Faculty Profiles - Ando Mizuo

Papers - Ando Mizuo

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Survey of pharyngeal foreign bodies in Japan: An ecological study using the nationwide claims data Reviewed International journal

Shintaro Tanaka, Kensuke Uraguchi, Etsuji Suzuki, Naomi Matsumoto, Munechika Tsumura, Shohei Fujimoto, Shotaro Miyamoto, Takashi Yorifuji, Mizuo Ando

International Journal of Pediatric Otorhinolaryngology 184 112055 - 112055 2024.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

OBJECTIVE: Pharyngeal foreign bodies (PFBs) are a prevalent disease affected by food culture and dietary habits, with fish bones as the leading cause. Most studies were limited to specific regions, and a nationwide survey was not conducted in Japan. In this ecological study, we aimed to conduct a nationwide analysis of outpatient PFB cases in Japan over three years, focusing on seasonal trends, sex- and age-stratified cases, and regional differences. METHODS: We used the National Database of Health Insurance Claims and Specific Health Checkups of Japan open data from April 2019 to March 2022. The case data were analyzed by month, age, sex, and prefecture. Additionally, we calculated the standardized claim ratios (SCRs) for each prefecture and investigated the association between dietary habits, food culture, and SCR of PFBs using a two-level linear regression model. RESULTS: We analyzed a total of 164,337 outpatient PFB cases in Japan, revealing an average incidence rate of 45.6 per 100,000 persons. The seasonal trend revealed a peak in July each year from 2019 to 2021, confirming seasonality in PFB incidents. Children reported a higher incidence rate. Living west of Japan and expenditure on fish and shellfish had a strongly positive association with the SCR of PFBs. CONCLUSION: Our nationwide survey reveals that, even within Japan, there were regional variations influenced by food culture and dietary habits. The data showed that PFB incidence was higher among children, highlighting the need for preventive education. LEVEL OF EVIDENCE: Level 3.

DOI： 10.1016/j.ijporl.2024.112055

Endoscopic Transpterygoid Repair of Sphenoid Sinus Meningocele: A Comprehensive Case Report and Literature Review. Reviewed International journal

Aiko Shimizu, Seiichiro Makihara, Ryoji Imoto, Koji Hirashita, Mizuo Ando

Auris, nasus, larynx 51 ( 5 ) 875 - 879 2024.8

Language：English Publishing type：Research paper (scientific journal)

We report a challenging and uncommon case involving a 53-year-old Japanese man with cerebrospinal fluid (CSF) leakage caused by a meningocele in the lateral recess of the sphenoid sinus. Our innovative treatment approach involved a combination of transpterygoid and endoscopic modified medial maxillectomy techniques, with special emphasis on the preservation of the sphenopalatine artery. This strategic preservation was pivotal to the successful use of the ipsilateral nasoseptal flap for reconstruction, which played a crucial role in the prevention of postoperative CSF leakage. Otolaryngologists and neurosurgeons collaborated to perform the bath-plugging technique; effective collaboration was instrumental to the success of the procedure. This report highlights significant advancement from conventional frontal craniotomy to a more sophisticated endoscopic technique, shows the importance of meticulous surgical planning and execution, emphasizes careful preservation of critical anatomical structures during complex neurosurgical and otolaryngological procedures, and underscores the evolving landscape of surgical approaches for managing complex medical conditions.

DOI： 10.1016/j.anl.2024.08.003

Shifting paradigms in endoscopic sinus surgery: a comprehensive analysis from Japan's national database. Reviewed International journal

Seiichiro Makihara, Kensuke Uraguchi, Shohei Fujimoto, Aiko Shimizu, Shin Kariya, Mitsuhiro Okano, Takashi Yorifuji, Mizuo Ando

Acta oto-laryngologica 1 - 6 2024.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: In 2013, Japan established a standardized classification system for categorizing endoscopic sinus surgery (ESS) into types I-V, yet no evaluation has been conducted thereof. OBJECTIVE: We assessed the ESS trends and status in Japan, focusing on outpatient and inpatient surgeries. MATERIAL AND METHODS: This descriptive retrospective cohort study used Japan's National Database of Health Insurance Claims and Specific Health Checkups between 2014 and 2021. The distribution of ESS types I-V and outpatient and inpatient surgeries was analysed, along with age groups and regional differences, focusing on ESS type III. RESULTS: Overall, 427,813 ESS procedures were performed, with types III and IV being most common. Outpatient ESS type III increased substantially compared to inpatient surgeries. Younger individuals favoured outpatient ESS type III over inpatient surgeries, with substantial regional variations across prefectures. CONCLUSIONS AND SIGNIFICANCE: The adoption of a standardized ESS classification in Japan has facilitated a detailed understanding of surgical trends. The shift toward outpatient surgeries, especially for type III ESS, aligns with global trends toward minimally invasive procedures and reflects changing patient preferences and healthcare delivery practices. Consequently, continuous monitoring and research are crucial for adapting surgical practices to the evolving healthcare needs and patient expectations.

DOI： 10.1080/00016489.2024.2389179

Exploring factors influencing the hearing test and hearing aid adoption among Japanese older adults: Implications of recognizing the hearing loss-dementia relationship. Reviewed International journal

Ichiro Fukumasu, Yuko Kataoka, Takahiro Tabuchi, Kentaro Egusa, Mizuo Ando

Auris, nasus, larynx 51 ( 4 ) 822 - 827 2024.8

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The hearing aid adoption rate among older adults in Japan is lower than that in other developed countries. Herein, a survey was conducted to identify this bottleneck and develop countermeasures. This study aimed to examine whether raising awareness of the relationship between hearing loss and dementia is significant for hearing tests and adopting hearing aids. METHODS: A questionnaire was administered to participants aged 65 or older who visited a general hospital to determine the background factors (1) for a recent history of hearing tests, (2) for the desire to visit an otolaryngologist and have a hearing test, (3) for recognizing the hearing loss-dementia relationship, and (4) for adopting hearing aids. RESULTS: A total of 517 patients (mean age, 78.06; SD 6.97), representing 2.4% of the region's older-adult population, participated in the survey. A history of hearing tests within five years was significantly associated with recognizing the hearing loss-dementia relationship (adjusted OR 2.36, 95% CI 1.49-3.72). The desire to visit an otolaryngologist or have a hearing test was significantly associated with recognizing the hearing loss-dementia relationship (adjusted OR 1.70, 95% CI 1.02-2.85). Moreover, 39.3% were aware of the hearing loss-dementia relationship. The significant associated factors were being female (OR 2.50, 95% CI 1.64-3.81) and having interpersonal hobbies (OR 1.66, 95% CI 1.11-2.49). The significant background factors for adopting hearing aids were older age (OR 6.95, 95% CI 1.90-25.40), self-reported severe hearing impairment (OR 5.49, 95% CI 2.55-11.80), and living alone (OR 2.63, 95% CI 1.18-5.89). Recognizing the hearing loss-dementia relationship was not a significant factor. CONCLUSION: Raising awareness of the hearing loss-dementia relationship was not associated with adopting hearing aids for self-reported hearing impairments. However, it may be associated with otolaryngology visits and hearing tests. Thus, steps like hearing screening for older adults are also essential.

DOI： 10.1016/j.anl.2024.07.001

A Rare Subglottic Pleomorphic Adenoma: Magnetic Resonance Findings. Reviewed

Chieko Furukawa, Tomoyasu Tachibana, Tetsuji Nobuhisa, Yuichiro Kanie, Yoji Wani, Jun-Ya Matsumoto, Akifumi Kariya, Asuka Sato, Iichiro Ishikawa, Yuto Naoi, Mizuo Ando

Acta medica Okayama 78 ( 4 ) 331 - 335 2024.8

Language：English Publishing type：Research paper (scientific journal)

No previous study has published magnetic resonance imaging (MRI) findings for a subglottic pleomorphic adenoma. Here, we describe the case of a 62-year-old man with a subglottic pleomorphic adenoma. Endoscopic findings revealed a smooth-surfaced tumor arising from the subglottic posterior wall. MRI revealed the lesion as an isointense region on T1-weighted images, which was homogeneously enhanced. This lesion showed a heterogeneously hyperintense region on T2-weighted images. Diffusion-weighted imaging (DWI) showed slightly high intensity in the same area, with a normal or only slightly high apparent diffusion coefficient (ADC). Laryngomicrosurgery was performed for transoral excision of the subglottic tumor, resulting in a postsurgical diagnosis of pleomorphic adenoma.

DOI： 10.18926/AMO/67549

Middle-Ear Salivary Gland Choristoma with Congenital, Single-Sided Hearing Loss. Reviewed

Yuichiro Tominaga, Akiko Sugaya, Shin Kariya, Aiko Shimizu, Yuko Kataoka, Mizuo Ando

Acta medica Okayama 78 ( 4 ) 349 - 355 2024.8

Language：English Publishing type：Research paper (scientific journal)

Middle-ear salivary gland choristoma (SGCh) is a rare, benign tumor that causes conductive hearing loss owing to middle-ear morphological abnormalities. Early diagnosis is challenging, and surgical resection is indispensable for a definitive diagnosis. We report the case of a 3-year-old boy diagnosed with middle-ear SGCh during the follow-up period for left-sided hearing loss discovered at newborn hearing screening (NHS). Long-term follow-up after the NHS result, subsequent computed tomography/magnetic resonance imaging, and surgical resection led to its relatively early diagnosis and treatment.

DOI： 10.18926/AMO/67554

Pneumocephalus with Inverted Papilloma in the Frontoethmoidal Sinus: Case Report and Literature Review. Reviewed

Seiichiro Makihara, Yoshihiro Otani, Kensuke Uraguchi, Sawako Ono, Aiko Shimizu, Ryosuke Ikemachi, Yosuke Okazaki, Tomoyuki Ota, Hiroshi Matsumoto, Shotaro Miyamoto, Munechika Tsumura, Seiya Hayashi, Michiari Umakoshi, Koji Hirashita, Mizuo Ando

Acta medica Okayama 78 ( 4 ) 337 - 343 2024.8

Language：English Publishing type：Research paper (scientific journal)

Here, we describe the unique case of a pneumocephalus originating from an inverted papilloma (IP) in the frontoethmoidal sinus. A 71-year-old man with diabetes presented with headaches and altered consciousness. Imaging revealed the pneumocephalus together with bone destruction in the left frontal sinus. He underwent simultaneous endoscopic endonasal and transcranial surgery using an ORBEYE exoscope. Pathological diagnosis of the tumor confirmed IP. Post-surgery, the pneumocephalus was significantly resolved and the squamous cell carcinoma antigen level, which had been elevated, decreased. This case underscores the importance of a multidisciplinary approach and innovative surgical methods in treating complex sinonasal pathologies.

DOI： 10.18926/AMO/67550

Neurectomy for allergic rhinitis in Japan: Increasing trends and surgeon preferences. Reviewed International journal

Seiichiro Makihara, Kei Hosoya, Kensuke Uraguchi, Yohei Maeda, Taro Komachi, Takashi Yorifuji, Mizuo Ando, Shoji Matsune, Kimihiro Okubo

Auris, nasus, larynx 51 ( 5 ) 834 - 839 2024.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: There is no consensus on the optimal surgical technique for allergic rhinitis (AR). Furthermore, the appropriateness of surgical intervention in children and older individuals remains debatable. This study aimed to analyze trends and patterns in the surgical management of AR in Japan, focusing on parasympathetic neurectomy. METHODS: Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB), we conducted a comprehensive review of procedures performed between April 2014 and March 2022. In addition, a cross-sectional survey targeting otolaryngologists across Japan was conducted to gather insights into surgical preferences and practices. RESULTS: The NDB data showed an increasing trend in neurectomies, with the most frequent age group being 25-29 years; the procedure was also performed in pediatric and older patients. The survey among otolaryngologists indicated that 58.2 % of surgeons preferred peripheral branch neurectomy of the posterior nasal nerve. The findings of this study also indicated a cautious approach toward conducting these procedures in children, with 51.2 % of surgeons considering patients less than 18 years of age unsuitable for the procedure. CONCLUSION: This study highlighted a shift toward simple and minimally invasive surgical methods, such as peripheral branch neurectomy, in Japan. However, further research is needed to understand the long-term outcomes and refine the surgical techniques. The findings of this study also emphasized the need for age-specific considerations when treating pediatric and older patients with AR.

