preoperative embolization should be considered for better control of the bleeding that occurs in ossifying fibromas, similar to that in other well-vascularized tumors.

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Selective EP2 and Cox-2 inhibition suppresses cell migration by reversing epithelial-to-mesenchymal transition and Cox-2 overexpression and E-cadherin downregulation are implicated in neck metastasis of hypopharyngeal cancer

Watanabe Y., Imanishi Y., Ozawa H., Sakamoto K., Fujii R., Shigetomi S., Habu N., Otsuka K., Sato Y., Sekimizu M., Ito F., Ikari Y., Saito S., Kameyama K., Ogawa K.

American Journal of Translational Research (American Journal of Translational Research) 12 ( 3 ) 1096 - 1113 2020

Cyclooxygenase-2 (Cox-2) has been shown to promote cancer initiation and progression through pleiotropic functions including induction of epithelial-to-mesenchymal transition (EMT) via its predominant product prostaglandin E that binds to the cognate receptor EP2. Hence, pharmacological inhibition at the level of EP2 is assumed to be a more selective alternative with less risk to Cox-2 inhibition. However, little is known regarding the anti-cancer effect of an EP2 antagonist on the malignant properties of cancers including hypopharyngeal squamous cell carcinoma (HPSCC). The present study found that both the Cox-2 inhibitor celecoxib and the EP2 antagonist PF-04418948 upregulated CDH-1 expression, restored membranous localization of E-cadherin, and reduced vimentin expression, by downregulating the transcriptional repressors of E-cadherin in BICR6 and FaDu cells. Such Cox-2 or EP2 inhibition-induced EMT reversal led to repressed migration ability in both cells. Immunohistochemical analysis of surgical HPSCC specimens demonstrated an inverse relationship in expression between Cox-2 and E-cadherin both in the context of statistics (P = 0.028) and of reciprocal immunolocalization in situ. Multivariate logistic regression revealed that overexpression of Cox-2 (P < 0.001) and downregulation of E-cadherin (P = 0.016) were both independently predictive of neck metastasis. These results suggest that suppression of cell migration ability via reversing EMT by inhibiting the Cox-2/EP2 signaling may contribute to preventing the development and progression of lymphatic metastasis. Collectively, targeting Cox-2/EP2, especially using EP2 antagonist, can be a promising therapeutic strategy by exerting an anti-metastatic effect via EMT reversal for improving the treatment outcomes of patients with various cancers including HPSCC. 2

Cyclo-oxygenase-2 expression is associated with lymph node metastasis in oropharyngeal squamous cell carcinoma under the new TNM classification

Sekimizu M., Ozawa H., Saito S., Ikari Y., Nakahara N., Nakamura S., Yoshihama K., Ito F., Watanabe Y., Imanishi Y., Kameyama K., Ogawa K.

Anticancer Research (Anticancer Research) 39 ( 10 ) 5623 - 5630 2019

ISSN 02507005

Background: This study aimed to investigate p16 and COX2 expression in oropharyngeal squamous cell carcinoma (OPSCC), and evaluate the prognostic role of COX2 expression under the new TNM classification. Materials and Methods: Biopsy specimens obtained from 75 patients with OPSCC were stained for p16 and COX2 expression immunohistochemically. The results and clinical records were analyzed retrospectively. Results: Fifty-nine patients (79%) were positive for p16. COX2 expression was correlated with poor relapse-free survival in patients overall, and in p16-positive patients. Smoking was positively associated with COX2 expression. Moreover, both positive COX2 expression and anterior wall tumor subsite were independently correlated with lymph node metastasis, which was the only independent prognostic factor in p16-positive OPSCC. Conclusion: The p16-positive rate in this study was comparable with that in the USA and Europe, and higher than that in other Asian countries. COX2 expression might affect the prognosis of p16-positive OPSCC through promoting lymph node metastasis.

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Usefulness of Hematological Inflammatory Markers in Predicting Severe Side-effects from Induction Chemotherapy in Head and Neck Cancer Patients

Mikoshiba T., Saito S., Ikari Y., Nakahara N., Ito F., Watanabe Y., Sekimizu M., Imanishi Y., Ogawa K., Ozawa H.

Anticancer Research (Anticancer Research) 39 ( 6 ) 3059 - 3065 2019

ISSN 02507005

Background: Induction chemotherapy (IC) for head and neck cancer (HNC) often causes severe side-effects. However, it has still been challenging to predict the adverse events. The present study aimed to evaluate the role of hematological inflammatory markers in predicting severe side-effects caused by IC. Materials and Methods: A total of 54 HNC patients who underwent IC were enrolled. The association between severe side-effects and pre-treatment hematological inflammatory markers [the C-reactive protein (CRP) to albumin ratio (CAR), the modified Glasgow Prognostic Score (mGPS), the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR)] were evaluated. Results: In the univariate analysis, the incidence of whole severe side-effects (grade 4), febrile neutropenia (above grade 3), and hyponatremia (above grade 3) were significantly higher in the high CAR and high GPS groups. Multivariate analysis revealed that high CAR and mGPS were independent predictors of these side-effects. Conclusion: CAR and mGPS were significant predictors of severe side-effects. These data can potentially offer patients an improved quality of life during cancer therapy.

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Prognostic Implication of Histopathologic Indicators in Salivary Duct Carcinoma: Proposal of a Novel Histologic Risk Stratification Model

Nakaguro M., Sato Y., Tada Y., Kawakita D., Hirai H., Urano M., Shimura T., Tsukahara K., Kano S., Ozawa H., Okami K., Sato Y., Fushimi C., Shimizu A., Takase S., Okada T., Sato H., Imanishi Y., Otsuka K., Watanabe Y., Sakai A., Ebisumoto K., Togashi T., Ueki Y., Ota H., Saigusa N., Takahashi H., Ando M., Hanazawa T., Nagao T.

American Journal of Surgical Pathology (American Journal of Surgical Pathology) 2019

ISSN 01475185

Salivary duct carcinoma (SDC) is a rare, aggressive malignancy that histologically resembles high-grade mammary duct carcinoma. Because of the rarity of this entity, data verifying the association between histologic features and patient survival are limited. We conducted a comprehensive histologic review of 151 SDC cases and performed an analysis of the association between various histomorphologic parameters and the clinical outcome with the aim of developing a histologic risk stratification model that predicts the prognosis of SDC patients. A multivariate analysis revealed that prominent nuclear pleomorphism (overall survival [OS]: P=0.013; progressionfree survival [PFS]: P= 0.019), ≥30 mitoses/10 HPF (PFS: P= 0.013), high tumor budding (OS: P= 0.011; PFS: P< 0.001), and high poorly differentiated clusters (OS: P<0.001; PFS: P< 0.001) were independent prognostic factors. Patients with vascular invasion demonstrated a marginally significant association with shorter PFS (P= 0.064) in a multivariate analysis. We proposed a 3-tier histologic risk stratification model based on the total number of positive factors among 4 prognostically relevant parameters (prominent nuclear pleomorphism, ≥30 mitoses/10 HPF, vascular invasion, and high poorly differentiated clusters). The OS and PFS of patients with low-risk (0 to 1 point) (23% of cases), intermediate-risk (2 to 3 points) (54% of cases), and highrisk (4 points) (23% of cases) tumors progressively deteriorated in this order (hazard ratio, 2.13 and 2.28, and 4.99 and 4.50, respectively; Ptrend <0.001). Our histologic risk stratification model could effectively predict patient survival and may be a useful aid to guide clinical decision-making in relation to the management of patients with SDC.

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The high expression of FOXA1 is correlated with a favourable prognosis in salivary duct carcinomas: a study of 142 cases

Urano M., Hirai H., Tada Y., Kawakita D., Shimura T., Tsukahara K., Kano S., Ozawa H., Okami K., Sato Y., Fushimi C., Shimizu A., Takase S., Okada T., Sato H., Imanishi Y., Otsuka K., Watanabe Y., Sakai A., Ebisumoto K., Togashi T., Ueki Y., Ota H., Sato Y., Saigusa N., Nakaguro M., Hanazawa T., Nagao T.

Histopathology (Histopathology) 73 ( 6 ) 943 - 952 2018.12

ISSN 03090167

Aims: Salivary duct carcinoma (SDC) is an uncommon, aggressive tumour that, histologically, resembles high-grade mammary ductal carcinoma, and is characterised by the expression of androgen receptor (AR). The androgen signalling pathway, a potential therapeutic target, can be regulated by FOXA1. This study aimed to evaluate the clinicopathological implications of FOXA1 in SDC. Methods and results: We examined the relationship between the immunoexpression of FOXA1 and FOXA1 mutations and clinicopathological factors, including the biomarker status and clinical outcome, in 142 SDCs. FOXA1 was expressed in 128 SDCs (90.1%); the immunoexpression was heterogeneous. SDCs with a higher FOXA1 labelling index (LI) (≥20%) more frequently showed less advanced tumors on T classification (P = 0.002). FOXA1 LI was correlated positively with the AR expression value (r = 0.430, P < 0.001). PI3K and p-mTOR positivity, and intact-PTEN, were associated with a higher FOXA1 LI. Twenty-two of 121 SDCs (18.2%) harboured FOXA1 gene mutations at the flanking regions in and around the forkhead DNA binding domain; however, the given gene mutation and the expression of FOXA1 were not significantly correlated. A multivariate analysis revealed that SDCs with a higher FOXA1 LI were associated with longer overall survival and progression-free survival (P = 0.029 and 0.016, respectively). Conclusions: In SDC, FOXA1, which may biologically interact with the AR and PI3K signalling pathways, is a putative biomarker that may be associated with a favourable prognosis. Further studies are needed to apply the findings to the development of targeted personalised therapy for patients with SDC.

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Visualization of nerve fibers around the carotid bifurcation with use of a 9.4 Tesla microscopic magnetic resonance diffusion tensor imaging with tractography

Saito S., Ozawa H., Fujioka M., Hikishima K., Hata J., Kurihara S., Okano H., Ogawa K.

Head and Neck (Head and Neck) 40 ( 10 ) 2228 - 2234 2018.10

ISSN 10433074

Background: Precise imaging of nerves have been challenging in the head and neck region, mainly due to low spatial resolution. Here, we investigated how nerves in the head and neck region could be visualized using an ultra-high magnetic field MR system. Methods: We used formol-carbol-fixed human cadaveric necks and obtained MR diffusion tensor images (DTIs) using a 9.4 Tesla (T) ultra-high magnetic field MR system. Afterward, we prepared tissue sections and checked the anatomic relationships between the neurons and the carotid artery in order to confirm that the visualized fibers are indeed neuron fibers. Results: We were able to identify nerves, including the vagus nerve, the hypoglossal nerve, and the spinal-accessory nerve. Hematoxylin-eosin stained histological sections confirmed neuron fibers in the same anatomic position. Conclusion: This technique has the feasibility to be applied for a more accurate anatomic understanding, maybe even close to a histological level.

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Pulmonary nocardiosis mimicking small cell lung cancer in ectopic ACTH syndrome associated with transformation of olfactory neuroblastoma: A case report

Kobayashi K., Asakura T., Ishii M., Ueda S., Irie H., Ozawa H., Saitoh K., Kurihara I., Itoh H., Betsuyaku T.

