Details of a Researcher - Ozawa, Hiroyuki

Papers - Ozawa, Hiroyuki

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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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