DOI： 10.1016/j.anl.2024.07.005

Role of nasal polyp-derived innate lymphoid cells in staphylococcal enterotoxin-induced cellular responses. Reviewed International journal

Kengo Kanai, Aiko Oka, Shin Kariya, Tazuko Fujiwara, Takaya Higaki, Seiichiro Makihara, Takenori Haruna, Maki Akamatsu, Kazunori Nishizaki, Mizuo Ando, Mitsuhiro Okano

Allergology international : official journal of the Japanese Society of Allergology 73 ( 3 ) 477 - 480 2024.7

A case of an electric toothbrush tip penetrating from the oral cavity to the submandibular gland. Reviewed International journal

Naoki Akisada, Takuma Makino, Yuto Naoi, Yoshinori Taguchi, Yuto Moriwaki, Mizuo Ando

Clinical case reports 12 ( 6 ) e8987 2024.6

Pediatric otitis media in Japan: A nationwide longitudinal study of the pre- and post-pneumococcal conjugate vaccine eras born in 2001 and 2010. Reviewed International journal

Kensuke Uraguchi, Naomi Matsumoto, Toshiharu Mitsuhashi, Soshi Takao, Seiichiro Makihara, Mizuo Ando, Takashi Yorifuji

Vaccine 42 ( 19 ) 4081 - 4087 2024.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Otitis media (OM) is a prevalent respiratory disease in children and poses significant public health challenges due to its impact on child health and economic burdens. However, there have no nationwide epidemiological studies conducted in Japan. This study investigates the epidemiological trends of OM in Japan, taking into account the impact of the 7-valent pneumococcal conjugate vaccine (PCV7) introduction. METHOD: This study was retrospective cohort study using secondary data on the nationwide longitudinal birth cohort. This survey followed two cohorts born in 2001 (pre-PCV era) and 2010 (post-PCV era) until the age of 9. Every year, parents were surveyed about their children's health status, including occurrences of OM. The annual period prevalence and cumulative incidence of OM were assessed in this study, and the two cohorts were compared using a modified Poisson regression model adjusted environmental factors with the 2001 cohort as reference. RESULT: The study included 47,015 children from the 2001 cohort and 38,554 from the 2010 cohort. Peak annual period prevalence of OM varied by era. Cumulative incidence was 13.8 % for the 2001 cohort and 18.5 % for the 2010 cohort by 1.5 years of age and 28.9 % and 33.3 %, respectively, by 3.5 years of age. In particular, from the fourth survey onward, covering ages 2.5-3.5 years, a shift was observed from an increased risk to a decreased risk of OM. CONCLUSION: This nationwide longitudinal study emphasizes variations in OM epidemiology across Japan over time, with changes potentially influenced by the introduction of PCV7. In this study, due to the absence of individual PCV7 vaccination data, the effect of PCV7 was estimated based on the vaccination rate at the population level. The results suggest a notable decrease in the incidence of OM in later years, aligning with the increased uptake of PCV7.

DOI： 10.1016/j.vaccine.2024.05.020

Upper airway obstruction due to congenital epiglottic cyst: Report of two cases. Reviewed International journal

Kensuke Uraguchi, Yuichiro Otsuka, Hidenori Marunaka, Mizuo Ando

Congenital anomalies 64 ( 4 ) 184 - 185 2024.5

Comprehensive genomic profiling of salivary gland carcinoma: Analysis of the Center for Cancer Genomics and Advanced Therapeutics database in Japan. Reviewed International journal

Sho Iwaki, Daisuke Kawakita, Toshitaka Nagao, Yuichiro Tada, Yoshitaka Honma, Mizuo Ando, Takuma Matoba, Kiyoshi Minohara, Satsuki Nakano, Takayuki Murase, Shinichi Iwasaki, Hiroshi Inagaki

International journal of cancer 155 ( 5 ) 871 - 882 2024.4

Language：English Publishing type：Research paper (scientific journal)

Comprehensive information on genetic alterations in salivary gland cancer (SGC) is limited. This study aimed to elucidate the genetic and clinical characteristics of patients with SGC using the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, a Japanese national genomic database. We analyzed data of 776 patients with SGC registered in the C-CAT database between June 1, 2019, and June 30, 2023. Adenoid cystic carcinoma was the most common histologic type, followed by salivary duct carcinoma (SDC) and adenocarcinoma not otherwise specified. Genetic data of 681 patients receiving FoundationOne® CDx were analyzed. We identified specific features of the combination of TP53 and CDKN2A alterations among the histological types. Specific LYN amplification was mainly detected in carcinoma ex pleomorphic adenoma and myoepithelial carcinoma. For SDC, the frequency of ERBB2 and BRAF alterations were higher in cases with metastatic lesions than in those with primary lesions. Although 28.6% patients were offered recommended treatment options, only 6.8% received the recommended treatments. This study highlights the differences in genetic alterations among the histological types of SGC, with comprehensive genomic profiling tests revealing lower drug accessibility. These findings could contribute to the development of personalized treatment for patients with SGC.

DOI： 10.1002/ijc.34972

CD106 in tumor-specific exhausted CD8+ T cells mediates immunosuppression by inhibiting TCR signaling. Reviewed International journal

Yuto Naoi, Takao Morinaga, Joji Nagasaki, Ryo Ariyasu, Youki Ueda, Kazuo Yamashita, Wenhao Zhou, Shusuke Kawashima, Katsushige Kawase, Akiko Honobe-Tabuchi, Takehiro Ohnuma, Tatsuyoshi Kawamura, Yoshiyasu Umeda, Yu Kawahara, Yasuhiro Nakamura, Yukiko Kiniwa, Osamu Yamasaki, Satoshi Fukushima, Masahito Kawazu, Yutaka Suzuki, Hiroyoshi Nishikawa, Toyoyuki Hanazawa, Mizuo Ando, Takashi Inozume, Yosuke Togashi

Cancer research 84 ( 13 ) 2109 - 2122 2024.4

Language：English Publishing type：Research paper (scientific journal)

T cell exhaustion is a major contributor to immunosuppression in the tumor microenvironment (TME). Blockade of key regulators of T cell exhaustion, such as PD-1, can reinvigorate tumor-specific T cells and activate anti-tumor immunity in various types of cancer. Here, we identified that CD106 was specifically expressed in exhausted CD8+ T cells in the TME using single-cell RNA-sequencing. High CD106 expression in the TME in clinical samples corresponded to improved response to cancer immunotherapy. CD106 in tumor-specific T cells suppressed anti-tumor immunity both in vitro and in vivo, and loss of CD106 in CD8+ T cells suppressed tumor growth and improved response to PD-1 blockade. Mechanistically, CD106 inhibited T-cell receptor (TCR) signaling by interacting with the TCR/CD3 complex and reducing its surface expression. Together, these findings provide insights into the immunosuppressive role of CD106 expressed in tumor-specific exhausted CD8+ T cells, identifying it as a potential biomarker and therapeutic target for cancer immunotherapy.

DOI： 10.1158/0008-5472.CAN-23-0453

Combined simultaneous endoscopic endonasal and transcranial surgery using high-definition three-dimensional exoscope for malignant tumors of the anterior skull base. Reviewed International journal

Seiichiro Makihara, Yoshihiro Otani, Kensuke Uraguchi, Aiko Shimizu, Aya Murai, Takaya Higaki, Naoki Akisada, Shohei Fujimoto, Takuma Makino, Joji Ishida, Kentaro Fujii, Takao Yasuhara, Tomoyuki Ota, Hiroshi Matsumoto, Mizuo Ando

Head & neck 46 ( 5 ) 1074 - 1082 2024.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Advanced surgical interventions are required to treat malignancies in the anterior skull base (ASB). This study investigates the utility of endoscopic endonasal and transcranial surgery (EETS) using a high-definition three-dimensional exoscope as an alternative to traditional microscopy. METHODS: Six patients with carcinomas of varying histopathologies underwent surgery employing the EETS maneuver, which synchronized three distinct surgical modalities: harvesting of the anterolateral thigh flap, initiation of the transnasal technique, and initiation of the transcranial procedure. RESULTS: The innovative strategy enabled successful tumor resection and skull base reconstruction without postoperative local neoplastic recurrence, cerebrospinal fluid leakage, or neurological deficits. CONCLUSION: The integration of the exoscope and EETS is a novel therapeutic approach for ASB malignancies. This strategy demonstrates the potential of the exoscope in augmenting surgical visualization, enhancing ergonomics, and achieving seamless alignment of multiple surgical interventions. This technique represents a progressive shift in the management of these complex oncological challenges.

DOI： 10.1002/hed.27724

Various arrangements of pharyngeal flap in soft palate reconstruction after cancer treatment. Reviewed International journal

Hiroshi Matsumoto, Tomoyuki Ota, Motoi Kato, Takuma Makino, Seiichiro Makihara, Mizuo Ando, Yoshihiro Kimata

Head & neck 46 ( 7 ) 1573 - 1581 2024.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: The pharyngeal flap (PF) is useful for reconstruction of soft palate defects, but effective arrangements of PF for various types of soft palate defects are controversial. Here, we classify three types of soft palate defects and discuss the arrangements of PF and their functional prognosis. METHODS: Reconstruction was performed based on the classification of the defects. Clinical details were collected, and postoperative function was analyzed. RESULTS: Eight patients were included in the study. The defect sizes ranged from 25 (width) × 40 (depth) to 40 × 60 mm. Six patients underwent pharyngeal flap reconstruction with free-flap reconstruction, and two underwent pharyngeal flap reconstruction. The pharyngeal flap was harvested at the maximum width of the posterior pharyngeal wall, ranging from 25 to 40 mm in length. Eating and speaking functions were maintained in all patients. CONCLUSIONS: Good postoperative function can be maintained by narrowing the velopharyngeal space with a pharyngeal flap.

DOI： 10.1002/hed.27712

Two Cases of Malignant External Otitis That Were Successfully Treated by Multidisciplinary Collaboration Reviewed

Akifumi Kariya, Tomoyasu Tachibana, Kazunori Kuroda, Yasutoshi Komatsubara, Mizuo Ando

Practica Oto-Rhino-Laryngologica 117 ( 3 ) 219 - 224 2024

Publishing type：Research paper (scientific journal)

Malignant external otitis (MEO) is an intractable disease with a high mortality rate, despite advances in the development of antimicrobial agents. MEO mainly requires administration of antibiotics, local treatment, and strict management of diabetes mellitus, which takes a long time. We present 2 cases of MEO in elderly patients that were successfully treated by multidisciplinary collaboration. The two patients were referred to our department after conservative treatment failed to improve their condition. In both cases, remission was achieved with hospitalization and multidisciplinary treatment for diabetes mellitus, impaired renal function, activities of daily living (ADL), and cognitive function. As one of the factors contributing to the poor prognosis of MEO, treatment can often not be completed in the elderly, who are more likely to show deterioration of ADL and cognitive functions. In addition, MEO is often not well known, not only to patients, but also to physicians. Awareness of this disease and multidisciplinary treatment are essential to improve the outcomes of MEO.

DOI： 10.5631/jibirin.117.219

Chronic rhinosinusitis possibly associated with decreased lung function in chronic cough patients. Reviewed International journal

Pengfei Zhao, Shin Kariya, Takaya Higaki, Seiichiro Makihara, Toru Rikimaru, Mitsuhiro Okano, Mizuo Ando

Brazilian journal of otorhinolaryngology 90 ( 4 ) 101424 - 101424 2024

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: The purpose of this study is to investigate the lung function in Chronic Rhinosinusitis (CRS) patients with Chronic Cough (CC). METHODS: A total of 1413 CC patients were retrospectively screened and 109 CRS patients with CC were enrolled. Lung function, Lund-Mackay Computed Tomography (CT) score, smoking status, peripheral blood eosinophil count, and immunoglobulin E concentration in serum samples, and Sino-Nasal Outcome Test were examined. Normal control subjects are also recruited. RESULTS: The Forced Expiratory Volume in 1 second (FEV1.0), Percent Predicted FEV1.0, and FEV1.0/Forced Vital Capacity (FVC) ratio in the patients were significantly low as compared with the control subjects. The FEV1.0/FVC ratio was negatively correlated with the Lund-Mackay CT scores of the patients with a high CT score. CONCLUSIONS: The CRS patients with CC should be investigated with lung function. In addition, the multidisciplinary evaluation including a pulmonologist is needed to manage the CRS patients with CC. LEVEL OF EVIDENCE: Level 4.

DOI： 10.1016/j.bjorl.2024.101424

The discovery of acatalasemia (lack of catalase in the blood) and its significance in human genetics. Invited Reviewed

Mizuo Ando, Kunihiro Fukushima, Kazunori Nishizaki

Proceedings of the Japan Academy. Series B, Physical and biological sciences 100 ( 7 ) 353 - 367 2024

Language：English Publishing type：Research paper (scientific journal)

Catalase, a heme-containing antioxidant enzyme, was once considered essential for human survival. It is widely distributed in the human body and is particularly abundant in red blood cells. The term "acatalasemia" first appeared in the Proceedings of the Japan Academy in 1951, drawing global attention to families genetically deficient in catalase. This deficiency not only altered the significance of catalase but also played a pioneering role in human genetics during an era of limited genetic methodology. In this article, we examine the discovery of acatalasemia by an otolaryngologist during surgery on an 11-year-old girl. This remarkable journey led to epoch-making research spanning biochemistry, hematology, and human genetics.