BMC Pulmonary Medicine (BMC Pulmonary Medicine) 18 ( 1 ) 2018.08

Background: Pulmonary nocardiosis frequently develops as an opportunistic infection in cell-mediated immunosuppressive patients, and sometimes requires differentiation from pulmonary malignancy. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a neoplastic disorder which leads to impaired cell-mediated immunity, and is commonly associated with small cell lung cancer (SCLC). Because pulmonary infection and causative malignancy can appear as pulmonary lesions with EAS, differentiation of these diseases remains a critical issue for physicians. Case presentation: A 52-year-old woman with progressive lower limb paralysis and general fatigue was referred to us. She had been diagnosed with olfactory neuroblastoma (ONB) and treated with surgery and radiation therapy 10 years before the referral and had required stereotactic radiosurgery and chemotherapy 4 years later for a relapse of the ONB. On referral, she presented with Cushing's syndrome with elevated cortisol and ACTH levels. Potassium supplement improved her symptoms; however, a month later, she was urgently hospitalized due to acute pleuritic chest pain on inspiration. Chest computed tomography revealed left lower lobular consolidations and a contralateral nodule in the right middle lobe. The clinical history and laboratory work-up suggested that her Cushing's syndrome had most likely arisen from EAS. Additionally, the lungs were suspected as the ACTH source due to high levels of progastrin-releasing peptide and progressive pulmonary consolidation with a contralateral nodule, suggesting SCLC. However, histological examination from bronchoscopy revealed no evidence of malignancy, and Nocardia cyriacigeorgica was isolated from bronchoalveolar lavage fluid. Sulfamethoxazole/trimethoprim improved her pulmonary lesions. Somatostatin receptor scintigraphy revealed strong tracer uptake in the ONB lesions, indicating that the origin of the EAS was the olfactory tumor. However, histological examination of ONB specimens resected 10 years earlier showed no intracytoplasmic immunopositivity for ACTH. Conclusions: We highlight a rare case of pulmonary nocardiosis, which was associated with EAS mimicking SCLC, and was related to ONB transformation. Nocardiosis has to be considered even though anamnestic, clinical, and radiological aspects suggest the presence of metastasis. Additionally, physicians should carefully monitor patients with ONB for the development of Cushing's symptoms because the tumor can transform into an ACTH-producing form, even after long-term follow-up.

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Integrated time course omics analysis distinguishes immediate therapeutic response from acquired resistance

Stein-O'Brien G., Kagohara L.T., Li S., Thakar M., Ranaweera R., Ozawa H., Cheng H., Considine M., Schmitz S., Favorov A.V., Danilova L.V., Califano J.A., Izumchenko E., Gaykalova D.A., Chung C.H., Fertig E.J.

Genome Medicine (Genome Medicine) 10 ( 1 ) 2018.05

Background: Targeted therapies specifically act by blocking the activity of proteins that are encoded by genes critical for tumorigenesis. However, most cancers acquire resistance and long-term disease remission is rarely observed. Understanding the time course of molecular changes responsible for the development of acquired resistance could enable optimization of patients' treatment options. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. Methods: To determine the dynamics of these molecular changes, we obtained high throughput omics data (RNA-sequencing and DNA methylation) weekly during the development of cetuximab resistance in a head and neck cancer in vitro model. The CoGAPS unsupervised algorithm was used to determine the dynamics of the molecular changes associated with resistance during the time course of resistance development. Results: CoGAPS was used to quantify the evolving transcriptional and epigenetic changes. Applying a PatternMarker statistic to the results from CoGAPS enabled novel heatmap-based visualization of the dynamics in these time course omics data. We demonstrate that transcriptional changes result from immediate therapeutic response or resistance, whereas epigenetic alterations only occur with resistance. Integrated analysis demonstrates delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance is stabilized epigenetically. Conclusions: Genes with epigenetic alterations associated with resistance that have concordant expression changes are hypothesized to stabilize the resistant phenotype. These genes include FGFR1, which was associated with EGFR inhibitors resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. This understanding of the time course progression of molecular changes in acquired resistance is important for the development of alternative treatment strategies that would introduce appropriate selection of new drugs to treat cancer before the resistant phenotype develops.

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Multi-institutional survey of carotid body tumors in Japan

Ikeda A., Shiga K., Katagiri K., Saito D., Miyaguchi J., Oikawa S.I., Tsuchida K., Asakage T., Ozawa H., Nibu K.I., Ohtsuki N., Fujimoto Y., Kaneko K.I.

Oncology Letters (Oncology Letters) 15 ( 4 ) 5318 - 5324 2018.04

ISSN 17921074

There has been no attempt to clarify the status of patients with carotid body tumor (CBT) in Japan. This multi-institutional survey analyzed patients with CBT throughout Japan by gathering information on these patients from institutions that performed head and neck surgeries. Information from a total of 150 patients from 25 institutions from the past 20 years was employed in the present survey. There were 87 females and 63 males, and their mean age was 48.0 years old. The most common chief complaint was a neck mass and the mean suffering period was 46.1 months. Eighteen patients had a family history of paragangliomas and fifteen patients had bilateral CBTs. Among the 94 patients who underwent surgery to remove a CBT, 23 patients had tumors classified as Shamblin type I, 59 had type II and 12 had type III. The most frequent feeding artery of these CBTs was the ascending pharyngeal artery. Preoperative embolization of these arteries was effective in reducing blood loss; however, the operation time in Shamblin type I and II tumors was not improved. Thus these results revealed the status of patients with CBT and their treatment throughout Japan.

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Clinical diagnosis and treatment outcomes for parapharyngeal space schwannomas: A single-institution review of 21 cases

Sato Y., Imanishi Y., Tomita T., Ozawa H., Sakamoto K., Fujii R., Shigetomi S., Habu N., Otsuka K., Watanabe Y., Sekimizu M., Ogawa K.

Head and Neck (Head and Neck) 40 ( 3 ) 569 - 576 2018.03

ISSN 10433074

Background: Because the incidence of schwannoma arising from the parapharyngeal space (PPS) is very low, no studies have analyzed extirpation methods and postoperative neurological complications exclusively in PPS schwannomas. Methods: The preoperative diagnosis and clinical outcomes of surgical treatment in 21 patients with PPS schwannoma who underwent surgery were investigated. Results: Neurological deficit of the involved nerve developed in all patients regardless of the extirpation method used. However, the incidence of first bite syndrome in sympathetic chain schwannoma was significantly lower after intracapsular enucleation (40%) than after total resection (100%; P =.045). Furthermore, the incidence of postoperative complications unrelated to the involved nerve was lower after intracapsular enucleation (0%) than after total resection (42.9%; P =.055). Conclusion: Although postoperative neurological deficit of the involved nerve was unavoidable in PPS schwannoma, intracapsular enucleation could be beneficial by reducing its severity and the incidence of complications unrelated to the involved nerve.

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Synovial sarcoma of the maxillary sinus: An extremely rare case with excellent response to chemotherapy

Saito S., Ozawa H., Ikari Y., Nakahara N., Ito F., Sekimizu M., Fukada J., Kameyama K., Ogawa K.

OncoTargets and Therapy (OncoTargets and Therapy) 11 483 - 488 2018.01

This paper presents an extremely rare case of synovial sarcoma arising from the maxillary sinus, which resulted in a clinically complete response to chemotherapy. Synovial sarcoma is a rare soft tissue malignant tumor, most commonly affecting the extremities. While ∼10% occur in the head and neck region, synovial sarcoma of the sinonasal tract is extremely rare, with only 11 cases having been reported previously. As with other sarcomas, the standard treatment is complete resection while allowing for a safe margin, but this is often difficult in the head and neck area due to the complicated anatomy there. This makes the treatment of head and neck sarcoma challenging and leads to the need for a multimodal approach in advanced cases. However, the exact efficacy of chemotherapy is not well understood. In this report, we present a case of unresectable maxillary sinus synovial sarcoma that was successfully treated by chemotherapy followed by radiation therapy. A 53-year-old Japanese man was referred to our hospital with a history of left nose obstruction over the previous couple of years. Computed tomography/magnetic resonance imaging revealed a tumor arising from the maxillary sinus that extended to adjacent tissues. A biopsy was performed, and the tumor was diagnosed as synovial sarcoma. Since the tumor was unresectable, neoadjuvant chemotherapy was administered. The response was excellent, and the tumor became undetectable under endoscopy and radiological imaging. This provided us with a clinical evaluation of “complete response”. The treatment was concluded with definitive radiotherapy and two more cycles of adjuvant chemotherapy. The patient remains free of disease 12 months after treatment. Synovial sarcoma of the head and neck is a rare entity; complete resection is the treatment of choice but (neo)adjuvant chemotherapy can be considered in unresectable cases, as we show here in the present case.

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Effectiveness of endoscopic optic nerve decompression surgery for traumatic optic neuropathy with optic nerve canal fracture

Ikari Y., Ozawa H., Yoshihama K., Saito S., Nakahara N., Ito F., Hiraga Y., Watanabe Y., Sekimizu M., Sato Y., Tomita T., Ohta Y., Kamamoto D., Toda M., Ogawa K.

Journal of Otolaryngology of Japan (Journal of Otolaryngology of Japan) 121 ( 11 ) 1373 - 1380 2018

ISSN 00306622

Traumatic optic neuropathy often occurs as a complication of head and mid facial injury, and can cause permanent impairment of the visual acuity. From previous studies, optic nerve decompression surgery has been recommended for cases of traumatic optic neuropathy with optic nerve canal fracture. However, the indications for this surgery still remain controversial. Moreover, optic nerve canal fracture cannot be detected even by computed tomography (CT) in some cases. Patients diagnosed as having traumatic optic neuropathy with optic nerve canal fracture are treated by endoscopic optic nerve decompression surgery and steroid administration, by otorhinolaryngologist in collaboration with neurosurgeons and ophthalmologists at Keio University Hospital. Six patients were treated between May 2015 and May 2017. They ranged in age from 17 to 78 years old, and the intervals from injury to surgery ranged from 19 hours to 6 days. Five patients had injury of the outer half of the eyebrows. Preoperative CT revealed optic canal fracture in only 3 cases, whereas intraoperatively, all 6 cases were detected to have fracture. Preoperative visual acuity was hand motion or better in 4 patients, and no light perception in 2 patients. The visual acuity improved postoperatively in 5 patients. No improvement was observed in the patient who underwent surgery 6 days after the injury. Blunt injury on the outer half of the eyebrow was a useful clue for the diagnosis of optic nerve canal fracture, especially in cases where it could not be detected by CT. In cases of traumatic optic neuropathy with optic nerve canal fracture, early decompression of the optic canal and steroid administration play a key role in the recovery of the visual acuity.

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Prognostic and histogenetic roles of gene alteration and the expression of key potentially actionable targets in salivary duct carcinomas

Shimura T., Tada Y., Hirai H., Kawakita D., Kano S., Tsukahara K., Shimizu A., Takase S., Imanishi Y., Ozawa H., Okami K., Sato Y., Sato Y., Fushimi C., Takahashi H., Okada T., Sato H., Otsuka K., Watanabe Y., Sakai A., Ebisumoto K., Togashi T., Ueki Y., Ota H., Ando M., Kohsaka S., Hanazawa T., Chazono H., Kadokura Y., Kobayashi H., Nagao T.

Oncotarget (Oncotarget) 9 ( 2 ) 1852 - 1867 2018

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53, 68%; PIK3CA, 18%; H-RAS, 16%; BRAF, 4%; and AKT1, 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.

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Lenvatinib administration for elderly patients (over 80 years old) with advanced thyroid cancer

Ozawa H., Sekimizu M., Ito F., Ikari Y., Nakahara N., Saito S., Yoshihama K., Ogawa K.

Japanese Journal of Head and Neck Cancer (Japanese Journal of Head and Neck Cancer) 44 ( 1 ) 46 - 50 2018

ISSN 13495747

When treating advanced thyroid cancer cases with Lenvatinib, most of these patients are old and we sometimes hesitate to administer the drug to elderly cases. We have experienced administering low-dose Lenvatinib to aging patients who were over 80 years old. The first case was a 92-year-old man. He was administered 10mg of Lenvatinib at the outpatient clinic, could continue the treatment without serious side effects, and maintained PR for one year. The second case was an 86-year-old female. She had an obstructed airway due to tumor invasion. Due to her poor general condition, we decided to start with 4 mg of Lenvatinib. The trachea-invading tumor shrank, and she was able to stay at home, but eventually died when the tumor progressed. Low-dose Lenvatinib administration was shown to be tolerated and to reduce side effects even in the elderly. This treatment, however, may have insufficient antitumor effects. The organ function, social status, and living environment of older adults are varied, so we should decide the administration dose and method according to the condition of each case.

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SMAD4 Loss Is Associated with Cetuximab Resistance and Induction of MAPK/JNK Activation in Head and Neck Cancer Cells

Ozawa, H., Ranaweera, R. S., Izumchenko, E., Makarev, E., Zhavoronkov, A., Fertig, E. J., Howard, J. D., Markovic, A., Bedi, A., Ravi, R., Perez, J., Le, Q. T., Kong, C. S., Jordan, R. C., Wang, H., Kang, H., Quon, H., Sidransky, D. and Chung, C. H.

Clinical Cancer Research 23 ( 17 ) 5162 - 5175 2017.09

ISSN 1078-0432

Purpose: We previously demonstrated an association between decreased SMAD4 expression and cetuximab resistance in head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to further elucidate the clinical relevance of SMAD4 loss in HNSCC. Experimental Design: SMAD4 expression was assessed by IHC in 130 newly diagnosed and 43 patients with recurrent HNSCC. Correlative statistical analysis with clinicopathologic data was also performed. OncoFinder, a bioinformatics tool, was used to analyze molecular signaling in TCGA tumors with low or high SMAD4 mRNA levels. The role of SMAD4 was investigated by shRNA knockdown and gene reconstitution of HPV-negative HNSCC cell lines in vitro and in vivo. Results: Our analysis revealed that SMAD4 loss was associated with an aggressive, HPV-negative, cetuximab-resistant phenotype. We found a signature of prosurvival and antiapoptotic pathways that were commonly dysregulated in SMAD4-low cases derived from TCGA-HNSCC dataset and an independent oral cavity squamous cell carcinoma (OSCC) cohort obtained from GEO. We show that SMAD4 depletion in an HNSCC cell line induces cetuximab resistance and results in worse survival in an orthotopic mouse model in vivo. We implicate JNK and MAPK activation as mediators of cetuximab resistance and provide the foundation for the concomitant EGFR and JNK/MAPK inhibition as a potential strategy for overcoming cetuximab resistance in HNSCCs with SMAD4 loss. Conclusions: Our study demonstrates that loss of SMAD4 expression is a signature characterizing the cetuximab-resistant phenotype and suggests that SMAD4 expression may be a determinant of sensitivity/resistance to EGFR/MAPK or EGFR/JNK inhibition in HPV-negative HNSCC tumors. (C) 2017 AACR.

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Biomarker immunoprofile in salivary duct carcinomas: clinicopathological and prognostic implications with evaluation of the revised classification

Takase, S., Kano, S., Tada, Y., Kawakita, D., Shimura, T., Hirai, H., Tsukahara, K., Shimizu, A., Imanishi, Y., Ozawa, H., Okami, K., Sato, Y., Sato, Y., Fushimi, C., Okada, T., Sato, H., Otsuka, K., Watanabe, Y., Sakai, A., Ebisumoto, K., Togashi, T., Ueki, Y., Ota, H., Hanazawa, T., Chazono, H., Osamura, R. Y. and Nagao, T.

Oncotarget 8 ( 35 ) 59023 - 59035 2017.08

ISSN 1949-2553

Salivary duct carcinoma (SDC) is an uncommon, aggressive malignant neoplasm histologically resembling high-grade mammary ductal carcinoma. SDC can arise de novo or ex pleomorphic adenoma. To clarify the correlation of biomarker immunoprofile with clinicopathological findings and clinical outcome of SDC, we conducted immunohistochemistry for EGFR, HER2, HER3, AR, CK5/6, p53, and Ki-67, along with HER2 fluorescence in situ hybridization in 151 SDCs. SDCs ex pleomorphic adenoma more commonly overexpressed EGFR, HER2, HER3, and Ki-67 than de novo SDCs (P = 0.015, < 0.001, 0.045, and 0.02, respectively). In multivariate analysis, AR-and CK5/6+ were associated with shorter progression-free survival (P = 0.027 and 0.004, respectively). Moreover, patients with p53-extreme negative/positive demonstrated poorer overall survival (P = 0.007). On assessing the revised classification by the combination of biomarker expression, the percentages of each subtype were as follows: 'apocrine A' (AR+/HER2-/Ki-67-low) (24%), 'apocrine B' (AR+/HER2-/Ki-67-high) (18%), 'apocrine HER2' (AR+/HER2+) (35%), 'HER2-enriched' (AR-/HER2+) (12%), and 'double negative' (AR-/HER2-) (11%). 'Double negative' was further subclassified into 'basal-like' (EGFR and/or CK5/6+) (7%) and 'unclassified' (3%). Consequently,patients with 'apocrine A' showed a better progression-free survival than those with any other subtypes. Our revised immunoprofiling classification was valuable for predicting the survival and might be useful in personalized therapy for patients with SDC.

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Clinical outcomes of transoral videolaryngoscopic surgery for hypopharyngeal and supraglottic cancer

Imanishi, Y., Ozawa, H., Sakamoto, K., Fujii, R., Shigetomi, S., Habu, N., Otsuka, K., Sato, Y., Watanabe, Y., Sekimizu, M., Ito, F., Tomita, T. and Ogawa, K.

Bmc Cancer 17 2017.06

ISSN 1471-2407

Background: Transoral videolaryngoscopic surgery (TOVS) was developed as a new distinct surgical procedure for hypopharyngeal cancer (HPC) and supraglottic cancer (SGC) staged at up to T3. However, long-term treatment outcomes of TOVS remain to be validated. Methods: Under a straight broad intraluminal view provided by combined use of a distending laryngoscope and a videolaryngoscope, we performed en bloc tumor resection via direct bimanual handling of the ready-made straight-form surgical instruments and devices. We retrospectively analyzed functional and oncologic outcomes of 72 patients with HPC (n = 58) or SGC (n = 14) whose minimum follow-up was 24 months or until death. Results: The cohort comprised nine patients of Tis, 23 of T1, 33 of T2, and 7 of T3. Among 36 patients (50%) who underwent neck dissection simultaneously, all but one were pathologically node-positive. Twelve patients underwent postoperative concurrent chemoradiation (CCRT) as adjuvant treatment, and another four patients underwent radiation or CCRT for second or later primary cancer. The endotracheal tube was removed in an operation room in all but two patients who underwent temporary tracheostomy. Pharyngeal fistula was formed transiently in two patients. The median time until patients resumed oral intake and could take a soft meal was 2 and 5 days, respectively. Eventually, 69 patients (96%) took normal meals. The 5-year cause-specific survival (CSS), overall survival (OS), larynx-preserved CSS, and loco-regional controlled CSS were 87.3%, 77.9%, 86.0%, and 88.0%, respectively. Multivariate analysis revealed N2-3 as an independent prognostic factor in both CSS (hazard ratio [HR] = 25.51, P = 0.008) and OS (HR = 4.90, P = 0.022), which indirectly reflected higher risk of delayed distant metastasis. Conclusions: Considering its sound functional and oncological outcomes with various practical advantages, TOVS can be a dependable, less invasive, and cost-effective surgical option of an organ-function preservation strategy for HPC and SGC.

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Impact of hematological inflammatory markers on clinical outcome in patients with salivary duct carcinoma: a multi-institutional study in Japan

Kawakita, D., Tada, Y., Imanishi, Y., Beppu, S., Tsukahara, K., Kano, S., Ozawa, H., Okami, K., Sato, Y., Shimizu, A., Sato, Y., Fushimi, C., Takase, S., Okada, T., Sato, H., Otsuka, K., Watanabe, Y., Sakai, A., Ebisumoto, K., Togashi, T., Ueki, Y., Ota, H., Shimura, T., Hanazawa, T., Murakami, S. and Nagao, T.

Oncotarget 8 ( 1 ) 1083 - 1091 2017.01

ISSN 1949-2553

The prognostic role of modified Glasgow Prognostic Score (mGPS), neutrophil-to- lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in patients with salivary duct carcinoma (SDC) remains unclear. We conducted a multi-institutional retrospective cohort study of 140 SDC patients. The survival impact of these hematological markers was evaluated using multivariate proportional hazard models. High mGPS (>= 1) was significantly associated with worse survival (3-year overall survival (OS): 16.7% vs 66.1%, p-value=0.003; 3-year progression-free survival (PFS): 0.0% vs 27.9%, p-value<0.001). Additionally, high C-reactive protein (CRP) (>= 0.39 mg/dl) was significantly associated with worse survival (3-year OS: 32.1% vs 68.2%, p-value= 0.001; 3-year PFS: 7.1% vs 31.1%, p-value<0.001). These associations were consistent with multivariate analysis adjusted for established prognostic factors. Although we also found significant association of high NLR (>= 2.5) with OS (HR 1.80; 95% confidence interval, 1.05-3.08) in multivariate analysis, this association were inconsistent with the results of PFS. In addition, we found no significant associations of PLR with survival. In conclusion, we found that mGPS, CRP and NLR were identified as prognostic factors associated with survival in SDC patients.

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Endonasal endoscopic approach for a giant cavernous sinus meningioma that extended to the middle cranial fossa with preoperative embolization

Tamura, R., Toda, M., Kohno, M., Ozawa, H., Tomita, T., Akiyama, T., Ogawa, K. and Yoshida, K.

Interdisciplinary Neurosurgery-Advanced Techniques and Case Management 6 20 - 22 2016.12

ISSN 2214-7519

Background: Transcranial surgery is considered more appropriate than an endonasal endoscopic approach (EEA) for a large cavernous sinus meningioma with lateral extension. Case presentation: A 6-cm-diameter hypervascular meningioma around cavernous sinus invaded the orbital apex and infratemporal fossa. 80% of the tumor was removed without too much blood loss via endoscopic endonasal transpterygoidal-infratemporal approach. Preoperative embolization from some feeding arteries was done, and 80% of the tumor staining disappeared. Discussion: Tumor removal rates for giant meningioma are worse with EEA than with the transcranial approach because of various anatomical limitations and blood control. Recently, EEA has become more widely used with approaches such as the transpterygoidal approach. The operation can be done safely with preoperative embolization because the operative view is clear without bleeding. Conclusion: Preoperative embolization for a large hypervascular tumor makes EEA more effective. A giant meningioma can be removed by EEA if the anatomical limitations can be identified and approached safely and effectively. (C) 2016 The Authors. Published by Elsevier B.V.

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CoGAPS matrix factorization algorithm identifies transcriptional changes in AP-2alpha target genes in feedback from therapeutic inhibition of the EGFR network

Fertig, E. J., Ozawa, H., Thakar, M., Howard, J. D., Kagohara, L. T., Krigsfeld, G., Ranaweera, R. S., Hughes, R. M., Perez, J., Jones, S., Favorov, A. V., Carey, J., Stein-O'Brien, G., Gaykalova, D. A., Ochs, M. F. and Chung, C. H.

Oncotarget 7 ( 45 ) 73845 - 73864 2016.11

ISSN 1949-2553

Patients with oncogene driven tumors are treated with targeted therapeutics including EGFR inhibitors. Genomic data from The Cancer Genome Atlas (TCGA) demonstrates molecular alterations to EGFR, MAPK, and PI3K pathways in previously untreated tumors. Therefore, this study uses bioinformatics algorithms to delineate interactions resulting from EGFR inhibitor use in cancer cells with these genetic alterations. We modify the HaCaT keratinocyte cell line model to simulate cancer cells with constitutive activation of EGFR, HRAS, and PI3K in a controlled genetic background. We then measure gene expression after treating modified HaCaT cells with gefitinib, afatinib, and cetuximab. The CoGAPS algorithm distinguishes a gene expression signature associated with the anticipated silencing of the EGFR network. It also infers a feedback signature with EGFR gene expression itself increasing in cells that are responsive to EGFR inhibitors. This feedback signature has increased expression of several growth factor receptors regulated by the AP-2 family of transcription factors. The gene expression signatures for AP-2alpha are further correlated with sensitivity to cetuximab treatment in HNSCC cell lines and changes in EGFR expression in HNSCC tumors with low CDKN2A gene expression. In addition, the AP-2alpha gene expression signatures are also associated with inhibition of MEK, PI3K, and mTOR pathways in the Library of Integrated Network-Based Cellular Signatures (LINCS) data. These results suggest that AP-2 transcription factors are activated as feedback from EGFR network inhibition and may mediate EGFR inhibitor resistance.