DOI： 10.2183/pjab.100.024

Association Between Clinical Remission of Infantile-Onset Allergic Rhinitis During the School-Age Period and the Type of Housing: A Longitudinal Population-Based Japanese Study. Reviewed International journal

Kensuke Uraguchi, Naomi Matsumoto, Toshiharu Mitsuhashi, Soshi Takao, Seiichiro Makihara, Mizuo Ando, Takashi Yorifuji

Journal of pediatric health care : official publication of National Association of Pediatric Nurse Associates & Practitioners 2023.12

Language：English Publishing type：Research paper (scientific journal)

This study investigated the association between housing type and clinical remission of infantile-onset allergic rhinitis (AR) in 53,575 children born in 2001 in Japan. Infantile-onset AR was defined as the presence of AR symptoms reported between ages 1.5 and 4.5 years, and remission was assessed between ages 10 and 12. The type of housing was categorized into detached houses and multi-unit residential buildings with 1-2, 3-5, or ≥6 floors. Among the 4,352 infantile-onset AR, 42.9% experienced remission. Notably, living in multi-unit residential buildings, particularly those with 1-2 and ≥6 floors, was positively associated with AR remission.

DOI： 10.1016/j.pedhc.2023.11.011

Primary Thyroid Lymphoma: Clinical Factors Predicting the Possibility of Diffuse Large B-Cell Lymphoma. Reviewed International journal

Akifumi Kariya, Tomoyasu Tachibana, Yasushi Hiramatsu, Yoji Wani, Jun-Ya Matsumoto, Chieko Furukawa, Asuka Sato, Yuto Naoi, Yorihisa Orita, Yasuharu Sato, Mizuo Ando

Ear, nose, & throat journal 1455613231218130 - 1455613231218130 2023.12

Language：English Publishing type：Research paper (scientific journal)

Aims: Among primary thyroid lymphomas (PTLs), diffuse large B-cell lymphoma (DLBCL) has a poorer prognosis than other indolent lymphomas such as mucosa-associated lymphoid tissue (MALT) or follicular lymphoma (FL). However, the clinical differences between DLBCL and indolent lymphoma remain unclear. Therefore, this retrospective study on PTL was aimed at investigating the clinical differences between DLBCL and indolent lymphomas and identifying the factors differentiating DLBCL from indolent lymphomas. Materials and Methods: Medical records of 28 patients diagnosed with PTL and treated at our institution between 2005 and 2022 were retrospectively analyzed. Data on the following clinical variables were extracted: sex, age, symptoms (pain and dysphagia), ultrasonographic appearance patterns, the presence of airway stenosis on computed tomography and laryngeal endoscopy, blood test results, disease stage, and pathological diagnosis. Results: In all, 13 patients were histologically diagnosed with DLBCL, 12 with MALT lymphoma, and 3 with FL. Significant differences in disease-specific survival rates were evident between the DLBCL and indolent lymphoma groups (68.2 vs 100%, P = .043). High lactate dehydrogenase levels (>230 U/mL) and airway stenosis were observed only in patients with DLBCL. Multivariate analysis identified that the presence of a linear echoic strand pattern and the absence of an echoic nodular pattern on ultrasound were independently associated with DLBCL (P = .0497 and .012, respectively). Conclusion: DLBCL can cause airway stenosis. The linear echogenic strand pattern and the absence of a nodular pattern should be recognized as predictive factors of DLBCL.

DOI： 10.1177/01455613231218130

Ultra-high combined positive score and high serum albumin are favorable prognostic biomarkers for immune checkpoint inhibitors in head and neck squamous cell carcinoma. Reviewed International journal

Yuki Saito, Kenya Kobayashi, Osamu Fukuoka, Toshihiko Sakai, Koji Yamamura, Mizuo Ando, Kenji Kondo

Head & neck 2023.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Biomarkers that predict response to immune checkpoint inhibitor (ICI) in recurrent metastatic squamous cell carcinoma of the head and neck (RMHNSCC) are not well known. METHODS: We prospectively measured the combined positive score (CPS) and administered ICI to patients with RMHNSCC. RESULTS: Of 51 patients, 23 patients had a CPS <20 and 12 patients (23.5%) had a CPS ≥90. CPS showed a negative correlation with serum albumin. Survival analysis showed a 2-year survival rate of 24.1%. In multivariate analysis, CPS ≥90 (HR 0.3026, p = 0.02614) and albumin >3.5 (HR 0.3463, p = 0.01354) were the significant factors and plus chemotherapy (HR 0.4648, p = 0.07632) was not significant. Seven patients (14%) with CPS ≥90 and albumin >3.5 showed a 2-year survival rate of 66. 7%. CONCLUSIONS: CPS ≥90 and albumin >3.5 cases are a subgroup of RMHNSCC that respond extremely well to ICI.

DOI： 10.1002/hed.27576

Cochlear Implantation in the Poorer-Hearing Ear Is a Reasonable Choice. Reviewed

Ryotaro Omichi, Shin Kariya, Yukihide Maeda, Kunihiro Fukushima, Yuko Kataoka, Akiko Sugaya, Kazunori Nishizaki, Mizuo Ando

Acta medica Okayama 77 ( 6 ) 589 - 593 2023.12

Language：English Publishing type：Research paper (scientific journal)

Choosing the optimal side for cochlear implantation (CI) remains a major challenge because of the lack of evidence. We investigated the choice of the surgery side for CI (i.e., the better- or poorer-hearing ear) in patients with asymmetric hearing. Audiological records of 74 adults with a unilateral hearing aid who had undergone surgery at Okayama University Hospital were reviewed. The definition of 'better-hearing ear' was the aided ear, and the unaided ear was considered the poorer-hearing ear. We performed a multiple regression analysis to identify potential predictors of speech recognition performance after unilateral CI in the patients. Fifty-two patients underwent CI in the poorer-hearing ear. The post-Ci bimodal hearing rate was far higher in the poorer-ear group (77.8% vs. 22.2%). A multivariate analysis revealed that prelingual hearing loss and the patient's age at CI significantly affected the speech recognition outcome (beta coefficients: 24.6 and -0.33, 95% confidence intervals [11.75-37.45] and [-0.58 to -0.09], respectively), but the CI surgery side did not (-6.76, [-14.92-1.39]). Unilateral CI in the poorer-hearing ear may therefore be a reasonable choice for adult patients with postlingual severe hearing loss, providing a greater opportunity for postoperative bimodal hearing.

DOI： 10.18926/AMO/66150

p16 status and high-risk human papilloma virus infection in squamous cell carcinoma of the nasal vestibule. Reviewed International journal

Koji Yamamura, Yuki Saito, Kenya Kobayashi, Toshiyuki Mukai, Osamu Fukuoka, Ken Akashi, Masafumi Yoshida, Mizuo Ando, Tatsuya Yamasoba

Auris, nasus, larynx 50 ( 6 ) 942 - 947 2023.12

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The status of human papilloma virus (HPV) and p16 overexpression for nasal vestibule squamous cell carcinoma (NVSCC) is unclear. The purpose of this retrospective study was to analyze the presence of HPV and the role of p16 overexpression as a surrogate marker in cases of NVSCC. METHODS: Retrospective analysis was performed on patients who were diagnosed and treated for NVSCC at the University of Tokyo Hospital, Japan. p16 immunohistochemistry was considered positive with at least moderate staining intensity and diffuse staining (≥75% of tumor cells), according to the 8th edition of the American Joint Commission on Cancer. HPV-DNA testing was performed using multiplex polymerase chain reaction. RESULTS: Five patients were included in the study. Ages ranged from 55 to 78 years; there were two men and three women; two had T2N0, and three had T4aN0. Surgery was performed in one case, surgery plus radiation therapy (RT) in one case, and chemoradiation therapy (CRT) in three cases. Four of the five tumors showed p16 overexpression. One of five cases had an HPV-16 genotype. The mean follow-up period was 73 months, and all the patients survived. One patient with p16-negative carcinoma had local recurrence and underwent salvage surgery. Of the four patients with p16-positive carcinoma, one with CRT and one with surgery plus RT, each had delayed cervical lymph node metastasis, which was salvaged with neck dissection subsequent RT. CONCLUSIONS: In NVSCC, four of the five cases were p16-positive, and one was high-risk HPV infection.

DOI： 10.1016/j.anl.2023.03.008

Risk Factors for Anterior Skull Base Injury in Endoscopic Sinus Surgery Reviewed International journal

Seiichiro Makihara, Kensuke Uraguchi, Tomoyuki Naito, Aiko Shimizu, Aya Murai, Takaya Higaki, Yohei Noda, Shin Kariya, Mitsuhiro Okano, Mizuo Ando

Cureus 15 ( 11 ) e49273 2023.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Objectives This retrospective study aimed to investigate the relationships between the Keros classification, the Gera classification, the vertical height of the posterior ethmoid roof (ER), and anterior ethmoidal artery (AEA) types in Japanese patients. Methods We investigated the computed tomography (CT) slices of paranasal sinuses (120 sides) of 60 patients; measured the cribriform plate (CP) depth, lateral lamella CP angle (LLCPA), and vertical height of the lateral ER from the hard palate (LERHP) at the coronal plane of the posterior ethmoidal artery (PEA); and reviewed the AEA types, whether floating or non-floating. Results CP depth was positively correlated with LLCPA (r=0.63; p<0.01) and the height of LERHP (r=0.19; p<0.05). The height of the LERHP in females was significantly lower than that in males. With increased CP depth, floating AEAs became prevalent (p<0.001). Conclusion In females, low height of the posterior ethmoid sinus roof, where cerebrospinal fluid (CSF) leaks occurred while penetrating the basal lamella, often existed; the heights positively correlated with the Keros classification in Japanese patients. The Keros and Gera classifications, AEA type, and posterior ER height do not individually constitute a complete risk assessment but may correlate, preventing major complications, such as CSF leak and orbital hemorrhage.

DOI： 10.7759/cureus.49273

Revision cochlear implant surgery in adults and children is a safe and effective technique: a retrospective single faculty study in Okayama University Hospital, Japan. Reviewed International journal

Akiko Sugaya, Shin Kariya, Kunihiro Fukushima, Ryotaro Omichi, Mizuo Ando

Acta oto-laryngologica 1 - 5 2023.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Cochlear implant (CI) surgery is a safe surgical technique, although some patients require revision CI surgery. AIMS/OBJECTIVES: This study investigated the cause and underlying reason of revision CI surgery as well as hearing outcomes in a single institution. PATIENTS AND METHODS: This retrospective study evaluated patients who underwent CI surgery between April 2006 to March 2022 (n = 351). Sex, aetiology of hearing loss (HL), age and period from initial CI surgery to reimplantation, cause of revision, and related factors were examined. RESULTS: Twelve patients (8 males, 4 females) received CI reimplantation. The revision surgery rate was 2.59% (3.15% children, 1.69% adults); the period from initial surgery to reoperation was 8.60 ± 6.56 years for 9 children with congenital HL and 15.27 ± 5.72 years for 3 adults with progressive HL. Device failure was the most common cause (n = 8), followed by infections (n = 2), advanced facial irritation symptoms (n = 1), and electrode slip-out (n = 1). Mean preoperative and postoperative CI thresholds were 44.0 ± 9.46 dBnHL and 39.19 ± 8.89 dBnHL (p < .068), respectively. CONCLUSION AND SIGNIFICANCE: Caregiver education, surgical technique advances, flap design, and extensive antibiotic use may decrease the revision surgery rate. The lack of post-revision deterioration of the hearing threshold contributed to well-being in patients with CI.

DOI： 10.1080/00016489.2023.2270701

Nasopharyngeal low-grade papillary schneiderian carcinoma with cervical metastasis. Reviewed International journal

Kensuke Uraguchi, Kenji Nishida, Takuma Makino, Seiichiro Makihara, Masahiro Tabata, Shin Kariya, Mizuo Ando

Auris, nasus, larynx 50 ( 5 ) 821 - 826 2023.10

Language：English

Low-grade papillary Schneiderian carcinoma (LGPSC) is a rare and newly described type of cancer arising from the Schneiderian epithelium. Owing to cellular atypia, it is difficult to differentiate this type from other papillomas and malignancies. Although this condition remains unclear, it is associated with mortality and recurrence. Therefore, treating physicians should be aware of the possibility of LGPSC for prompt diagnosis and treatment. In this article, we present an additional case of nasopharyngeal LGPSC with cervical lymph node metastasis and reviewed the 14 cases reported thus far in the literature. A 76-year-old female was referred to our department for detailed examination of nasopharyngeal and cervical lymph node tumors detected by positron emission tomography-computed tomography. Based on the biopsy of the nasopharyngeal tumor, we suspected LGPSC. Considering the clinical course and pathological findings, the patient was diagnosed with cervical lymph node metastasis through neck dissection. We performed radiotherapy for the primary lesion of the nasopharynx, which led to the disappearance of the tumor. After 13 months following the radiotherapy, the patient died from a recurrence of retroperitoneal liposarcoma without the recurrence of LGPSC.