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Clinical Outcomes and Prognostic Factors for Salivary Duct Carcinoma: A Multi-Institutional Analysis of 141 Patients

Otsuka, K., Imanishi, Y., Tada, Y., Kawakita, D., Kano, S., Tsukahara, K., Shimizu, A., Ozawa, H., Okami, K., Sakai, A., Sato, Y., Ueki, Y., Sato, Y., Hanazawa, T., Chazono, H., Ogawa, K. and Nagao, T.

Annals of Surgical Oncology 23 ( 6 ) 2038 - 2045 2016.06

ISSN 1068-9265

Among salivary gland malignancies, the prognosis of salivary duct carcinoma (SDC) is assumed to be the poorest. However, because of its low incidence, reliable survival estimates and prognostic factors based on a large number of patients remain to be elucidated, thereby making it impossible to standardize the optimal treatment for SDC. We performed this multi-institutional, retrospective analysis by collecting the clinical information of 141 patients with SDC without distant metastasis who underwent curative surgery as the initial treatment to elucidate overall survival (OS) and disease-free survival (DFS) along with their prognostic factors. The 3-year OS and DFS rates were 70.5 and 38.2 %, respectively. Multivariate analysis revealed that age a parts per thousand yen65 years (p < 0.001) and N1 and N2 (p = 0.047 and < 0.001, respectively) were independent prognostic factors for OS, whereas the primary site of the minor salivary and sublingual gland (p < 0.001) and N2 (p < 0.001) were those for DFS. The most common treatment failure was distant metastasis (55 patients, 39.0 %). For early parotid SDC, neither total parotidectomy in the patients with early T stage nor nerve resection in the patients without facial nerve palsy showed survival benefits. Advanced N stage independently affects both OS and DFS. Partial parotidectomy with facial nerve preservation could be a less invasive standard surgical procedure for parotid gland SDC in the early T stage without facial nerve palsy. Effective systemic therapy is imperative to improve DFS of SDC.

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Sigmoid incision rescue nasoseptal flap technique for endoscopic endonasal skull base surgery

Ozawa, H., Tomita, T., Watanabe, Y., Sekimizu, M., Ito, F., Ikari, Y., Saito, S., Toda, M. and Ogawa, K.

Acta Oto-Laryngologica 136 ( 6 ) 636 - 640 2016.06

ISSN 0001-6489

Conclusion The sigmoid-incision (S-I) rescue flap technique has the advantage of both reduced-invasiveness and providing a sufficient surgical corridor for endoscopic endonasal skull base surgery (EESBS). Objective Skull base reconstruction with nasoseptal flap (NSF) is critically important in managing post-operative cerebrospinal fluid (CSF) leakage after tumor removal by EESBS. The NSF needs to be elevated before sphenoidotomy and posterior septectomy to preserve the pedicle. However, most extradural surgery without CSF leakage does not require NSF and, therefore, NSF preparation is often futile. As a result, a rescue flap technique to overcome this problem has been developed, whereby a new S-I rescue flap method is used that enables wide exposure of the sphenoidal rostrum and smooth manipulation of surgical instruments to preserve the NSF pedicle. Materials and methods Starting in April 2014, 19 cases underwent EESBS with S-I rescue flap. Results All patients underwent tumor resection under an adequate operative field with smooth manipulation of surgical instruments. Two complications were experienced. One patient had CSF leak after removal of the nasal packing, but the leakage was successfully closed by conventional NSF. Another patient had epistaxis from the septal wall, but this was controlled by electrocautery.

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Vascularized middle turbinate flap for the endoscopic endonasal reconstruction of the anterior olfactory groove

Tamura, R., Toda, M., Kohno, M., Watanabe, Y., Ozawa, H., Tomita, T., Ogawa, K. and Yoshida, K.

Neurosurgical Review 39 ( 2 ) 297 - 302 2016.04

ISSN 0344-5607

A vascularized middle turbinate flap (MTF) might be useful in the repair of lesions in the anterior olfactory groove. The sizes of the MTF and inferior turbinate flap (ITF) and these distances up to the frontal base were analyzed by computed tomography (CT) using a picture archiving and communication system (PACS) in 20 patients. The minimum flap measurement to reconstruct the skull base was defined as the distance from the basal plate to the medial slope or lateral slope edge of the MTF and the ITF on the coronal view. Next, we reviewed clinical data from three patients with dural deficits who underwent endoscopic vascularized MTF reconstruction. The distance to the frontal base from the ITF was significantly longer than that from the MTF. The minimum length of the MTF measured by coronal CT was similar to the distance to the frontal base. In contrast, the minimum length of the ITF was shorter than the distance to the frontal base. These results suggest that the MTF might be superior to the ITF for coverage of the anterior frontal base. Three patients who underwent MTF reconstruction for a defect in the anterior olfactory groove had good outcomes and no complications. The MTF is a good option for reconstruction of defects in the anterior part of the olfactory groove.

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Cetuximab activity in dysplastic lesions of the upper aerodigestive tract

Khan, Z., Epstein, J. B., Marur, S., Gillespie, M. B., Feldman, L., Tsai, H. L., Zhang, Z., Wang, H., Sciubba, J., Ferris, R., Grandis, J. R., Gibson, M., Koch, W., Tufano, R., Westra, W., Tsottles, N., Ozawa, H., Chung, C. and Califano, J. A.

Oral Oncology 53 60 - 66 2016.02

ISSN 1368-8375

Background: High risk head and neck mucosal premalignancy has a malignant conversion rate of up to 40%, despite adequate surgical therapy. Epidermal Growth Factor Receptor (EGFR) blocking agents, including cetuximab, have shown activity in head and neck squamous cell carcinoma (HNSCC) and have potential for therapy in high risk premalignancy. Methods: We conducted a randomized, prospective, phase II clinical trial to determine the effects of cetuximab on patients with high risk premalignancy. Patients were randomized to treatment with cetuximab 400 mg/m2 on week one followed by 250 mg/m2 on week 2-8 or observation, with the option for crossover to cetuximab therapy for patients originally randomized to the observation arm. Results: Two of 19 enrolled patients did not complete therapy due to treatment toxicity. Analysis of 17 patients who completed the trial regimen show a trend toward a larger mean decrease in grade of dysplasia in the cetuximab treated group (-1.0) vs. the observation group (-0.2) (P = 0.082, one-sided exact Wilcoxon rank sum test). However, in the observation group, none of the 5 patients (0%) achieved complete resolution of dysplasia; while 4 of 12 (33.3%) cetuximab treated patients had no remaining dysplasia after therapy. Conclusions: Treatment of high risk premalignancy of the upper aerodigestive tract with cetuximab alone may result in significant, durable, and complete clinical and histological resolution of moderate to severe dysplasia in at least a subset of high risk patients. These results warrant further investigation in larger studies with increased statistical power. (C) 2015 Elsevier Ltd. All rights reserved.

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NF-κB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma

Gaykalova Daria A., Manola Judith B., Ozawa Hiroyuki, Zizkova Veronika, Morton Kathryn, Bishop Justin A., Sharma Rajni, Zhang Chi, Michailidi Christina, Considine Michael, Tan Marietta, Fertig Elana J., Hennessey Patrick T., Ahn Julie, Koch Wayne M., Westra William H., Khan Zubair, Chung Christine H., Ochs Michael F., Califano Joseph A.

International Journal of Cancer 137 ( 8 ) 1879 - 1889 2015.10

ISSN 0020-7136

Using high-throughput analyses and the TRANSFAC database, we characterized TF signatures of head and neck squamous cell carcinoma (HNSCC) subgroups by inferential analysis of target gene expression, correcting for the effects of DNA methylation and copy number. Using this discovery pipeline, we determined that human papillomavirus-related (HPV+) and HPV- HNSCC differed significantly based on the activity levels of key TFs including AP1, STATs, NF-κB and p53. Immunohistochemical analysis confirmed that HPV- HNSCC is characterized by co-activated STAT3 and NF-κB pathways and functional studies demonstrate that this phenotype can be effectively targeted with combined anti-NF-κB and anti-STAT therapies. These discoveries correlate strongly with previous findings connecting STATs, NF-κB and AP1 in HNSCC. We identified five top-scoring pair biomarkers from STATs, NF-κB and AP1 pathways that distinguish HPV+ from HPV- HNSCC based on TF activity and validated these biomarkers on TCGA and on independent validation cohorts. We conclude that a novel approach to TF pathway analysis can provide insight into therapeutic targeting of patient subgroup for heterogeneous disease such as HNSCC. What's new? Changes in transcription factor (TF) expression contribute to genetic and epigenetic abnormalities in cancer. In order to capitalize on those changes and advance diagnostic and therapeutic strategies for cancer, researchers must first find a way to detect and quantify changes in TF activity. Here, TF activity was estimated globally in primary head and neck squamous cell carcinoma (HNSCC) using a novel inferential approach that accounted for gene silencing and loss of heterozygosity and homozygosity. Top-scoring pair biomarkers were identified and linked to human papillomavirus (HPV) status, enabling HPV+ and HPV- HNSCC to be distinguished based on TF activity.

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Expression of Oct3/4 and Nanog in the head and neck squamous carcinoma cells and its clinical implications for delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma

Habu, N., Imanishi, Y., Kameyama, K., Shimoda, M., Tokumaru, Y., Sakamoto, K., Fujii, R., Shigetomi, S., Otsuka, K., Sato, Y., Watanabe, Y., Ozawa, H., Tomita, T., Fujii, M. and Ogawa, K.

Bmc Cancer 15 2015.10

ISSN 1471-2407

Background: The side population (SP) of cancer cells is reportedly enriched with cancer stem cells (CSCs), however, the functional role and clinical relevance of CSC marker molecules upregulated in the SP of head and neck squamous carcinoma (HNSCC) cells are yet to be elucidated. Patients with clinical stage I/II (T1-2N0M0) tongue squamous cell carcinoma (TSCC) typically undergo partial glossectomy; however, development of delayed neck metastasis (DNM) tends to reduce their survival. In the present study, we aimed to determine the CSC markers in the SP of HNSCC cells along with their functions in cellular behaviors, and to clarify the association of these markers with DNM. Methods: Flow cytometry was applied to isolate SP from main population (MP) in HNSCC cells. The expression of the CSC markers was examined by semi-quantitative RT-PCR and immunocytochemistry. In vitro proliferation, migration, and invasion assays were performed to assess cellular behaviors. Clinicopathological factors and immunohistochemical expressions of Oct3/4 and Nanog were evaluated using surgical specimens from 50 patients with stage I/II TSCC. Results: SPs were isolated in all three cell lines examined. Expression levels of Oct3/4 and Nanog were higher in SP cells than MP cells. Additionally, cell migration and invasion abilities were higher in SP cells than MP cells, whereas there was no difference in proliferation. Univariate analysis showed that expression of Oct3/4 and Nanog, vascular and muscular invasion, and mode of invasion were significantly correlated with DNM. Multivariate logistic regression revealed that Oct3/4 expression (risk ratio = 14.78, p = 0.002) and vascular invasion (risk ratio = 12.93, p = 0.017) were independently predictive of DNM. Regarding the diagnostic performance, Oct3/4 showed the highest accuracy, sensitivity, and NPV of 82.0 %, 61.5 %, and 86.8 %, respectively, while vascular invasion showed the highest specificity and PPV of 94.6 % and 71.4 %, respectively. Conclusion: These results suggest that Oct3/4 and Nanog represent probable CSC markers in HNSCC, which contribute to the development of DNM in part by enhancing cell motility and invasiveness. Moreover, along with vascular invasion, expression of Oct3/4 can be considered a potential predictor for selecting patients at high risk of developing DNM.

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Decreased SMAD4 expression is associated with induction of epithelial-to-mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma

Cheng, H. X., Fertig, E. J., Ozawa, H., Hatakeyama, H., Howard, J. D., Perez, J., Considine, M., Thakar, M., Ranaweera, R., Krigsfeld, G. and Chung, C. H.