DOI： 10.1016/j.anl.2022.12.010

Near-infrared photoimmunotherapy for salivary duct carcinoma. Reviewed International journal

Takuma Makino, Yasuharu Sato, Kensuke Uraguchi, Yuto Naoi, Yujiro Fukuda, Mizuo Ando

Auris, nasus, larynx 2023.9

Language：English

In Japan, near-infrared photoimmunotherapy (NIR-PIT) was introduced in 2021 as a treatment option for unresectable recurrent head and neck cancer. The treatment targets the epidermal growth factor receptor (EGFR), which is overexpressed in 80-90 % of head and neck squamous cell carcinoma (HNSCC). NIR-PIT should theoretically show therapeutic efficacy if EGFR is expressed, even in nonsquamous cell carcinomas (non-SCC). To the best of our knowledge, there are no case reports of NIR-PIT for non-SCC. We performed NIR-PIT in a patient with non-SCC of the head and neck region. After performing two NIR-PIT treatments, small free clusters of residual tumor cells were observed. Immunostaining in this specimen revealed EGFR expression in residual tumor cells. The residual tumor cells had been irradiated sufficiently to achieve necrosis. It is suggested that not only laser irradiation and expression of EGFR but also other factors are involved in the efficacy of this treatment. Further investigation for these other factors is warranted.

DOI： 10.1016/j.anl.2023.09.006

Summary of Japanese clinical practice guidelines for head and neck cancer - 2022 update edited by the Japan society for head and neck cancer. Reviewed International journal

Akihiro Homma, Mizuo Ando, Nobuhiro Hanai, Hiroyuki Harada, Yoshitaka Honma, Tomonori Kanda, Satoshi Kano, Daisuke Kawakita, Naomi Kiyota, Yoshiyuki Kizawa, Masahiro Nakagawa, Takenori Ogawa, Hirotaka Shinomiya, Takeshi Shinozaki, Motoyuki Suzuki, Tetsuya Tsuji, Koichi Yasuda, Sadamoto Zenda, Takeshi Kodaira, Tadaaki Kirita, Ken-Ichi Nibu

Auris, nasus, larynx 2023.7

Language：English Publishing type：Research paper (scientific journal)

The aim of the "Japanese Clinical Practice Guidelines for Head and Neck Cancer - 2022 Update" is to review the latest evidence regarding head and neck cancer and to present the current standard approaches for diagnosis and treatment. These evidence-based recommendations were created with the consensus of the Guideline Committee, which is composed of otorhinolaryngologists and head and neck surgeons, together with radiologists, radiation oncologists, medical oncologists, plastic surgeons, dentists, palliative care physicians, and rehabilitation physicians. These guidelines were created by the Clinical Practice Guideline Committee of the Japan Society for Head and Neck Cancer based on the "Head and Neck Cancer Treatment Guidelines 2018 Edition," and the revised draft was compiled after evaluation by the Assessment Committee and public comments. The 'Clinical questions and recommendations' section consists of 13 categories, and 59 clinical questions are described in total. Here we describe 6 clinical questions specific to other sets of guidelines with recommendations and comments.

DOI： 10.1016/j.anl.2023.07.003

Genome Doubling Shapes High-Grade Transformation and Novel EWSR1::LARP4 Fusion Shows SOX10 Immunostaining in Hyalinizing Clear Cell Carcinoma of Salivary Gland. Reviewed International journal

Kenya Kobayashi, Masahito Kawazu, Seiichi Yoshimoto, Toshihide Ueno, Go Omura, Yuki Saito, Mizuo Ando, Eigitsu Ryo, Airi Sakyo, Akihiko Yoshida, Yasushi Yatabe, Hiroyuki Mano, Taisuke Mori

Laboratory investigation; a journal of technical methods and pathology 103 ( 10 ) 100213 - 100213 2023.7

Language：English Publishing type：Research paper (scientific journal)

Hyalinizing clear cell carcinoma (HCCC) is a rare indolent malignant tumor of minor salivary gland origin with EWSR1::ATF1 rearrangement. Pathologically, the tumor cells possess a clear cytoplasm in a background of hyalinized stroma. Generally, the tumor cells are positive for p63 and p40 and negative for s100 and α-smooth muscle actin, suggesting that they differentiate into squamous epithelium and not into myoepithelium. In this study, we performed a detailed histopathological and genomic analysis of 6 cases of HCCC, including 2 atypical subtypes-a case of "high-grade transformation" and 1 "possessing a novel partner gene for EWSR1." We performed a sequential analysis of the primary and recurrent tumor by whole-exome sequencing, RNA sequencing, Sanger sequencing, and fluorescence in situ hybridization to investigate the effect of genomic changes on histopathology and clinical prognosis. A fusion gene involving the EWSR1 gene was detected in all cases. Five cases, including the "high-grade transformation," harbored a known EWSR1::ATF1 fusion gene; however, 1 case harbored a novel EWSR1::LARP4 fusion gene. This novel EWSR1::LARP4-fused HCCC has a SOX10-positive staining, which is different from the EWSR1::ATF1-fused HCCC. According to whole-exome sequencing and fluorescence in situ hybridization analysis, the "whole-genome doubling" and focal deletion involving CDKN2A, CDKN2B, and PTEN were detected in HCCC with "high-grade transformation." Conclusively, we identified a novel partner gene for EWSR1, LARP4, in indolent HCCC. Importantly, "high-grade transformation" and poor prognosis were caused by whole-genome doubling and subsequent genomic aberrations.

DOI： 10.1016/j.labinv.2023.100213

Association between handwashing and gargling education for children and prevention of respiratory tract infections: a longitudinal Japanese children population-based study Reviewed International journal

Kensuke Uraguchi, Toshiharu Mitsuhashi, Naomi Matsumoto, Soshi Takao, Seiichiro Makihara, Mizuo Ando, Takashi Yorifuji

European Journal of Pediatrics 182 ( 9 ) 4037 - 4047 2023.7

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

PURPOSE: A longitudinal study was conducted to examine the effects of handwashing and gargling education for children on the prevention of respiratory tract infections (RTIs) in children in Japan. METHODS: The study included 38,554 children born in 2010 who were enrolled in a longitudinal study. Information on children's hygiene education regarding handwashing and gargling was collected in a survey at the age of 3.5 years. Based on parents' reports of doctors' diagnoses, airway infections and influenza events in the 12-month duration before the survey were evaluated for RTIs at the ages of 4.5 and 9 years. Poisson regression with robust variance was performed to examine the effects of hygiene education on RTIs prevention. The supplementary analysis was stratified by household income. RESULTS: Children were categorized into different groups: 38% in the handwashing and gargling group, 29% in the handwashing group, 0.1% in the gargling group, and 9.7% in the no-education group. Exclusions were made for non-respondent children (23%) and those in the gargling group. Hygiene education was associated with decreased influenza at the age of 4.5 years in the handwashing (adjusted RR [aRR] = 0.8; 95% CI, 0.8-0.9) and handwashing and gargling groups (aRR = 0.8; 95% CI, 0.8-0.9) compared with no education. However, no preventive effects on airway infections at the age of 4.5 and 9, influenza at the age of 9, or hospitalization between the ages of 3.5 and 9 years were detected. Handwashing and gargling could significantly prevent influenza in low-income households (aRR = 0.7; 95% CI, 0.6-0.8). Conclusions: Gargling education was widespread and mostly combined with handwashing education in Japan. Hygiene education significantly affected prevention of influenza infections at the age of 4.5 years, especially in low-income households. WHAT IS KNOWN: • Previous intervention studies showed handwashing and gargling are effective in preventing respiratory tract infections. WHAT IS NEW: • We conducted a longitudinal study on handwashing and gargling education in Japanese children and found that handwashing and gargling were widely practiced together. • Handwashing and gargling education were related to a reduction in influenza, particularly in low-income households.

DOI： 10.1007/s00431-023-05062-5

Other Link： https://link.springer.com/article/10.1007/s00431-023-05062-5/fulltext.html

Endolymphatic Hydrops on Magnetic Resonance Imaging May Be an Independent Finding on Aging in Neurotologic Patients. Reviewed International journal

Yukihide Maeda, Katsuhide Kojima, Soshi Takao, Ryotaro Omichi, Shin Kariya, Mizuo Ando

Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 44 ( 7 ) 737 - 741 2023.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To clarify whether age impacts the development of endolymphatic hydrops (ELH) in neurotologic patients. Documentation of ELH in living patients on magnetic resonance imaging (MRI) allows analysis of patient age and formation of ELH, which is impossible by means of postmortem temporal bone pathology. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Fifty patients (100 ears) with top 3 diagnoses of definite Menière's disease, delayed ELH, or probable Menière's disease. INTERVENTIONS: Endolymph MRI after intravenous gadolinium injection and pure-tone audiometry. MAIN OUTCOME MEASURES: Cochlear and vestibular ELH confirmed by MRI. RESULTS: The prevalences of ears showing both cochlear and vestibular ELH were similar among age groups <30 years (30%), 30-59 years (25.9%), and ≥60 years (34.4%; p > 0.05; χ2 test). Using logistic regression modeling, mean hearing level at the six frequencies was positively associated with a higher risk of cochlear ELH (odds ratio, 1.3; 95% confidence interval, 1.1-1.5 per 10-dB increment). In the same regression model, age did not impact the outcome of cochlear ELH (odds ratio, 1.0; 95%confidence interval, 0.7-1.4 per 10-year increment). Age did not differ among ears with no ELH (mean ± standard deviation age, 48.6 ± 14.4 yr), ears with only cochlear ELH (59.3 ± 10.7 yr), ears with only vestibular ELH (50.4 ± 16.9 yr), or ears with both cochlear and vestibular ELH (51.5 ± 18.4 yr; p > 0.05, analysis of variance). CONCLUSION: Chronological age was not associated with the formation of ELH. Aging per se may not be associated with the development of ELH in neurotologic patients.

DOI： 10.1097/MAO.0000000000003945

Efficacy of Chemotherapy After Immune Checkpoint Inhibitor Discontinuation in Head and Neck Cancer. Reviewed International journal

Osamu Fukuoka, Yuki Saito, Toshiyuki Mukai, Takaaki Hayashi, Koji Yamamura, Toshihiko Sakai, Kenya Kobayashi, Ken Akashi, Masafumi Yoshida, Mizuo Ando, Tatsuya Yamasoba

The Laryngoscope 134 ( 1 ) 228 - 235 2023.6

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Immune checkpoint inhibitors (ICI) have become widely used becuse of their effectiveness and relatively low rate of severe adverse events. However, active treatment should be continued after discontinuation of ICI as response rates are lower than that of conventional cytotoxic chemotherapy. The purpose of the present study was to determine the efficacy of treatment after ICI discontinuation. METHODS: This was a retrospective study from hospital charts of 99 consecutive cases treated with ICI at our facility since 2017. Of these, 79 cases of squamous cell carcinoma which had already discontinued ICI were enrolled in the present study. RESULTS: After discontinuation of ICI, 40 cases received active treatment with salvage chemotherapy (SCTx; 33 cases) or surgery or radiotherapy (seven patients) and 39 cases received nonactive treatment. SCTx comprising paclitaxel and cetuximab (PTX-Cmab) was administered to 15 cases and other SCTx regimens to 18 cases. A significant increase in overall survival (OS) was observed with active treatment compared with nonactive treatment. No significant differences in OS or progression-free survival (PFS) were observed between SCTx regimens; however, there was a trend toward increased survival with PTX-Cmab. Univariate analysis of overall response rate (ORR) demonstrated significant differences in the site of disease at ICI and SCTx regimens. A significant difference in disease control rate was observed between SCTx regimens. Multivariate analysis of ORR demonstrated a significant correlation with PTX-Cmab treatment. CONCLUSION: Active treatment after ICI discontinuation and the use of PTX-Cmab as SCTx may increase OS in head and neck squamous cell carcinoma. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 2023.