Cancer Biology & Therapy 16 ( 8 ) 1252 - 1258 2015.08

ISSN 1538-4047

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and cetuximab, a monoclonal antibody targeting this receptor, is widely used to treat these patients. In the following investigation, we examined the role of SMAD4 down-regulation in mediating epithelial-to-mesenchymal transition (EMT) and cetuximab resistance in HNSCC. We determined that SMAD4 downregulation was significantly associated with increased cell motility, increased expression of vimentin, and cetuximab resistance in HNSCC cell lines. In the HNSCC genomic dataset obtained from The Cancer Genome Atlas, SMAD4 was altered in 20/279 (7%) of HNSCC via homozygous deletion, and nonsense, missense, and silent mutations. When SMAD4 expression was compared with respect to human papillomavirus (HPV) status, HPV-positive tumors had higher expression compared to HPV-negative tumors. Furthermore, higher SMAD4 expression also correlated with higher CDKN2A (p16) expression. Our data suggest that SMAD4 down-regulation plays an important role in the induction of EMT and cetuximab resistance. Patients with higher SMAD4 expression may benefit from cetuximab use in the clinic.

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PiCO2 monitoring of transferred jejunum perfusion using an air tonometry technique after hypopharyngeal cancer surgery

Ozawa Hiroyuki, Imanishi Yorihisa, Ito Fumihiro, Watanabe Yoshihiro, Kato Takashi, Nameki Hideo, Isobe Kiyoshi, Ogawa Kaoru

Medicine (United States) 94 ( 11 ) e632 2015.03

ISSN 0025-7974

This study aimed to investigate the usefulness of intraluminal Pco 2 (Pico 2) monitoring by air tonometry for the assessment of the vascular condition of the transferred jejunum after surgery for hypopharyngeal cancer. Pico 2 in the transplanted jejunum of 24 patients was monitored using air tonometry after radical surgery for hypopharyngeal cancer from 2003 to 2010. All but 1 patient, who removed the catheter before monitoring began, were monitored safely. Pico 2 in the transferred jejunum correlated with arterial Pco 2 (Paco 2) that was measured concurrently, and dissociation of Pico 2 from Paco 2 was observed in cases with vascular complication. In those cases without postoperative vascular complication, the Pico 2 value gradually increased for 3 hours but then decreased by 12 hours after surgery. Three patients experienced major vascular complication. All 3 patients had continuous elevation of Pico 2 >100mm Hg, although vascular flow in 1 patient recovered by removal of a venous thrombosis and reanastomosis of the vein 7.5 hours after surgery. Four other patients who experienced elevation of Pico 2 had their skin suture released for decompression of their neck wound, resulting in a decrease in Pico 2 after treatment. The current results demonstrated that continuous monitoring of Pico 2 by air tonometry accurately reflects the vascular condition of the transferred jejunum, and this method is one of the best options for postoperative monitoring of jejunum blood perfusion.

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Restoration of E-cadherin expression by selective Cox-2 inhibition and the clinical relevance of the epithelial-to-mesenchymal transition in head and neck squamous cell carcinoma

Fujii Ryoichi, Imanishi Yorihisa, Shibata Katsushi, Sakai Nobuya, Sakamoto Koji, Shigetomi Seiji, Habu Noboru, Otsuka Kuninori, Sato Yoichiro, Watanabe Yoshihiro, Ozawa Hiroyuki, Tomita Toshiki, Kameyama Kaori, Fujii Masato, Ogawa Kaoru

Journal of Experimental and Clinical Cancer Research 33 ( 1 ) 2014.05

ISSN 0392-9078

Background: The epithelial-to-mesenchymal transition (EMT) accompanied by the downregulation of E-cadherin has been thought to promote metastasis. Cyclooxygenase-2 (Cox-2) is presumed to contribute to cancer progression through its multifaceted function, and recently its inverse relationship with E-cadherin was suggested. The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC. Methods. We used quantitative real-time PCR to examine the effects of three selective Cox-2 inhibitors, i.e., celecoxib, NS-398, and SC-791 on the gene expressions of E-cadherin (CDH-1) and its transcriptional repressors (SIP1, Snail, Twist) in the human HNSCC cell lines HSC-2 and HSC-4. To evaluate the changes in E-cadherin expression on the cell surface, we used a flowcytometer and immunofluorescent staining in addition to Western blotting. We evaluated and statistically analyzed the clinicopathological factors and mRNA expressions of Cox-2, CDH-1 and its repressors in surgical specimens of 40 patients with tongue squamous cell carcinoma (TSCC). Results: The selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors. The extent of this effect depended on the baseline expression levels of both E-cadherin and Cox-2 in each cell line. A univariate analysis showed that higher Cox-2 mRNA expression (p = 0.037), lower CDH-1 mRNA expression (p = 0.020), and advanced T-classification (p = 0.036) were significantly correlated with lymph node metastasis in TSCC. A multivariate logistic regression revealed that lower CDH-1 mRNA expression was the independent risk factor affecting lymph node metastasis (p = 0.041). Conclusions: These findings suggest that the appropriately selective administration of certain Cox-2 inhibitors may have an anti-metastatic effect through suppression of the EMT by restoring E-cadherin expression. In addition, the downregulation of CDH-1 resulting from the EMT may be closely involved in lymph node metastasis in TSCC. © 2014 Fujii et al.; licensee BioMed Central Ltd.

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Clinical outcome and clinicopathological prognostic factors in adenoid cystic carcinoma of the head and neck

Shigetomi Seiji, Imanishi Yorihisa, Shimoda Masayuki, Tomita Toshiki, Ozawa Hiroyuki, Sakamoto Koji, Fujii Ryoichi, Habu Noboru, Otsuka Kuninori, Yamashita Taku, Fujii Masato, Ogawa Kaoru

Journal of Otolaryngology of Japan 117 ( 5 ) 658 - 665 2014

ISSN 0030-6622

We retrospectively reviewed the records of the 30 patients with adenoid cystic carcinoma of the head and neck (ACCHN) who had undergone initial treatment in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine between 1988 and 2007. The primary tumor site was the parotid gland in 10 patients and the submandibular gland in 4 patients, which account for about a half of the subjects. Thirty patients underwent surgical resection with curative intent as the primary treatment, of which 10 patients had post-operative radiotherapy. The 5- and 10-year disease-specific survival (DSS) was 73.9% and 62.4%, respectively, whereas the 5- and 10-year disease-free survival (DFS) was 64.3% and 59.7%, respectively. A univariate analysis revealed that DSS was significantly correlated with perineural invasion (p = 0.010) and lymphatic invasion (p = 0.036), while DFS was significantly correlated with higher T-stage (p = 0.044), a positive surgical margin (p = 0.012) and perineural invasion (p = 0.019). A multivariate analysis demonstrated that perineural invasion (/> = 0.034, risk ratio = 9.530) was the independent prognostic factor for DSS, whereas for DFS it was a positive surgical margin (p = 0.038, risk ratio = 8.897). The histological grade classification, defined specifically for ACC, showed no correlation with the survival. Extended resection with wider margin and additional resection in cases with positive margin may improve treatment results, however, surgical resection alone can prevent neither the development of local recurrence mainly attributed to undetectable perineural invasion, nor that of delayed distant, metastasis. Therefore, the roles of adjuvant radiotherapy and effective systemic therapies are also significant in ACCHN, although a reliable regimen for the latter has not yet been established. Development of a personalized strategy for the adjuvant therapy, which should be based on the accurate prediction of the long-term prognosis in combination with dependable molecular biomarkers, would be indispensable in the future to improve the clinical outcome of the patients with ACCHN.

A case of igg4-related pharyngolaryngitis

Suzuki Narihisa, Fujioka Masato, Araki Yasutomo, Ozawa Hiroyuki, Kawaura Mitsuhiro

Practica Oto-Rhino-Laryngologica 107 ( 3 ) 227 - 233 2014

ISSN 0032-6313

IgG4-related inflammatory diseases, including autoimmune pancreatitis and Mikulicz syndrome, have become known to physicians as new clinical entities, especially over the past few years. We would like to present a case of IgG4-related oropharyngolaryngitis. We encountered a case with a severe and intractable inflammation distributed exclusively in the hypopharynx and laryngeal surface of the epiglottis. The patient did not spontaneously recover and the disease was resistant to antibiotics and NSAIDs that were administered for 4 weeks. Frequent fiberscope inspections and punch biopsies failed to provide a diagnosis, and were followed by a detailed examination under laryngomicrosurgery, with multiple tissue samplings under general anesthesia. The samples revealed proliferative, non-malignant inflammatory lesions and the pathology showed IgG4-related symptoms; indicated by all of the criteria including blood and local IgG4 elevation being met. Symptoms were quickly suppressed by a week of steroid infusion drips, followed by a gradual tapering of oral steroids in accordance with a regimen for autoimmune pancreatitis. For many years, ENT physicians have often used corticosteroids empirically for atypical pharyngitis, but usage of steroids on conditions with uncertain criteria has always been criticized. This is, as far as we know, the first report of oropharyngolaryngitis to be associated with IgG4-related symptoms. The case is thought-provoking in that some of those recurrent atypical oropharyngolaryngitis cases might be explained in accordance with this information. Moreover, the results suggest that the serum IgG4 level might be a predictive marker for the requirement of corticosteroids administration.

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A phase II study of temsirolimus and erlotinib in patients with recurrent and/or metastatic, platinum-refractory head and neck squamous cell carcinoma

Bauman Julie E., Arias-Pulido Hugo, Lee Sang Joon, Fekrazad M. Houman, Ozawa Hiroyuki, Fertig Elana, Howard Jason, Bishop Justin, Wang Hao, Olson Garth T., Spafford Michael J., Jones Dennie V., Chung Christine H.

Oral Oncology 49 ( 5 ) 461 - 467 2013.05

ISSN 1368-8375

Objectives: The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy. Materials and methods: Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines. Results: Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression. Conclusions: The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted. © 2012 Elsevier Ltd. All rights reserved.

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A case of nasopharyngeal carcinoma ex pleomorphic adenoma

Wasano Koichiro, Ikari Yuichi, Hashiguchi Sayuri, Suzuki Noriomi, Kawasaki Taiji, Ozawa Hiroyuki

Practica Oto-Rhino-Laryngologica 106 ( 12 ) 1083 - 1088 2013

ISSN 0032-6313

Malignant tumors of the minor salivary glands are very rare and most cases occur in the oral cavity, e.g., the palate, tongue, cheek and lip. We report herein on an extremely rare case of carcinoma ex pleomorphic adenoma arising in the fossa of Rosenmuller. An 83-year-old man, who had consulted another clinic with a complaint of hemosputum, was referred to our hospital because of the presence of a nasopharyngeal tumor. The tumor was resected via a transnasal endoscopic procedure without any major complications. The tumor was found to have arisen in the fossa of Rosenmuller and extended to superior lateral side behind the Eustachian tube cartilage. Histological examination showed that the main part of the tumor consisted of a pleomorphic adenoma, however, capsular invasion, nuclear atypia and mitosis were observed in a limited area where the MIB-1 index was high. We diagnosed the lesion as a carcinoma ex pleomorphic adenoma. We did not perform any postoperative therapy, because the area containing malignancy was far from the surgical margin and the patient was rather elderly. Three years and 10 months after the surgery, he remains in follow-up and has not shown any recurrence of the tumor.