DOI： 10.1002/lary.30851

Macroarray expression analysis of cytokines and prostaglandin metabolism-related genes in chronic rhinosinusitis Reviewed International journal

Aiko Oka, Kengo Kanai, Takaya Higaki, Seiichiro Makihara, Yohei Noda, Shin Kariya, Mizuo Ando, Wataru Nishimura, Mitsuhiro Okano

Journal of Allergy and Clinical Immunology: Global 2 ( 3 ) 100123 - 100123 2023.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier BV

BACKGROUND: Chronic rhinosinusitis (CRS) can be divided into endotypes by functional or pathophysiologic findings. OBJECTIVE: The aim of this study was to analyze the expression of cytokines, prostaglandin (PG) synthases, and their receptors related to the pathogenesis of CRS, especially those contributing to nasal polyp (NP) formation. METHODS: NPs and uncinate tissue (UT) samples were collected from 90 patients who underwent endoscopic sinus surgery. They included 75 patients with CRS (including 45 with eosinophilic CRS [eCRS] and 30 with non-eCRS) and 15 patients without CRS. A total of 30 genes were selected for our original DNA array plate to analyze the levels of expression of 10 cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-13, IL-17A, IL-22, IL-25, IL-33, and TSLP), 4 prostaglandin synthases (prostaglandin D2 [PGD2] synthase, prostaglandin E2 synthase, COX-1, and COX-2), and their 16 receptors. Clustering analysis was performed according to the expression results, and clinical findings of patients from each cluster were investigated. RESULTS: The samples could be divided into 3 clusters. Cluster 1 showed elevated levels of expression of IL4, IL5, IL13, TSLP, IL1RL1 (ST2 [an IL-33 receptor]), HPGDS, and GPR44 (CRTH2, a PGD2 receptor); cluster 2 showed elevated levels of expression of IL17A and PTGES; and cluster 3 showed an elevated level of expression of IL25. Regarding clinical features, the main characteristics of each cluster were as follows: NPs from patients with eCRS for cluster 1, NPs and/or UT samples from patients with non-eCRS for cluster 2, and UTs from patients with non-CRS for cluster 3. CONCLUSION: The results suggest that there are associations between type 2 inflammation/PGD2 and eCRS and also between type 3 inflammation/prostaglandin E2 and non-eCRS.

DOI： 10.1016/j.jacig.2023.100123

Risk factors for incomplete resection with pharyngeal endoscopic submucosal dissection and long-term prognosis after resection. Reviewed International journal

Yoshiki Sakaguchi, Yuki Saito, Mizuo Ando, Masafumi Yoshida, Osamu Fukuoka, Kenya Kobayashi, Dai Kubota, Daisuke Ohki, Hiroya Mizutani, Keiko Niimi, Yosuke Tsuji, Mitsuhiro Fujishiro, Tatsuya Yamasoba

Surgical endoscopy 37 ( 5 ) 3593 - 3601 2023.5

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Advances in endoscopic imaging technology have led to an increase in detection of superficial pharyngeal squamous carcinoma. Endoscopic submucosal dissection (ESD) has been reported to be effective for the treatment of these lesions, however there is still insufficient evidence on the long-term results of pharyngeal ESD. METHODS: This is a single-center retrospective study of all cases of superficial pharyngeal cancer that underwent ESD as primary treatment between January 2010 and May 2022. A total of 83 lesions in 63 patients were analyzed. RESULTS: The en bloc resection rate was 100%, and R0 resection rate was 59.0%, with an adverse event rate of 6.0%. During a mean observation period of 1134 days, there were 0 cases of disease-specific metastasis or death. However, the 5-year cumulative incidence of metachronous head and neck cancer after resection was 27.1% and the 5-year overall survival and 10-year overall survival after pharyngeal ESD were 87.0% and 69.6%, respectively. Of the 34 cases with non-R0 resection, local recurrence occurred in 8.8%. Location of lesion (p = 0.011), disparity between demarcation of the lesion with NBI and iodine staining (p = 0.026), and non-effective laryngeal elevation (p = 0.080) were risk factors for non-R0 resection. CONCLUSION: Pharyngeal ESD is effective and safe. Further studies are needed to improve and standardize indications and strategies for pharyngeal ESD.

DOI： 10.1007/s00464-022-09820-8

A Case of Radiation-Induced Osteosarcoma with RB1 Gene Alteration Treated by Skull Base Surgery and Craniofacial Reconstruction. Reviewed

Yuki Matsuda, Yoshihiro Otani, Takao Yasuhara, Mizuo Ando, Takaya Higaki, Takuma Makino, Hiroshi Matsumoto, Tadashi Oyama, Hisakazu Nishimori, Isao Date

Acta medica Okayama 77 ( 1 ) 85 - 90 2023.2

Language：English

A 35-year-old female presented with headache, photophobia and developed sudden loss of vision after having undergone right-side ophthalmectomy and radiochemotherapy for retinoblastoma in infancy. A neoplastic lesion was found in the left middle cranial fossa and was surgically removed. The diagnosis was radiation-induced osteosarcoma with RB1 gene alteration. Although she received chemotherapy for the residual tumor, it progressed 17 months later. Maximal surgical resection with craniofacial reconstruction was required. We utilized two three-dimensional models for surgical planning. She was discharged without neurological deficits other than loss of light perception subsequent to left ophthalmectomy. In cases where retinoblastoma is treated with radiotherapy, long-term follow-up is necessary to monitor for radiation-induced tumor development.

DOI： 10.18926/AMO/64367

A Case of Relapsing Polychondritis Localized to the Nasal Septum Which Showed Spontaneous Healing Reviewed

Tomoyasu Tachibana, Yoji Wani, Hidetoshi Kagawa, Yasutoshi Komatsubara, Kazunori Kuroda, Akifumi Kariya, Yuto Naoi, Mizuo Ando

Practica Oto-Rhino-Laryngologica 116 ( 6 ) 573 - 577 2023

Publishing type：Research paper (scientific journal)

We present the case of a 77-year-old male patient with relapsing polychondritis localized to the nasal septum, who presented with a history of recurrent epistaxis and nasal pain. After definitive confirmation of the diagnosis of relapsing polychondritis by biopsy, the patient was kept under observation and the lesion healed spontaneously, without steroid administration; the patient was followed up for 5 years, with no signs of recurrence. Careful follow-up might be an option for patients with localized relapsing polychondritis without systemic symptoms.

DOI： 10.5631/jibirin.116.573

A Case of Cerebrospinal Fluid Rhinorrhea of the Clivus Reviewed

Tomoyasu Tachibana, Shohei Kohno, Yasutoshi Komatsubara, Kazunori Kuroda, Akifumi Kariya, Yuto Naoi, Mizuo Ando

Practica Oto-Rhino-Laryngologica 116 ( 9 ) 881 - 885 2023

Publishing type：Research paper (scientific journal)

We present the case of a 63-year-old woman with cerebrospinal fluid (CSF) rhinorrhea of the clivus. She presented with a 6-week history of left-sided watery nasal discharge. RI cisternography showed evidence of a CSF leak in the sphenoid sinus at the previous institution, so the patient was referred to our hospital for further examination. CT and MR imaging revealed fluid collection in the left-sided sphenoid sinus and a clival bone defect. Transnasal endoscopic repair was performed using autologous grafts of her abdominal fat and fascia, and a mucosal flap from the nasal septum. Histological examination showed no evidence of tumor. We made the final diagnosis of idiopathic CSF rhinorrhea. There were no signs of a CFS leak or any new lesion at the clivus at the 2-year follow-up. Reconstruction with a mucosal flap from the nasal septum is considered as being useful for CSF rhinorrhea in the clivus.

DOI： 10.5631/jibirin.116.881

Tumor-stroma ratio can predict lymph-node metastasis in cT1/2N0 oral tongue squamous cell carcinoma independent of tumor budding grade. Reviewed

Toshihiko Sakai, Yuki Saito, Yoko Tateishi, Sho Yamazawa, Osamu Fukuoka, Kenya Kobayashi, Go Omura, Ken Akashi, Masafumi Yoshida, Mizuo Ando, Yasuhiro Ebihara, Tatsuya Yamasoba

International journal of clinical oncology 27 ( 12 ) 1818 - 1827 2022.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: cT1/2 oral tongue squamous cell carcinoma (OTSCC) often metastasizes to cervical lymph nodes. However, predicting neck lymph-node metastasis (NLM) remains challenging. Pathomorphological evaluation of tumor budding grade (TBG) and tumor-stroma ratio (TSR) reportedly can predict lymph-node metastases. Hence, this study aimed to evaluate TBG and TSR in OTSCC and investigate their relationship to occult NLM and cancer relapse. METHODS: Clinicopathological data of patients with cT1/2N0 OTSCC treated at the University of Tokyo Hospital between 2007 and 2017 were collected. TBG and TSR were evaluated using hematoxylin-eosin staining and cytokeratin AE1/AE3 immunostaining. RESULTS: Out of 70 patients, 16 underwent elective neck dissection in addition to primary-tumor resection, whereas 54 did not. During follow-up, NLM was found in 35 patients. NLM correlated with the pathological depth of invasion (pDOI) (p < 0.001), TBG (p = 0.008), and TSR (p < 0.001) in univariate analysis and pDOI (p = 0.01) and TSR (p = 0.02) in multivariate analysis. The 5-year recurrence-free survival rate (RFS) was 78% for patients with a pDOI ≤ 5 mm and stroma-poor tumors and 33% for patients with a pDOI > 5 mm and stroma-rich tumors. CONCLUSION: Patients with a pDOI > 5 mm and stroma-rich tumors have a high risk for cancer relapse. TSR and pDOI may be promising NLM predictors in cT1/2N0 OTSCC.

DOI： 10.1007/s10147-022-02249-y

Identification of novel prognostic and predictive biomarkers in salivary duct carcinoma via comprehensive molecular profiling. Reviewed International journal

Shinji Kohsaka, Yuichiro Tada, Mizuo Ando, Masato Nakaguro, Yukina Shirai, Toshihide Ueno, Shinya Kojima, Hideaki Hirai, Natsuki Saigusa, Satoshi Kano, Kiyoaki Tsukahara, Takafumi Togashi, Hiroyuki Ozawa, Takahito Kondo, Kenji Okami, Hideaki Takahashi, Daisuke Kawakita, Chihiro Fushimi, Takayoshi Suzuki, Akira Shimizu, Isaku Okamoto, Takuro Okada, Yuichiro Sato, Yorihisa Imanishi, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Yukiko Sato, Makoto Urano, Yoshitaka Honma, Keisuke Yamazaki, Yushi Ueki, Toyoyuki Hanazawa, Yuki Saito, Tomotaka Shimura, Toshitaka Nagao, Hiroyuki Mano

NPJ precision oncology 6 ( 1 ) 82 - 82 2022.11

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1038/s41698-022-00324-1

Serum 1,25-dihydroxyvitamin D3 Levels in Patients with Eosinophilic Chronic Rhinosinusitis. Reviewed

Seiichiro Makihara, Shin Kariya, Shotaro Miyamoto, Kensuke Uraguchi, Aiko Oka, Munechika Tsumura, Yohei Noda, Mizuo Ando, Mitsuhiro Okano

Acta medica Okayama 76 ( 5 ) 527 - 533 2022.10

Subcutaneous axillary primary epithelioid hemangioendothelioma: report of a rare case. Reviewed International journal

Takayoshi Niwa, Takaaki Konishi, Asako Sasahara, Ayaka Sato, Arisa Morizono, Mayumi Harada, Kotoe Nishioka, Osamu Fukuoka, Naohiro Makise, Yuki Saito, Mizuo Ando, Takako Yoshimoto, Takeshi Shikama, Satoshi Yamashita, Masahiko Tanabe, Yasuyuki Seto

Surgical case reports 8 ( 1 ) 166 - 166 2022.9

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Epithelioid hemangioendothelioma (EHE) is a rare and slow-growing malignant vascular neoplasm composed of epithelioid endothelial cells within a distinctive myxohyaline stroma. It most commonly involves somatic soft tissue, lungs, liver and bone. Herein, we describe a case of EHE arising in the axillary region. CASE PRESENTATION: A 61-year-old man was under observation for multiple hepatic hemangiomas. Fluorodeoxyglucose-positron emission tomography/computed tomography showed specific uptake in a right axillary tumor. The patient was referred to our department for further investigation of the axillary tumor. An elastic-soft and poorly mobile tumor was palpable in the right axilla. Contrast-enhanced computed tomography showed a right axillary tumor and enlarged hepatic hemangiomas. In addition, multiple nodules in both lungs, a left renal angiomyolipoma, and left adrenal adenoma were revealed. Ultrasonography showed masses in both lobes of the thyroid gland, and a 30-mm lobulated hypoechoic mass in the axilla with well-defined and rough borders, showing internal heterogeneity. Fine-needle aspiration cytology was performed on the thyroid and axillary tumors: the thyroid tumor was class V, raising suspicion of papillary thyroid cancer (PTC); the left superior internal jugular node was class V, raising suspicion of metastasis of PTC; and the axillary tumor was class III, raising suspicion of a mesenchymal tumor with few epithelioid cells. The multiple lung nodules were diagnosed as metastatic tumors derived from thyroid cancer. We diagnosed these diseases as PTC of T1b(m)N1bM1(lung) Stage IVB and a right axillary tumor of unclear origin. However, it was assumed to be a primary mesenchymal tumor or a lymph node metastasis from lung cancer or occult breast cancer. We performed total thyroidectomy, left cervical lymph node dissection, and right axillary tumor excision. Histopathologic examination revealed the thyroid tumor as a PTC and the axillary tumor as an EHE. The EHE showed nuclear atypia, necrosis and high mitotic figures. Hence, it was considered to be a high-risk EHE. CONCLUSIONS: We experienced a rare primary subcutaneous axillary EHE with metastatic thyroid cancer in the lung. Since our case was classified as a high-risk EHE, a close follow-up would be appropriate.