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Statistical analysis of 32 patients with nasopharyngeal Carcinoma

Fujii Ryoichi, Imanishi Yorihisa, Tomita Toshiki, Sakamoto Koji, Shigetomi Seiji, Habu Noboru, Ootsuka Kuninori, Sato Yoichiro, Ozawa Hiroyuki, Yamashita Taku, Fujii Masato, Shigematsu Naoyuki, Ogawa Kaoru

Journal of Otolaryngology of Japan 115 ( 8 ) 773 - 782 2012.08

ISSN 0030-6622

In order to assess the clinical outcome and prognostic factors of patients with nasopharyngeal carcinoma (NPC) who were initially treated in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine between 1997 and 2006, statistical analyses were performed based on the patient medical records. Cause-specific survival (CSS) and disease-free survival (DFS) in all cases (stage I to IV, n = 32) and advanced cases (stage III and IV, n = 22) were estimated using the Kaplan-Meier method. The independent prognostic values of the clinical and therapeutic factors were determined using multivariate Cox proportional hazards models. Results: The 5-year CSS/DFS were 43.4%/34.8% in all cases and 34.596/29.8% in advanced cases. Multivariate analysis revealed that, in all cases, the independent prognostic factors for CSS were age ≥ 61 vs. ≤60, risk ratio (RR) =5.717, p = 0.006), T-stage (3/4 vs. 1/2, RR = 6.957, p = 0.004), and the use of platinum agents (unused vs. used, RR = 3.911, p = 0.012), whereas those for DFS were T-stage (3/4 vs. 1/2, RR=3.499, p = 0.019) and the use of platinum agents (unused vs. used, RR=2.947, p = 0.028). In advanced cases, the use of platinum agents alone was significant for both CSS (RR = 4.503, p = 0.023)and DFS (RR=4.218, p = 0.014). The patients who received neoadjuvant chemotherapy (NAC) showed better CSS and DFS than the patients who did not (p = 0.066 and p = 0.025, respectively) in a univariate analysis (Log-rank test), although no significant difference was seen between these groups in the multivariate analysis. Conclusion: The advantage of the administration of platinum agents in the treatment of NPC was statistically corroborated even in our study with its small sample size. As agents combined with chemoradiotherapy, the efficacy of do-cetaxel alone did not seem comparable to that of platinum agents. The docetaxel-CDDP-5-FU regimen applied as NAC was suggested to be possibly beneficial for advanced cases of NPC.

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Overexpression of SIP1 and downregulation of e-cadherin predict delayed neck metastasis in stage I/II oral tongue squamous cell carcinoma after partial glossectomy

Sakamoto Koji, Imanishi Yorihisa, Tomita Toshiki, Shimoda Masayuki, Kameyama Kaori, Shibata Katsushi, Sakai Nobuya, Ozawa Hiroyuki, Shigetomi Seiji, Fujii Ryoichi, Fujii Masato, Ogawa Kaoru

Annals of Surgical Oncology 19 ( 2 ) 612 - 619 2012.02

ISSN 1068-9265

Background: Patients with clinical stage I/II (T1-2N0M0) oral tongue squamous cell carcinoma (TSCC) usually undergo partial glossectomy alone. However, 14-48% of them develop delayed neck metastasis (DNM), which may lead to an unfavorable course. Recently epithelial-to-mesenchymal transition (EMT) has been thought to play a crucial role in cancer metastasis. The present study aimed to examine the associations of EMT-involved molecular factors and clinicopathological factors with DNM in stage I/II TSCC. Methods: mRNA expression levels of E-cadherin and its transcriptional repressors (snail, SIP1, and twist) in 7 head and neck squamous cell carcinoma (HNSCC) cell lines were evaluated by quantitative real-time PCR. Clinicopathological parameters and immunohistochemical expressions of E-cadherin and its repressors were examined in surgical specimens of 37 stage I/II TSCC patients who underwent partial glossectomy alone. Results: In HNSCC cells, E-cadherin expression was inversely correlated with SIP1 expression (P = 0.023). Univariate analysis of immunohistochemistry showed that overexpression of SIP1 and loss of E-cadherin were significantly correlated with DNM, although no inverse correlation was found between E-cadherin and its repressors. Multiple logistic regression analysis including clinicopathological and molecular factors revealed that overexpression of SIP1 (P = 0.005), loss of E-cadherin (P = 0.046), and vascular invasion (P = 0.024) were independently correlated with DNM. Conclusions: These results suggest that development of DNM in stage I/II TSCC is closely related to induction of EMT in primary tumor cells. Especially, SIP1 and E-cadherin are considered to be the possible markers for selecting patients at high risk of DNM. © 2011 Society of Surgical Oncology.

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Thyroglobulin concentration measurement in fine-needle aspiration fluid from cystic cervical lymph node metastases of papillary thyroid carcinoma

Inagaki Yozo, Sakamoto Koji, Inoue Yasuhiro, Imanishi Yorihisa, Tomita Toshiki, Shinden Seiichi, Ozawa Hiroyuki, Fujii Ryoichi, Shigetomi Seiji, Watabe Takahisa, Yamada Hiroyuki, Ogawa Kaoru

Journal of Otolaryngology of Japan 114 ( 12 ) 912 - 916 2011.12

ISSN 0030-6622

Background: Combining ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) and fine-needle aspiration cytology (FNAC) usually results in the best preoperative diagnosis of cervical masses, including neoplasms. This may not be tnie, however, especially in occult papillary thyroid carcinoma (PTC) associated with single cystic cervical lymph node metastasis. We assessed the role of thyroglobulin measurement in FNA fluid (FNATg) in differentially diagnosing cystic cervical mass lesions, including PTC cystic lymph node metastasis. Methods: We reviewed the records of 17 subjects with cervical cystic masses undergoing both FNATg measure ment and surgery. FNA was done under ultrasonographic guidance. We also measured FNATg concentrations from extrathyroid lesions, consisting of cystic cervical lymph node metastases and benign cystic lesions. Results: Pathological diagnosis involved 5 PTC lymph node metastases, 3 lateral cervical cysts, 7 thyroglossal duct cysts, and 2 squamous cell carcinoma (lung and oropharynx) lymph node metastases. FNATg of PTC lymph node metastasis was much higher than the reference range of blood serum thyroglobulin, although much lower for the lateral cervical cyst detection threshold. FNAC and FNATg measurement are thought to be mutually complementary in the differential-diagnosis of PTC cystic lymph node metastasis. Conclusion : High concentrations of FNATg in a cystic cervical mass is considered specific to PTC lymph node metastasis, indicating its usefulness in distinguish PTC cystic metastasis from other cystic lesions. Including FNATg measurement with FNAC may thus improve preoperative diagnosis accuracy without additionally stressing subjects with PTC cystic lymph node metastasis.

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Clinical review and statistical analysis of tongue squamous cell carcinoma

Sakamoto Koji, Imanishi Yorihisa, Tomita Toshiki, Ozawa Hiroyuki, Tagawa Takamasa, Fujii Ryoichi, Shigetomi Seiji, Habu Noboru, Ootsuka Kuninori, Yamashita Taku, Kanke Minoru, Fujii Masato, Ogawa Kaoru

Japanese Journal of Head and Neck Cancer 37 ( 4 ) 529 - 535 2011

ISSN 1349-5747

We reviewed 86 patients with oral tongue squamous cell carcinoma who were initially treated with curative intent in the Department of Otorhinolaryngology, Head and Neck Surgery, Keio University School of Medicine between 1996 and 2007. Statistical analysis was performed to examine the prognostic value of the clinical features. Eighty patients underwent surgery and six underwent radiotherapy as the initial treatment. The five-year disease-free survival (DFS) rates determined by the Kaplan-Meier method were as follows: 75.8% in all stages, 88.7% in stage I (n = 30), 82.6% in stage II (n = 24), 77.1% in stage III (n = 14), and 39.7% in stage IV (n = 18). Univariate analysis demonstrated that stage III/IV, T 3/4, and N2 were significantly correlated with poor prognosis, whereas multivariate analysis showed that only N2 was independently correlated with poor prognosis. Neoadjuvant chemotherapy (NAC) was applied for 24 patients. Although the DFS of the responders (CR+PR) was higher than that of the non-responders (NC+PD), the difference was not significant. Among 80 patients who received surgical treatment initially, neck dissection (ND) was performed in 42 patients. Five-year DFS was significantly higher in the patients with no or single node metastasis than in the patients with multiple node metastases (93.8% vs. 32.7%). These outcomes suggest that more aggressive postoperative therapy should be recommended for patients found to have pathologically multiple positive nodes.

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The outpatient palliative care conference for the home palliative care shift (the second report)--the conference was used to look back on the case where the patient's QOL was kept and improved

Asaba Kaori, Chigira Mayumi, Hashimoto Eiko, Hano Ayumi, Sofue Akira, Umeki Mikiko, Murotsu Keizo, Ozawa Hiroyuki, Shiraishi K.

Gan to kagaku ryoho. Cancer & chemotherapy 36 Suppl 1 84 - 88 2009.12

ISSN 0385-0684

The patient was a 30-year-old woman with right tongue cancer and SCC (T4N2bM0). After it had relapsed, the outpatient palliative care conference intervened. The purpose of intervention was as follows: pain control, nutrition management, home recuperation support, and relief of a spiritual pain. We could achieve the patient's desire to recuperate at home as long as possible by sharing a goal and information. The patient was treated for a total of 457 days. Since the relapse, she was treated for 274 days, and was hospitalized for 49 days. By offering necessary home care supports, the patient and family fully demonstrated their potentials what they could do to recuperate and resulted in a long home stay. It was thought that our relationship with the patient and family appeared to have enhanced their self-resistance feelings against the disease. Consequently, we contributed the improvement of QOL.

Promoted cell proliferation by connexin 30 gene transfection to head-and-neck cancer cell line

Ozawa Hiroyuki, Mutai Hideki, Matsunaga Tatsuo, Tokumaru Yutaka, Fujii Masato, Sakamoto Kouji, Tomita Toshiki, Ogawa Kaoru

Anticancer Research 29 ( 6 ) 1981 - 1985 2009.06

ISSN 0250-7005

Background: There have been inconsistent results regarding the contribution of the connexin family of genes to tumor cell proliferation. Materials and Methods: We aimed to clarify the role of connexin 30 (Cx30), by transfecting three kinds of vectors that express either full length Cx30 (Cx30-Full), Cx30 devoid of C-terminal region (Cx30-DelC) or Cx30 C-terminal region (Cx30-CT), in HSC-4, a head-and-neck cancer cell line. Results: Transfected Cx30-Full was localized on the plasma membrane, while Cx30-DelC and Cx30-CT was expressed in the cytoplasm or circumnuclear sites. We studied the effect on the growth rate followed by immunostaining with anti-Ki-67 (MIB-1). The MIB indices of HSC-4 cells transfected with Cx30-Full and Cx30-DelC, but not Cx30-CT were shown to be significantly higher than that of the controls. Conclusion: Our results demonstrated that Cx30 enhanced the proliferation of HSC-4 cells and the proliferating activity was considered to be achieved without the transport of the protein onto the plasma membrane.

Diagnosis and management of cervical sympathetic chain schwannoma

Tomita Toshiki, Ozawa Hiroyuki, Sakamoto Koji, Ogawa Kaoru, Kameyama Kaori, Fujii Masato

Acta Oto-Laryngologica 129 ( 3 ) 324 - 329 2009.03

ISSN 0001-6489

Conclusions. Cervical sympathetic chain schwannoma (CSCS) sometimes mimics carotid body tumor (CBT). Differential diagnosis between these tumors is sometimes difficult using MRI alone. MRA, color Doppler ultrasonography, and fine needle aspiration (FNA) after imaging may be helpful to rule out CBT. Surgical resection of CSCS is relatively effortless, and Horner's syndrome is an expected but acceptable postoperative complication. Intratumoral hemorrhage and vasodilation may be the main reasons for significant enhancement on MRI. Objectives. CSCSs are rare and known to mimic carotid body tumors. We report 9 cases of CSCS with an emphasis on imaging, surgical management, and pathological findings. Moreover, we describe the differential diagnosis of CSCS and CBT, and speculate the reasons behind significant enhancement on MRI. Patients and methods. Nine cases of CSCS treated at a tertiary referral center between 1996 and 2008 were reviewed. Results. MRI revealed 3 of 9 cases (33%) splayed the carotid bifurcation and displayed marked contrast enhancement with gadolinium. All patients underwent surgical excision of the mass with minimal blood loss. Postoperative Horner's syndrome was encountered in all patients, which required no treatment. Marked gadolinium enhancement tended to be associated with histological findings such as intratumoral hemorrhage and vasodilation. © 2009 Informa UK Ltd. (Informa Healthcare, Taylor & Francis As).