DOI： 10.1186/s40792-022-01521-7

Candidemia in patients with head and neck cancer: mortality and a novel risk factor. Reviewed International journal

Kensuke Uraguchi, Takuma Makino, Shin Kariya, Youhei Noda, Hidenori Marunaka, Akira Doi, Kenichi Kozakura, Soshi Takao, Mizuo Ando

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 30 ( 7 ) 5921 - 5930 2022.7

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Candidemia is a bloodstream infection (BSI) by Candida spp. and is associated with high mortality. However, there have been few reports about BSI in head and neck cancer (HNC). We aimed to evaluate the impact of candidemia in patients with HNC and compared it with bacteremia. STUDY DESIGN: A multicenter retrospective study. METHODS: We retrospectively analyzed 83 BSI episodes in HNC (2011 to 2020) and divided them into the candidemia and bacteremia groups. We then compared the survival rate and risk factors for candidemia between the groups. RESULTS: The overall cumulative incidence (risk) of candidemia in BSI was 12 out of 83 episodes (14.5%). The 1-year mortality for the bacteremia and candidemia groups was 33.3% and 58.3%, respectively (log-rank p = 0.041). Broad-spectrum antibiotics (odds ratio [OR]: 29.5; 95% confidence interval [CI], 2.49-350), mucositis (OR 11.0; 95% CI, 1.52-80.1), and malignant wounds (OR 79.5; 95% CI 1.33-4737) were significant risk factors for candidemia in HNC. CONCLUSIONS: Candidemia causes high mortality in patients with HNC. To our knowledge, malignant wounds have not been previously reported as a risk factor for candidemia. For early diagnosis and treatment of candidemia, risk factors should be considered, and antifungal therapy started earlier.

DOI： 10.1007/s00520-022-07010-9

The add-on effect of an intranasal antihistamine with an intranasal corticosteroid in Japanese cedar pollinosis. Reviewed International journal

Takenori Haruna, Shin Kariya, Takaya Higaki, Aya Murai, Kengo Kanai, Aiko Oka, Maki Akamatsu, Mizuo Ando, Kazunori Nishizaki, Mitsuhiro Okano

Auris, nasus, larynx 50 ( 1 ) 81 - 86 2022.6

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Combination intranasal drugs with a corticosteroid and antihistamine are available in several countries with better effect than treatments with single agents. However, it remains unclear whether this effect is also seen in Japanese cedar pollinosis (JCP), the most prevalent seasonal allergic rhinitis in Japan. We investigated the effect of an add-on intranasal antihistamine with an intranasal corticosteroid in JCP during the pollen dispersal period. (UMIN000025508) METHODS: We performed a double-blinded, randomized, placebo-controlled trial from March 1 to 14, 2017. Patients (n = 20 per group) received either a mometasone furoate nasal spray (MFNS) plus a levocabastine nasal spray (levocabastine group) or MFNS plus a placebo nasal spray (placebo group). The primary endpoint was the difference in the total nasal symptom score (TNSS) after treatment between the two groups. Differences in the total ocular symptom score, total symptom score, total medication score, total symptom-medication score, and five individual symptoms as well as safety were the secondary endpoints. RESULTS: The change in the TNSS from baseline was significantly greater in the levocabastine group than in the placebo group. A significant reduction in the TNSS was observed more than 6 days earlier in the levocabastine group than in the placebo group. Such add-on effects were also seen in the secondary endpoints. Both treatments were well-tolerated. CONCLUSION: The intranasal antihistamine provided better control of not only nasal symptoms, but also of ocular symptoms, and decreased the need for rescue medications when added to intranasal corticosteroid treatment in JCP patients.

DOI： 10.1016/j.anl.2022.05.007

Labyrinthitis ossificans following severe acute otitis media. International journal

Kensuke Uraguchi, Shin Kariya, Mizuo Ando

Clinical case reports 10 ( 5 ) e05898 2022.5

Relationship between spontaneous nystagmus and video Head Impulse Test findings among patients with chronic neurotologic conditions. Reviewed International journal

Yukihide Maeda, Soshi Takao, Iku Abe-Fujisawa, Shin Kariya, Mizuo Ando

Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 99 244 - 247 2022.5

Language：English Publishing type：Research paper (scientific journal)

The vestibulo-ocular reflex (VOR) in neurotologic patients can be evaluated most quickly by spontaneous nystagmus examinations, and the video Head Impulse Test (vHIT) quantitatively evaluates the VOR of the semicircular canals. We aimed to clarify the concordance and discrepancies between spontaneous nystagmus and vHIT findings, to provide guidance on screening vestibular functions by initial spontaneous nystagmus examination then vHIT. We evaluated 169 outpatients by spontaneous nystagmus examination in the dark using a charge-coupled device camera, then by horizontal vHIT the same day. Vestibular loss on vHIT was defined if both reduced VOR gain (<0.8) and corrective saccade were observed. Adjusted logistic regression modelling revealed that differences in right and left VOR gain positively impacted the presence of nystagmus, which suggests lateralised vestibular dysfunction (P<0.05; odds ratio 1.39 [95% confidence interval, 1.1-1.8] per 0.1 increment). When vHIT is regarded as the standard clinical test, the positive predictive value of nystagmus for vestibular loss on vHIT was 44.4%, and the negative predictive value was 93.5%. The adjusted odds ratio of adults ≥65 years old compared to younger patients associated with a discrepancy of nystagmus and vHIT was significant (2.4 [1.1-5.3]). In conclusion, if spontaneous nystagmus is initially observed in patients, further assessment by vHIT could confirm vestibular dysfunction in 40-50% of cases. If no nystagmus is observed, vHIT might also result in a negative finding in >90% of cases. Older adults appear more likely to show discrepancies between nystagmus and vHIT.

DOI： 10.1016/j.jocn.2022.03.018

Subclinical obstructive lung function changes in patients with sinus fungus ball. International journal

Seiichiro Makihara, Shin Kariya, Ryotaro Omichi, Shotaro Miyamoto, Tomoyuki Naito, Kensuke Uraguchi, Aiko Oka, Munechika Tsumura, Mitsuhiro Okano, Mizuo Ando

Allergology international : official journal of the Japanese Society of Allergology 71 ( 4 ) 539 - 541 2022.4

The fine-needle aspiration cytology and clinical findings of Kikuchi-Fujimoto disease in pediatric patients: a retrospective clinical study. International journal

Yuto Naoi, Tomoyasu Tachibana, Yoji Wani, Machiko Hotta, Katsuya Haruna, Yasutoshi Komatsubara, Kazunori Kuroda, Soichiro Fushimi, Tami Nagatani, Yuko Kataoka, Kazunori Nishizaki, Yasuharu Sato, Mizuo Ando

Acta oto-laryngologica 142 ( 3-4 ) 1 - 5 2022.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Histological evaluation of lymph node is crucial for the definitive diagnosis of Kikuchi-Fujimoto disease (KFD). However, lymph node biopsy under local anesthesia is often difficult in pediatric patients. OBJECTIVES: We evaluated cytological findings for pediatric patients with prolonged cervical lymphadenitis clinically suggestive of KFD and investigated the clinical characteristics of patients diagnosed with KFD by fine-needle aspiration cytology (FNAC). METHODS: This retrospective clinical study included 58 Japanese pediatric patients with cervical lymphadenitis who underwent FNAC. RESULTS: Cytological diagnosis was KFD for 22 and suspicion of KFD for 11 patients. The remaining 25 patients were diagnosed with non-specific lymphadenitis (NSL). Tenderness was independently associated with a higher frequency of both KFD in narrow and broad senses, compared with NSL (p = .009; p = .038). The percentage of patients who underwent FNAC within 28 days from symptom onset tended to be higher among patients with KFD in a narrow sense than those with NSL (p = .052). CONCLUSION: This study indicated that the period from symptom onset to FNAC (<28 days) and the symptom of tenderness were associated with the cytological diagnosis of KFD.

DOI： 10.1080/00016489.2022.2040744

Protothecosis in the mucosa of the pharynx mimicking pharyngeal cancer in an immunocompetent individual: a case report. Reviewed International journal

Marie Yamashita, Mahoko Ikeda, Ito Kato, Yuki Ohama, Mizuo Ando, Masako Ikemura, Daisuke Jubishi, Yoshiaki Kanno, Koh Okamoto, Takashi Umeyama, Shigeki Nakamura, Yoshitsugu Miyazaki, Shu Okugawa, Kyoji Moriya

Annals of clinical microbiology and antimicrobials 21 ( 1 ) 5 - 5 2022.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Protothecosis is a rare infection in humans and animals caused by the achlorophyllic algae Prototheca species. More than half of the protothecosis cases are cutaneous infections, and most cases are observed in immunocompromised individuals. CASE PRESENTATION: We report a case of Prototheca wickerhamii infection in the mucosa of the pharynx in a 53-year-old immunocompetent woman with an incidentally found mass lesion at the left tongue base. Histopathological findings of the mass lesion suggested cryptococcosis, but P. wickerhamii was identified from the oropharynx scrape culture based on DNA sequencing. After surgical resection, fosfluconazole treatment was initiated, and subsequently, treatment was switched to topical amphotericin B. The residual mass lesion did not deteriorate during the 4-month antifungal treatment and 1-year observational period. CONCLUSIONS: Prototheca species can be easily misdiagnosed as yeasts because of their morphological and pathological similarities. Prototheca, in addition to Cryptococcus should be considered if slow-growing, large Gram-positive organisms are encountered. Lactophenol cotton blue staining of the colony helps distinguish these organisms. Further study is needed to determine the appropriate treatment according to the infection focus.

DOI： 10.1186/s12941-022-00495-6

Clinicopathologic Analysis of Sinonasal Inverted Papilloma, with Focus on Human Papillomavirus Infection Status Reviewed

Munechika Tsumura, Seiichiro Makihara, Asami Nishikori, Yuka Gion, Toshiaki Morito, Shotaro Miyamoto, Tomoyuki Naito, Kensuke Uraguchi, Aiko Oka, Tomoyasu Tachibana, Yorihisa Orita, Shin Kariya, Mitsuhiro Okano, Mizuo Ando, Yasuharu Sato

Diagnostics 12 ( 2 ) 454 - 454 2022.2

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

Sinonasal inverted papilloma (SNIP) can recur; however, the factors related to tumor recurrence remain unclear. This study aimed to analyze risk factors, including human papillomavirus (HPV) infection, as well as other factors associated with SNIP recurrence. Thirty-two patients who were diagnosed with SNIP and underwent surgery between 2010 and 2019 were enrolled: 24 men and 8 women, with a mean age of 59.2 years. The mean follow-up was 57.3 months. Demographics and information about history of smoking, diabetes mellitus (DM), hypertension, allergic rhinitis, alcohol consumption, tumor stage, surgical approach, and recurrence were reviewed retrospectively. Specimens were investigated using polymerase chain reaction to detect HPV DNA (high-risk subtypes: 16, 18, 31, 33, 35, 52b, and 58; low-risk subtypes: 6 and 11). Seven patients (21.9%) experienced recurrence. HPV DNA was detected in five (15.6%) patients (high-risk subtypes, n = 2; low-risk subtypes, n = 3). Patients with recurrence of SNIP had a higher proportion of young adults and displayed higher rates of HPV infection, DM, and advanced tumor stage than those without recurrence. HPV infection, young adulthood, DM, and advanced tumor stage could be associated with a high recurrence rate, which suggests that patients with these risk factors could require close follow-up after surgery.

DOI： 10.3390/diagnostics12020454

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 Reviewed

Natsuki Saigusa, Hideaki Hirai, Yuichiro Tada, Daisuke Kawakita, Masato Nakaguro, Kiyoaki Tsukahara, Satoshi Kano, Hiroyuki Ozawa, Takahito Kondo, Kenji Okami, Takafumi Togashi, Yukiko Sato, Makoto Urano, Manami Kajiwara, Tomotaka Shimura, Chihiro Fushimi, Akira Shimizu, Isaku Okamoto, Takuro Okada, Takayoshi Suzuki, Yorihisa Imanishi, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Yuichiro Sato, Yoshitaka Honma, Keisuke Yamazaki, Yushi Ueki, Toyoyuki Hanazawa, Yuki Saito, Hideaki Takahashi, Mizuo Ando, Shinji Kohsaka, Takashi Matsuki, Toshitaka Nagao

Frontiers in Oncology 11 2022.2

Publishing type：Research paper (scientific journal) Publisher：Frontiers Media SA

<sec><title>Objective</title>Salivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only <italic>de novo</italic> 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.

</sec><sec><title>Materials and Methods</title>The EZH2 and H3K27me3 immunohistochemical expression and <italic>EZH2</italic> 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).

</sec><sec><title>Results</title>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. <italic>EZH2</italic> 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.

</sec><sec><title>Conclusions</title>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.

</sec>

DOI： 10.3389/fonc.2021.779882

Dermatomyositis With Carcinoma of Unknown Primary Disease in the Head and Neck Diagnosed by Muscle Biopsy During Neck Dissection. Reviewed International journal

Kensuke Uraguchi, Seiichiro Makihara, Makoto Tsugita, Toshiaki Morito, Shin Kariya, Mizuo Ando

JAMA otolaryngology-- head & neck surgery 148 ( 2 ) 195 - 196 2022.2

Usefulness of circulating tumor DNA by targeting human papilloma virus-derived sequences as a biomarker in p16-positive oropharyngeal cancer. Reviewed International journal

Ken Akashi, Toshihiko Sakai, Osamu Fukuoka, Yuki Saito, Masafumi Yoshida, Mizuo Ando, Takeshi Ito, Yoshinori Murakami, Tatsuya Yamasoba

Scientific reports 12 ( 1 ) 572 - 572 2022.1

Language：English Publishing type：Research paper (scientific journal)

In head and neck cancer, early detection of recurrence after treatment is important. The contemporary development of therapeutic agents have improved the prognosis after recurrence; however, no biomarker has been established for evaluating therapeutic effects or detecting recurrence. Recently, circulating tumor DNA (ctDNA), which comprises DNA derived from tumor cells and exists in the form of cell-free DNA in the blood, has attracted attention as a minimally invasive and repeatable biomarker for detecting cancer. We validated the usefulness of ctDNA of human papilloma virus (HPV)-derived sequences as a biomarker in HPV-related p16-positive oropharyngeal cancer by assessing 25 patients with p16-positive oropharyngeal cancer. Blood samples were collected from each patient at multiple time points during the treatment, and the plasma was preserved. The ctDNA was extracted from the plasma and analyzed using digital polymerase chain reaction. HPV-derived ctDNA was detected in 14 (56%) of the 25 patients. In all the patients, the samples were found to be ctDNA-negative after initial treatment. Cancer recurrence was observed in 2 of the 14 patients; HPV-derived ctDNA was detected at the time of recurrence. Our results indicate that HPV-derived ctDNA can be a prospective biomarker for predicting the recurrence of p16-positive oropharyngeal cancer.

DOI： 10.1038/s41598-021-04307-3

Midline involvement and perineural invasion predict contralateral neck metastasis that affects overall and disease-free survival in locally advanced oral tongue squamous cell carcinoma. Reviewed International journal

Maki Akamatsu, Takuma Makino, Shinya Morita, Yohei Noda, Shin Kariya, Tomoo Onoda, Mizuo Ando, Yoshihiro Kimata, Kazunori Nishizaki, Mitsuhiro Okano, Aiko Oka, Kengo Kanai, Yoshihiro Watanabe, Yorihisa Imanishi

Frontiers in oncology 12 1010252 - 1010252 2022

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Although patients with oral squamous cell carcinoma who develop contralateral neck metastasis (CLNM) have worse survival outcomes than those without CLNM, accurate prediction of occult CLNM in clinically negative contralateral neck (contralateral cN0) remains difficult. This study aimed to identify clinicopathological factors that could reliably predict CLNM in patients with locally advanced (clinical T3 and T4a) tongue squamous cell carcinoma (TSCC). PATIENTS AND METHODS: The medical data of 32 patients with cT3-4a TSCC who underwent curative surgery between 2010 and 2017 were retrospectively analyzed. The correlation of clinicopathological variables with CLNM was examined using logistic regression analysis. The diagnostic performance of significant variables was evaluated using the area under the receiver operating characteristic curves (AUC). Overall survival (OS) and disease-free survival (DFS) were assessed using a Cox proportional hazards model. RESULTS: CLNM was eventually confirmed in 11 patients (34.4%). Multivariate logistic regression showed that midline involvement [odds ratio (OR) = 23.10, P = 0.017] and perineural invasion (PNI, OR = 14.96, P = 0.014) were independent predictors of CLNM. Notably, the prediction model comprising a combination of midline involvement and PNI exhibited superior diagnostic performance with an even higher OR of 80.00 (P < 0.001), accuracy of 90.3%, and AUC of 0.876. The multivariate Cox hazards model revealed independent significance of CLNM as an unfavorable prognostic factor for both OS [hazard ratio (HR) = 5.154, P = 0.031] and DFS (HR = 3.359, P = 0.038), as well as that of PNI for OS (HR = 5.623, P = 0.033). CONCLUSION: Our findings suggest that coexisting midline involvement and PNI of the primary tumor is highly predictive of CLNM development, which independently affects both OS and DFS in patients with locally advanced TSCC. Such reliable prediction enables efficient control of CLNM by optimizing management of the contralateral cN0 neck, which will likely contribute to improved prognosis of those patients without unnecessarily compromising their quality of life.

DOI： 10.3389/fonc.2022.1010252

Survival benefit of HER2-targeted or androgen deprivation therapy in salivary duct carcinoma. Reviewed International journal

Daisuke Kawakita, Toshitaka Nagao, Hideaki Takahashi, Satoshi Kano, Yoshitaka Honma, Hideaki Hirai, Natsuki Saigusa, Kohei Akazawa, Kaori Tani, Hiroya Ojiri, Kiyoaki Tsukahara, Hiroyuki Ozawa, Kenji Okami, Takahito Kondo, Takafumi Togashi, Chihiro Fushimi, Tomotaka Shimura, Akira Shimizu, Isaku Okamoto, Takuro Okada, Yorihisa Imanishi, Yoshihiro Watanabe, Kuninori Otsuka, Akihiro Sakai, Koji Ebisumoto, Yuichiro Sato, Keisuke Yamazaki, Yushi Ueki, Toyoyuki Hanazawa, Yuki Saito, Mizuo Ando, Takashi Matsuki, Masato Nakaguro, Yukiko Sato, Makoto Urano, Yoshitaka Utsumi, Shinji Kohsaka, Takashi Saotome, Yuichiro Tada

Therapeutic advances in medical oncology 14 17588359221119538 - 17588359221119538 2022

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1177/17588359221119538

Static posturographic balance in neurotologic patients may be associated with middle-high-frequency hearing levels during ageing process. Reviewed International journal

Yukihide Maeda, Soshi Takao, Iku Abe-Fujisawa, Shin Kariya, Mizuo Ando

Acta oto-laryngologica 142 ( 3-4 ) 280 - 284 2022

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Understanding how sensorineural hearing loss (SNHL) impacts postural balance in patients is important, as postural balance predicts the risk of falls. AIMS/OBJECTIVES: We aimed to clarify the relationship between characteristics in the configuration of audiograms and static postural balance as measured by posturography. MATERIALS AND METHODS: We evaluated 385 outpatients (mean [± standard deviation] age, 58.4 ± 18.4 years) with SNHL by audiometry and posturography. Data were analysed by multiple regression models with the outcome of postural sway area with eyes closed (PSA) and predictive variables of audiometric data, adjusted for sex, age and the presence of nystagmus. RESULTS: The increased hearing threshold in the better hearing ear was associated with poorer or higher PSA (beta coefficient [β] = 0.39, 95% confidence interval [CI] = 0.03-0.75, per 10-dB increment). No difference in PSA was detected between patients with asymmetric or symmetric SNHL. None of the frequent diagnoses (presbyacusis, Meniere's disease, and idiopathic sudden SNHL) were associated with poorer PSA. Hearing thresholds at middle (β = 0.39, 95%CI = 0.10-0.67) and high frequencies (β = 0.31, 95%CI = 0.07-0.55) were associated with poorer PSA, whereas those at low frequencies was not. CONCLUSIONS AND SIGNIFICANCE: Postural balance in neurotologic patients may be associated with middle-high-frequency hearing levels during ageing.

DOI： 10.1080/00016489.2022.2047222

Transcript-targeted analysis reveals isoform alterations and double-hop fusions in breast cancer. Reviewed International journal

Shinichi Namba, Toshihide Ueno, Shinya Kojima, Kenya Kobayashi, Katsushige Kawase, Yosuke Tanaka, Satoshi Inoue, Fumishi Kishigami, Shusuke Kawashima, Noriko Maeda, Tomoko Ogawa, Shoichi Hazama, Yosuke Togashi, Mizuo Ando, Yuichi Shiraishi, Hiroyuki Mano, Masahito Kawazu

Communications biology 4 ( 1 ) 1320 - 1320 2021.11

Language：English Publishing type：Research paper (scientific journal)

Although transcriptome alteration is an essential driver of carcinogenesis, the effects of chromosomal structural alterations on the cancer transcriptome are not yet fully understood. Short-read transcript sequencing has prevented researchers from directly exploring full-length transcripts, forcing them to focus on individual splice sites. Here, we develop a pipeline for Multi-Sample long-read Transcriptome Assembly (MuSTA), which enables construction of a transcriptome from long-read sequence data. Using the constructed transcriptome as a reference, we analyze RNA extracted from 22 clinical breast cancer specimens. We identify a comprehensive set of subtype-specific and differentially used isoforms, which extended our knowledge of isoform regulation to unannotated isoforms including a short form TNS3. We also find that the exon-intron structure of fusion transcripts depends on their genomic context, and we identify double-hop fusion transcripts that are transcribed from complex structural rearrangements. For example, a double-hop fusion results in aberrant expression of an endogenous retroviral gene, ERVFRD-1, which is normally expressed exclusively in placenta and is thought to protect fetus from maternal rejection; expression is elevated in several TCGA samples with ERVFRD-1 fusions. Our analyses provide direct evidence that full-length transcript sequencing of clinical samples can add to our understanding of cancer biology and genomics in general.

DOI： 10.1038/s42003-021-02833-4

Outcomes of long-term nivolumab and subsequent chemotherapy in Japanese patients with head and neck cancer: 2-year follow-up from a multicenter real-world study. Reviewed

Ryuji Yasumatsu, Yasushi Shimizu, Nobuhiro Hanai, Shin Kariya, Tomoya Yokota, Takashi Fujii, Kiyoaki Tsukahara, Mizuo Ando, Kenji Hanyu, Tsutomu Ueda, Hitoshi Hirakawa, Shunji Takahashi, Takeharu Ono, Daisuke Sano, Moriyasu Yamauchi, Akihito Watanabe, Koichi Omori, Tomoko Yamazaki, Nobuya Monden, Naomi Kudo, Makoto Arai, Syuji Yonekura, Takahiro Asakage, Takahiro Nekado, Takayuki Yamada, Akihiro Homma

International journal of clinical oncology 27 ( 1 ) 95 - 104 2021.11

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: We have previously reported the effectiveness and safety of nivolumab in patients with head and neck cancer (HNC) in real-world clinical practice in Japan. Here, we report long-term outcomes from this study in the overall population and subgroups stratified by subsequent chemotherapy. METHODS: In this multicenter, retrospective observational study, Japanese patients with recurrent or metastatic (R/M) HNC receiving nivolumab were followed up for 2 years. Effectiveness endpoints included overall survival (OS), OS rate, progression-free survival (PFS), and PFS rate. Safety endpoints included the incidence of immune-related adverse events (irAEs). RESULTS: Overall, 256 patients received a median of 6.0 doses (range: 1-52) of nivolumab over a median duration of 72.5 days (range: 1-736). Median OS was 9.5 months [95% confidence interval (CI) 8.2-12.0] and median PFS was 2.1 months (95% CI 1.8-2.7). A significant difference between 2-year survivors (n = 62) and non-2-year survivors was observed by median age (P = 0.0227) and ECOG PS (P = 0.0001). Of 95 patients who received subsequent chemotherapy, 54.7% received paclitaxel ± cetuximab. The median OS and PFS from the start of paclitaxel ± cetuximab were 6.9 months (95% CI 5.9-11.9) and 3.5 months (95% CI 2.3-5.5), respectively. IrAEs were reported in 17.2% of patients. Endocrine (7.0%) and lung (4.3%) disorders were the most common irAEs; kidney disorder (n = 1) was newly identified in this follow-up analysis. CONCLUSIONS: Results demonstrated the long-term effectiveness of nivolumab and potential effectiveness of subsequent chemotherapy in patients with R/M HNC in the real-world setting. Safety was consistent with that over the 1-year follow-up.