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Mucoepidermoid carcinoma of the head and neck

Ozawa Hiroyuki, Tomita Toshiki, Sakamoto Koji, Tagawa Takamasa, Fujii Ryoichi, Kanzaki Sho, Ogawa Kaoru, Kameyama Kaori, Fujii Masato

Japanese Journal of Clinical Oncology 38 ( 6 ) 414 - 418 2008.06

ISSN 0368-2811

Objective: It is well known that mucoepidermoid carcinoma (MEC) displays a variety of biological behaviors. While the high-grade type is a highly aggressive tumor, its low-grade counterpart usually demonstrates a more benign nature and several systems have, therefore, been proposed to grade this neoplasm. Methods: This report analyzes 43 patients suffering from head and neck MEC, who were treated in our department during the period from 1989 to 2005. The relationship between clinical and pathologic characteristics and survival rate was investigated. Results: The 5-year overall and disease-free survival rate was 62.3 and 57.2%. Multivariate analysis demonstrated that the parameters that significantly affected survival were the patient's age (P = 0.040) and treatment method (P = 0.011). Conclusions: The patient's age and treatment method is the prognostic parameter in this study. Although complete surgical resection is the standard treatment for MEC, we should aggressively consider adjunctive radiotherapy in those cases that have a high risk of recurrence and poor prognosis. © The Author 2008. Published by Oxford University Press. All rights reserved.

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A multidisciplinary approach to carotid body tumors. Report of five cases

Tomita Toshiki, Ozawa Hiroyuki, Tagawa Takamasa, Sakamoto Koji, Ogawa Kaoru

Journal of Otolaryngology of Japan 110 ( 12 ) 743 - 751 2007.12

ISSN 0030-6622

We performed a retrospective review of five patients with carotid body tumors at our institution between 1997 and 2005. Out of the five patients, three patients were treated by surgical resection of the tumor, and 2 patients were observed. It would seem that it is difficult to suspect this disease based only on the clinical findings, because the disease was suspected in only one patient at the first medical examination. Imaging tests are important for establishment of the diagnosis. Color Doppler sonography and MR angiography in addition to MRI are useful. Angiography and balloon Matas test are important for selection of candidates for the operation. The resected tumors were all classified in Shamblin's group II. Delayed cerebral infarction was caused in one patient postoperatively, although the carotid artery was preserved. The dissection in a tumor-adventitial plane using the bipolar coagulation technique under the microscope was performed in the other two cases. Histological examination of the specimen revealed no tumor cells in the excision stump. Dissection in the tumor-adventitial plane using bipolar coagulation under the microscope is important for carotid artery preservation and radical resection of Shamblin's group I and II tumors. It is necessary to compare the risk of the operation with the problems of observation in the process of decision making and to achieve reliable informed consent. Moreover, it is necessary to examine the indications for operation in individual cases referring to the age, past history, expected Shamblin's classification, and result of the balloon Matas test. A multidisciplinary approach should be used, involving the fields of otolaryngology, radiology, neurosurgery and vascular surgery to treat these patients.

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Liposarcoma of the retropharyngeal space

Ozawa Hiroyuki, Soma Keiko, Ito Mari, Ogawa Kaoru

Auris Nasus Larynx 34 ( 3 ) 417 - 421 2007.09

ISSN 0385-8146

Liposarcoma is a soft tissue malignant tumor that is common in adults, though the incidence of this type of tumor in the head and neck region is extremely low. Herein, we report a case of myxoid liposarcoma occurring in the retropharyngeal space. We were unable to make a proper diagnosis of this tumor prior to surgery because of the radiographic findings and the anatomical location resembled those of neurogenic tumor. Myxoid liposarcoma often recurs. So its excision must be carried out carefully and radical dissection is recommended. In the past, liposarcomas arising in the retropharyngeal space were not radically resected because the extent of resection in the head and neck area risked poor functional outcome. In the present case, functional resection and radiotherapy were performed and proved to be efficacious in that no recurrence was observed for 2 years. © 2007 Elsevier Ireland Ltd. All rights reserved.

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Decreased expression of connexin-30 and aberrant expression of connexin-26 in human head and neck cancer

Ozawa Hiroyuki, Matsunaga Tatsuo, Kamiya Kazusaku, Tokumaru Yutaka, Fujii Masato, Tomita Toshiki, Ogawa Kaoru

Anticancer Research 27 ( 4 B ) 2189 - 2195 2007.07

ISSN 0250-7005

Background: The relation of connexins and carcinogenesis has been studied in various organs and cell lines, with connexins currently being considered tumor suppressors. Materials and Methods: The expression of connexin-26 (Cx26) and connexin-30 (Cx30) in human head and neck carcinomas, as well as in adjacent normal mucosa, was evaluated by immunohistochemistry. Furthermore, the expression of these connexins with regard to apoptosis and cell differentiation was investigated. Results: In the cancer tissues, Cx30 expression was drastically reduced compared to apparently normal mucosa while Cx26 expression was almost the same. The intracellular distribution patterns of Cx26 and Cx30 in cancer cells differed between cancer locations. In the cancer tissues, expression of Cx26 and Cx30 was not related to apoptosis assessed by TdT-mediated dUTP-biotin nick end labeling (TUNEL) reaction or to cell differentiation assessed by immunoreaction to involucrin. Conclusion: The present results suggest that connexins may play a role in the carcinogenesis of head and neck cancer.

Clinical study of 28 cases of cervical lymph node metastasis from an unknown primary carcinoma

Tagawa Takamasa, Tomita Toshiki, Yamaguchi Hiroshi, Ozawa Hiroyuki, Sakamoto Koji, Ogawa Kaoru, Fujii Masato

Journal of Otolaryngology of Japan 110 ( 7 ) 503 - 505 2007.07

ISSN 0030-6622

From 1989 to 2005, 28 patients-20 men and 8 women-with cervical lymph node metastasis from an unknown primary carcinoma were treated and studied retrospectively. In histological diagnosis, open biopsy was conducted in 11 patients and non-open biopsy (FNA or frozen section diagnosis during surgery) in 17. Blind biopsy under general anesthesia was conducted in 10 patients, showing one primary tumor in the nasopharynx. Tonsillectomy for diagnosis was not done. In region of maximum-size lymph node metastasis, the upper cervical region accounted for 22 cases (79%). The N stage of cervical lymph nodes was as follows : N2a in 4, N2b in 14, N2c in 3, and N3 in 7. The histopathological diagnosis of cervical lymph node was as follows : squamous cell carcinoma in 21, adenocarcinoma in 3, mucoepidermoid carcinoma in 2, and others in 2. Therapy was as follows : only neck dissection in 7, neck dissection with postoperative radiation therapy in 13, and irradiation and chemotherapy in 8. All patients treated with irradiation and chemotherapy had been judged to be inoperable, Seven patients were found to have a subsequent primary tumor. Primary tumor sites were as follows : tonsils in 3 and upper gingiva, base of tongue, lung, and nasopharynx in 1 each. FDG-PET was conducted in 7 patients but revealed no primary tumor. Overall 5-year survival in this study was 46%. We should pay particular attention to the tonsils for detecting primary tumors in patients with cervical metastasis from an unknown primary carcinoma.

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Planned neck dissection after weekly docetaxel and concurrent radiotherapy for advanced oropharyngeal cancer

Tomita Toshiki, Ozawa Hiroyuki, Sakamoto Koji, Fujii Ryoichi, Ogawa Kaoru, Fujii Masato, Yamashita Taku, Shinden Seiichi

Journal of Otolaryngology of Japan 110 ( 3 ) 95 - 102 2007.03

ISSN 0030-6622

Small oropharyngeal carcinomas with advanced neck metastases (stage N2 or greater) are common. Patients with small T with large N oropharyngeal carcinoma have high rates of local control but lower rates of regional control when treated with chemoradiotherapy. Clinical assessment after chemoradiotherapy cannot ensure the absence of neck disease. In the last 5 years, we have treated patients with T1-2 with N2-3 oropharyngeal carcinoma with weekly docetaxel radiotherapy followed by planned neck dissection (PND). Our objectives were to clarify the pathologically complete response (CR) rate of neck metastasis after weekly docetaxel radiotherapy, to identify the clinical predictor of residual neck disease, and to determine the mobidity of planned neck dissection. After chemoradiotherapy, all 12 patients had a complete response at the primary site. We conducted 15 neck dissections. Of these, 6 (40%) had positive nodes. The pathological CR rate of neck metastasis was 58.3%, whereas overall 2-year neck control rate was 91.7%. These findings lend support to the role of PND after chemoradiotherapy in N2-3 neck disease. After chemoradiotherapy, clinical parameters including TN status, feasibility of chemoradiotherapy, largest lymph node size or size reduction in MRI, did not identify patients with residual neck disease. We conducted selective neck dissection (SND) in 80% of patients. SND as PND appears to be appropriate in this group of patients because of the low incidence of complications. A further cohort study including the comparison of PND nonenforcement group is necessary to clarify the validity of the addition of PND in weekly docetaxel radiotherapy.

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Pulse-oximetery is useful in determining the indications for adeno-tonsillectomy in pediatric sleep-disordered breathing

Saito Hideyuki, Araki Kouji, Ozawa Hiroyuki, Mizutari Kunio, Inagaki Kouji, Habu Noboru, Yamashita Taku, Fujii Ryouichi, Miyazaki Soichiro, Ogawa Kaoru

International Journal of Pediatric Otorhinolaryngology 71 ( 1 ) 1 - 6 2007.01

ISSN 0165-5876

Objective: Although first line therapy of sleep-disordered breathing (SDB) in children is adeno-tonsillectomy, the indications for this operation have not yet been clearly established. We investigated whether pulse-oximetry is useful for determining the optional treatment modality for pediatric SDB. Method: Two hundred and thirty-two children presenting with snoring and gasping had their oxygen saturation levels examined during sleep. Among them, 86 underwent on adeno-tonsillectomy and were evaluated pre- and post-surgery. We also examined 25 healthy children as controls. Results: Little desaturation was observed in healthy children. The difference in oxygen saturation levels of the patients between pre- and post-surgery was closely correlated with the pre-surgery levels. We examined the reaction operation characteristics and concluded that children with an oxygen desaturation index of 4% or more (ODI4) of more than 1.5 and/or ODI3 of more than 3.5 should undergo surgery. Conclusion: Pulse-oximetry is useful in determining the indications for adeno-tonsillectomy. © 2006 Elsevier Ireland Ltd. All rights reserved.

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Hypothyroidism after radiotherapy for patients with head and neck cancer

Ozawa Hiroyuki, Saitou Hideyuki, Mizutari Kunio, Takata Yasunori, Ogawa Kaoru

American Journal of Otolaryngology - Head and Neck Medicine and Surgery 28 ( 1 ) 46 - 49 2007.01

ISSN 0196-0709

We report on 2 cases of hypothyroidism presenting clinical symptoms that occurred after radiotherapy for cancer of the head and neck and on the results of estimating thyroid function in patients with head and neck cancer who received radiotherapy. The first patient underwent total laryngectomy for laryngeal cancer without sacrificing the thyroid gland and partial gastrectomy for gastric cancer. Radiotherapy of the neck was carried out postoperatively. Two years later, the patient developed chest pain; pericardial effusion was detected, leading to a diagnosis of myxedema caused by hypothyroidism. The second patient received radiotherapy alone for laryngeal cancer. Two months later, low serum sodium concentration and anemia were detected in this patient. The cause of these changes was subsequently found to be hypothyroidism. Based on our experience with these 2 cases, we measured thyroid function in 35 patients who had undergone neck radiation for head and neck cancer at our hospital over the past 10 years. Hypothyroidism was observed in 13 of the 35 patients (37%). The prevalence of hypothyroidism was 46% (6/13) for patients treated with both radiation and surgery, as compared with 32% (7/22) for those who received radiation alone. The risk factors responsible for hypothyroidism were not evident from the statistical analysis of these cases. We believe that thyroid function should be evaluated periodically in patients who have undergone neck radiation because it is often difficult to diagnose hypothyroidism only from clinical symptoms. © 2007 Elsevier Inc. All rights reserved.

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Oncocytic carcinoma of the parotid gland

Ozawa Hiroyuki, Fujii Masato, Matsunaga Tatsuo, Masuda Kanaka, Hirose Shigemichi, Taiji Hidenobu

Journal of Otolaryngology 35 ( 3 ) 189 - 192 2006.06

ISSN 0381-6605

Critical spontaneous rupture of a common carotid artery pseudo-aneurysm

Masuda Kanako, Ozawa Hiroyuki, Fujii Masato, Kimura Satoko, Nagasaki Kazuhito, Matsunaga Tatsuro, Tsunoda Koichi

Lancet 366 ( 9502 ) 2034 2005.12

ISSN 0140-6736

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Aphonia and dysphagia after total gastrectomy

Ozawa Hiroyuki, Kimura Satoko, Mizutari Kunio, Fujimine Takekatsu, Fujii Masato, Ikeuchi Syunji, Matunaga Tatsuo, Tsunoda Koichi

Acta Oto-Laryngologica 125 ( 11 ) 1244 - 1246 2005.11

ISSN 0001-6489

A 67-year-old male was referred to our otolaryngological clinic because of aphonia and dysphagia. His voice was breathy and he could not even swallow saliva following a total gastrectomy for gastric carcinoma performed 2 weeks previously. Laryngeal fiberscopy revealed major glottal incompetence when he tried to phonate. However, both vocal folds abducted over the full range during inhalation. The patient could not swallow saliva because of a huge glottal chink, even during phonation. Based on these findings, he was diagnosed as having bilateral incomplete cricoarytenoid dislocation after intubation. The patient underwent speech therapy; within 1 min his vocal fold movement recovered dramatically and he was able to phonate and swallow. There have been few case reports of bilateral cricoarytenoid dislocation, and no effective rehabilitation has been reported. We believe that our method of vocal rehabilitation serves as a useful reference for physicians and surgeons worldwide. © 2005 Taylor & Francis.

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High-quality video recording and monitoring system for endoscopes

Tsunoda Koichi, Tsunoda Atsunobu, Ozawa Hiroyuki, Fujimine Takekatsu

Laryngoscope 115 ( 8 ) 1520 - 1521 2005.08

ISSN 0023-852X

We have developed a new recording system for endoscope images with the popular mini digital video (mini DV) camera. A special adaptor screws onto the lens top, and either a flexible or rigid endoscope can be attached to the camera. Using this system, we can monitor not only the endoscopic images but also the patient's condition. Satisfactory images can be obtained even with the finest fiberscope. Nevertheless, our new system costs only $1,000. Therefore, the system is both cost-effective and useful for the outpatient clinic or casual setting or for house calls for the purpose of patient education. © 2005 The American Laryngological, Rhinological and Otological Society, Inc.

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Intramuscular myxoma of scalene muscle

Ozawa Hiroyuki, Fujii Masato, Tomita Toshiki, Ogawa Kaoru

Auris Nasus Larynx 31 ( 3 ) 319 - 322 2004.09

ISSN 0385-8146

Intramuscular myxoma is a benign mesenchymal tumor that commonly occurs in the larger skeletal muscles, and is rare in the head and neck. A case of intramuscular myxoma in the scalene muscle is described. This is the first report of this tumor arising in that muscle. It is difficult to diagnose pre-operatively from clinical features, CT scan and ultrasonography of the neck because of the lack of characteristic manifestation or radiographic features. Intramuscular myxoma has an infiltrative tendency, so there are several reports of recurrence because of incomplete excision or enucleation. In our case no recurrence was observed for 4 years, since the tumor was removed with the muscle adherent to it. © 2004 Elsevier Ireland Ltd. All rights reserved.

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Review of 26 Patients Operated on for Primary Hyperparathyroidism

Mizutari Kunio, Saito Hideyuki, Ozawa Hiroyuki, Inagaki Koji, Inoue Takahiro

Journal of Otolaryngology of Japan 106 ( 12 ) 1121 - 1126 2003

ISSN 0030-6622

The traditional surgical approach for primary hyperparathyroidism (PHP) is routine bilateral neck exploration. At Saiseikai Utsunomiya Hospital, however, unilateral exploration, and the direct resection of one gland is performed if single gland enlargement is suspected, based on the findings of several preoperative localization procedures. Here, we reviewed 26 patients who underwent single gland operations for PHP at our institution between 1993 and 2001. The 26 patients (21 women and 5 men) ranged in age from 20 to 79 years (mean, 54.8 years). None of the patients had multiple endocrine neoplasia (MEN), familial hypercalcemia, or malignant tumors. At least three preoperative localization procedures, such as ultrasonography, computed tomography, thalium technetium scanning, 99mTc sestamibi scintigraphy, or magnetic resonance imaging, were performed in each patient. A parathyroidectomy was then performed under general anesthesia. Contralateral exploration was not routinely performed. In addition, an intraoperative biopsy of the other glands was not performed. The following data were retrospectively collected in all patients: serum calcium, and the HS-PTH at one month and 6 months after the parathyroidectomy. All patients were normocalcemic, and the serum HS-PTH concentration significantly decreased in all patients after this operation. Patients were divided into two groups (adenoma group, n = 16; hyperplasia group, n = 6) and the data was analyzed according to the histological and pathological diagnosis. In both pathological groups, all patients were normocalcemic and the serum HS-PTH concentration was significantly lower after surgery. The serum HS-PTH concentration showed no significant difference between the adenoma group and the hyperplasia group at 6 months after surgery. No complications, including recurrent laryngeal nerve palsy or permanent hypocalcemia, were observed after surgery. In conclusion, if a single gland disease is suspected based on the findings of multiple preoperative localization procedures, resection of the enlarged gland alone appears to provide good results for the treatment of either adenoma or hyperplasia resulting in PHP. In addition, this procedure also reduces the occurrence of postoperative hypocalcemia, because the normal glands are not injured by the biopsy procedures.

Sensorineural hearing loss from suspected Wegener's granulomatosis; report of 2 cases

Ozawa Hiroyuki, Saitou Hideyuki, Mizutari Kunio

Practica Oto-Rhino-Laryngologica 96 ( 5 ) 397 - 404 2003

ISSN 0032-6313

2 cases of suspected Wegener's granulomatosis showing inflammation in the middle ear and progressive sensorineural hearing loss (SNHL) are reported. The first patient was a 73-year-old female who visited our hospital with a complaint of sudden onset of hearing loss. She had SNHL and administration of steroid hormone improved her hearing acuity temporarily, but then her hearing deteriorated. Subsequently she showed subglottic stenosis, pneumonia and saddle nose. The second patient was a 55-year-old male with otalgia and hearing loss. He had progressive SNHL and ear polyp, and then showed saddle nose. His hearing loss was almost fully recovered after treatment with cyclophosphamide and predonisolone. It was considered in these cases that sensorineural hearing loss had an autoimmune origin. Otitis media is well known as an otological manifestation of Wegener's granulomatosis, but SNHL is comparatively rare. Diagnosis of Wegener's granulomatosis was made by clinical symptoms because c-ANCA titers of our cases were negative, and histopathological studies were not typical. In these cases, they took predonisolone before diagnosis. We suggest that steroid hormones may suppress disease activity and make diagnosis difficult. It is important to look for this disease among SNHL patients and perform general examination in the early stage, because early therapy can lead to an improvement in the morbidity and survival of this disease.

Nocturnal Pulse Oximetry Diagnosis for Screening Pediatric Obstructive Sleep Apnea Syndrome

Saito Hideyuki, Yamashita Taku, Inagaki Koji, Habu Noboru, Araki Koji, Ozawa Hiroyuki, Mizutari Kunio

Journal of Otolaryngology of Japan 106 ( 12 ) 1127 - 1134 2003

ISSN 0030-6622

We evaluated the diagnostic value of pulse oximetry during sleep in pediatric obstructive sleep apnea syndrome (OSAS) caused by adenoid-tonsil hypertrophy. Subjects were 22 healthy children free of symptoms such as snoring, sleep apnea and oral breathing and 163 children suspected of OSAS with snoring or sleep apnea. Subjects were measured for percutaneous oxygen saturation (SpO₂) during sleep. Of those with suspected OSAS, 69 underwent adenotonsillectomy and were measured for SpO₂ both pre- and postoperatively, then pre- and postoperative measurements were compared. After measurement, we analyzed three parameters: lowest saturation (LSpO₂), the desaturation index, and total desaturation duration under 95% (TDD95). Few abnormal findings were seen in healthy children. We calculated the mean and standard deviation (SD) of each parameter and set borderlines of mean-2SD for LSpO₂ and mean + 2SD for ODI and TDD95. With these borderlines, 105 children for LSpO₂, 75 for ODI and 76 for TDD 95 were judged to be normal among the 163 with suspected OSAS. Histograms showed that the mode of each parameter was situated near the borderline. Comparison between pre- and postoperative measurements showed that the effect of the surgery strongly correlated with preoperative measurement in patients undergoing surgery. Assuming that a patient with postoperative improvement is positive, we calculated sensitivity and specificity for each borderline measurement. We found that if success is 100%, the borderline should be 87% for LSpO ₂, 3.5 for ODI, and 30.0 for TDD95. If success exceeds 90%, the borderline should be 90% for LSpO₂, 2.0 for ODI, and 7.0 for TDD95. We therefore conclude that measurement of SpO₂ during sleep is useful in screening for pediatric OSAS.

Herpes zoster involving lower cranial nerves; a report of 2 cases

Mizutari Kunio, Saito Hideyuki, Ozawa Hiroyuki

Practica Oto-Rhino-Laryngologica 95 ( 9 ) 889 - 892 2002

ISSN 0032-6313

We report two cases of cranial nerve palsy due to varicella-zoster virus infection. One patient, a 53-year-old woman, was admitted to our hospital complaining of a sore throat, right otalgia and painful vesicle on the right auricle. Herpetic vesicles were present on the right soft palate and arytenoid. She also reported loss of hearing in the right ear but there was no facial palsy. The serum antibody titer for herpes zoster was significantly elevated, and the cerebrospinal fluid showed pleocytosis. She was diagnosed as having herpes zoster involving the vestibulocochlear nerve and glossopharyngeal nerve. She was treated with intravenous acyclovir and satellite ganglion block. She did not have any residual signs. The other patient, a 44-year-old woman, complained of a sore throat, hoarseness and difficulty in swallowing. She had no skin rash, but there was a single vesicle on the left arytenoid. Physical examination revealed poor elevation of soft palate on the left side, but gag reflex was preserved. The serum antibody titer for herpes zoster was significantly elevated. She was diagnosed as having herpes zoster involving vagus nerve. She was treated with intravenous acyclovir for 7 days. She did not have any residual sign. In cases of unilateral cranial nerve palsy with pain, herpes zoster should be considered, and serum antibody titer for herpes zoster should be evaluated.

Resection of an orbital tumor with coronal incision and frontal sinus fenestration

Saito Hideyuki, Araki Koji, Ozawa Hiroyuki, Takahashi Yuji

Practica Oto-Rhino-Laryngologica 95 ( 7 ) 715 - 718 2002

ISSN 0032-6313

A case of orbital tumor is reported. A 52-year-old man consulted our hospital with left exopthalmus and impaired vision. On opthalmologic exmination, left exopthalmos in Hertel statometer, left impaired visual acuity and degeneration of retina in superolateral region of the optic disk of his left eye were noted. Magnetic resonance imaging (MRI) demonstrated a tumor with clear margin in the retro bulbar space. He was referred to our oto-rhino- laryngological section for surgery. At surgery, coronal incision was made and the extended lateral orbitotomy was made with fenestration of the frontal sinus. The tumor was easily removed without any complication on visual acuity and eye-ocular movement. We conclude that the approach with coronal incision and frontal sinus fenestration is useful for resection of orbital tumor.

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