DOI： 10.1007/s10147-021-02047-y

Underwater posterior nasal neurectomy compared to resection of peripheral branches of posterior nerve in severe allergic rhinitis. Reviewed International journal

Seiichiro Makihara, Mitsuhiro Okano, Syotaro Miyamoto, Kensuke Uraguchi, Munechika Tsumura, Shin Kariya, Mizuo Ando

Acta oto-laryngologica 141 ( 8 ) 780 - 785 2021.8

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Several surgical procedures for posterior nasal neurectomy have been reported, but no conclusion has been reached about which procedure is best. OBJECTIVES: The aim is to evaluate the improvement in symptom medication scores for resection of the posterior nasal nerve trunk in an underwater environment, with submucous inferior turbinectomy, without injuring the sphenopalatine artery (SPA) in severe allergic rhinitis. MATERIAL AND METHODS: Improvements in symptom medication scores were retrospectively compared between 27 consecutive cases who underwent resection of the posterior nasal nerve trunk with turbinoplasty in an underwater environment without injuring the SPA (Underwater group) and, as a historical control, 16 consecutive cases who underwent resection of peripheral branches of the posterior nasal nerve with turbinoplasty (Control group). RESULTS: The improvements in symptom medication scores in the Underwater group were significantly better than in the Control group (3.07 vs. 1.96, p = 0.02). CONCLUSIONS AND SIGNIFICANCE: By using underwater posterior nasal neurectomy, we can easily and safely resect the posterior nasal nerve trunk under a clear surgical view without injuring the SPA. This technique with submucous inferior turbinectomy may, more than resection of peripheral branches of the posterior nasal nerve, be able to reduce the medication score and symptom medication score.

DOI： 10.1080/00016489.2021.1925151

Apocrine Hidrocystoma of the External Auditory Canal in a Child. Reviewed International journal

Tomoyasu Tachibana, Tomoaki Sasaki, Yoji Wani, Yuto Naoi, Yuko Kataoka, Kazunori Nishizaki, Mizuo Ando

Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 42 ( 8 ) e1181-e1183 2021.6

Transoral surgery for superficial head and neck cancer: National Multi-Center Survey in Japan. Reviewed International journal

Chikatoshi Katada, Manabu Muto, Satoshi Fujii, Tetsuji Yokoyama, Tomonori Yano, Akihito Watanabe, Toshiro Iizuka, Shigetaka Yoshinaga, Ichiro Tateya, Hiroki Mitani, Yuichi Shimizu, Akiko Takahashi, Tomoyuki Kamijo, Noboru Hanaoka, Makoto Abe, Akihiro Shiotani, Koichi Kano, Yukinori Asada, Tamotsu Matsuhashi, Hirohito Umeno, Kenji Okami, Kenichi Goda, Shinichiro Hori, Yoichiro Ono, Shuji Terai, Yasuaki Nagami, Kenichi Takemura, Kenro Kawada, Mizuo Ando, Naoto Shimeno, Akihito Arai, Yasutoshi Sakamoto, Masaaki Ichinoe, Tetsuo Nemoto, Masahiro Fujita, Hidenobu Watanabe, Tadakazu Shimoda, Atsushi Ochiai, Takakuni Kato, Ryuichi Hayashi

Cancer medicine 10 ( 12 ) 3848 - 3861 2021.6

Language：English Publishing type：Research paper (scientific journal)

Head and neck cancers, especially in hypopharynx and oropharynx, are often detected at advanced stage with poor prognosis. Narrow band imaging enables detection of superficial cancers and transoral surgery is performed with curative intent. However, pathological evaluation and real-world safety and clinical outcomes have not been clearly understood. The aim of this nationwide multicenter study was to investigate the safety and efficacy of transoral surgery for superficial head and neck cancer. We collected the patients with superficial head and neck squamous cell carcinoma who were treated by transoral surgery from 27 hospitals in Japan. Central pathology review was undertaken on all of the resected specimens. The primary objective was effectiveness of transoral surgery, and the secondary objective was safety including incidence and severity of adverse events. Among the 568 patients, a total of 662 lesions were primarily treated by 575 sessions of transoral surgery. The median tumor diameter was 12 mm (range 1-75) endoscopically. Among the lesions, 57.4% were diagnosed as squamous cell carcinoma in situ. The median procedure time was 48 minutes (range 2-357). Adverse events occurred in 12.7%. Life-threatening complications occurred in 0.5%, but there were no treatment-related deaths. During a median follow-up period of 46.1 months (range 1-113), the 3-year overall survival rate, relapse-free survival rate, cause-specific survival rate, and larynx-preservation survival rate were 88.1%, 84.4%, 99.6%, and 87.5%, respectively. Transoral surgery for superficial head and neck cancer offers effective minimally invasive treatment. Clinical trials registry number: UMIN000008276.

DOI： 10.1002/cam4.3927

A retrospective analysis of radiotherapy in the treatment of external auditory canal carcinoma. Reviewed International journal

Atsuto Katano, Ryousuke Takenaka, Hideomi Yamashita, Mizuo Ando, Masafumi Yoshida, Yuki Saito, Takahiro Asakage, Osamu Abe, Keiichi Nakagawa

Molecular and clinical oncology 14 ( 3 ) 45 - 45 2021.3

Language：English Publishing type：Research paper (scientific journal)

External auditory canal carcinoma (EACC) is a rare disease. The current study aimed to evaluate the clinical outcomes of patients treated with external beam radiotherapy (EBRT) for EACC. The present study retrospectively reviewed 34 consecutive patients treated for EACC with EBRT between February 2001 and January 2019 at the University of Tokyo Hospital. Clinical staging was performed according to the modified Pittsburgh classification. Of all the included patients, seven patients were in the early stages (I or II) and 27 in the advanced stages (III or IV) of EACC. A total of 16 patients underwent EBRT and surgery (S+RT) pre- and/or postoperatively, while 18 patients underwent definitive radiotherapy (dRT). The median prescribed doses for the S+RT and dRT groups were 66 and 70 Gy, respectively. The median follow-up period for all patients was 22.4 months (range, 2-205 months). The 5-year overall survival rates of the S+RT and dRT groups were 66.7 and 45.1%, respectively. The progression-free survival rate at 5-year was 55.6% (95% confidence interval: 36.5-71.1%) for the entire cohort. A total of 14 patients experienced disease relapse after treatment, consisting of 11 locoregional recurrences and three distant metastases. The current study revealed the clinical outcomes of EBRT for EACC.

DOI： 10.3892/mco.2021.2207

Reciprocal activation of HEY1 and NOTCH4 under SOX2 control promotes EMT in head and neck squamous cell carcinoma. Reviewed International journal

Takahito Fukusumi, Theresa W Guo, Shuling Ren, Sunny Haft, Chao Liu, Akihiro Sakai, Mizuo Ando, Yuki Saito, Sayed Sadat, Joseph A Califano

International journal of oncology 58 ( 2 ) 226 - 237 2021.2

Language：English Publishing type：Research paper (scientific journal)

Several comprehensive studies have demonstrated that the NOTCH pathway is altered in a bimodal manner in head and neck squamous cell carcinoma (HNSCC). In a previous study, it was found that the NOTCH4/HEY1 pathway was specifically upregulated in HNSCC and promoted epithelial‑mesenchymal transition (EMT), and that HEY1 activation supported SOX2 expression. However, the interactions in this pathway have not yet been fully elucidated. The present study investigated the NOTCH4/HEY1/SOX2 axis in HNSCC using in vitro models and the Cancer Genome Atlas (TCGA) database. To explore the association, reporter and ChIP RT‑qPCR assays using SOX2‑overexpressing (SOX2‑OE) cells were performed. The association between NOTCH4 and HEY1 was examined in the same manner using HEY1‑overexpressing (HEY1‑OE) cells. The results of the in vitro experiments indicated that HEY1 promoted EMT in the HNSCC cells. Furthermore, the overexpression of HEY1 also promoted sphere formation and increased murine xenograft tumorigenicity. Reporter assays and ChIP RT‑qPCR experiments indicated that SOX2 regulated HEY1 expression via direct binding of the HEY1 promoter. HEY1 expression significantly correlated with SOX2 expression in primary lung SCC and other SCCs using the TCGA database. HEY1 also regulated NOTCH4 expression to create a positive reciprocal feedback loop. On the whole, the present study demonstrates that HEY1 expression in HNSCC is regulated via the promotion of SOX2 and promotes EMT. The NOTCH4/HEY1 pathway is specifically upregulated via a positive reciprocal feedback loop mediated by the HEY1‑medaited regulation of NOTCH4 transcription, and SOX2 correlates with HEY1 expression in SCC from other primary sites.

DOI： 10.3892/ijo.2020.5156

Full-coverage TP53 deep sequencing of recurrent head and neck squamous cell carcinoma facilitates prognostic assessment after recurrence. Reviewed International journal

Kenya Kobayashi, Seiichi Yoshimoto, Mizuo Ando, Fumihiko Matsumoto, Naoya Murakami, Go Omura, Yoshitaka Honma, Yoshifumi Matsumoto, Atsuo Ikeda, Azusa Sakai, Kohtaro Eguchi, Akiko Ito, Eigitsu Ryo, Yasushi Yatabe, Taisuke Mori

Oral oncology 113 105091 - 105091 2021.2

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES: This study aims to evaluate whether the accumulation of TP53 mutations is associated with clinical outcome by comparing full-coverage TP53 deep sequencing of the initial and recurrent head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Medical records and surgical specimens of 400 patients with HNSCC surgically treated with curative intent, of which 95 patients developed local or locoregional recurrence, were reviewed. Of these patients, 63 were eligible for genomic analysis. Full-coverage TP53 deep sequencing of 126 paired initial and recurrent tumor samples was examined using next-generation sequencing (NGS). Temporal changes in the mutation status, molecular characterization, and clinical outcome were compared. Fisher's exact test, Kaplan-Meier method, log-rank test, and Cox regression models were used for statistical analysis. RESULTS: Of the recurrent tumors, 22% harbored accumulation of TP53 mutations, and 16% lost the original mutation. The accumulation of TP53 mutations was significantly more frequent in oral cancer than in pharyngeal or laryngeal cancer (33% vs. 7%, p = 0.016). Two-year post-recurrence survival (PRS) was associated with TP53 status for recurrent tumors, but not for initial tumors. The TP53 status for recurrent tumors was an independent risk factor in multivariate analysis (hazard ratio, 5.76; 95% confidence interval, 1.86-17.8; p = 0.0023). CONCLUSION: Approximately one-third of the recurrent HNSCC cases showed a different TP53 status from the initial tumor. Temporal changes in the mutation status differed by primary site. Full-coverage TP53 deep sequencing of recurrent tumors was useful in predicting post-recurrence prognosis.

DOI： 10.1016/j.oraloncology.2020.105091

Upregulation of a nuclear factor-kappa B-interacting immune gene network in mice cochleae with age-related hearing loss. Reviewed International journal

Kensuke Uraguchi, Yukihide Maeda, Junko Takahara, Ryotaro Omichi, Shohei Fujimoto, Shin Kariya, Kazunori Nishizaki, Mizuo Ando

PloS one 16 ( 10 ) e0258977 2021

Language：English Publishing type：Research paper (scientific journal)

Epidemiological data suggest that inflammation and innate immunity play significant roles in the pathogenesis of age-related hearing loss (ARHL) in humans. In this mouse study, real-time RT-PCR array targeting 84 immune-related genes revealed that the expressions of 40 genes (47.6%) were differentially regulated with greater than a twofold change in 12-month-old cochleae with ARHL relative to young control mice, 33 (39.3%) of which were upregulated. These differentially regulated genes (DEGs) were involved in functional pathways for cytokine-cytokine receptor interaction, chemokine signaling, TNF signaling, and Toll-like receptor signaling. An NF-κB subunit, Nfkb1, was upregulated in aged cochleae, and bioinformatic analyses predicted that NF-κB would interact with the genomic regulatory regions of eight upregulated DEGs, including Tnf and Ptgs2. In aging cochleae, major proinflammatory molecules, IL1B and IL18rap, were upregulated by 6 months of age and thereafter. Remarkable upregulations of seven immune-related genes (Casp1, IL18r1, IL1B, Card9, Clec4e, Ifit1, and Tlr9) occurred at an advanced stage (between 9 and 12 months of age) of ARHL. Immunohistochemistry analysis of cochlear sections from the 12-month-old mice indicated that IL-18r1 and IL-1B were localized to the spiral ligament, spiral limbus, and organ of Corti. The two NF-κB-interacting inflammatory molecules, TNFα and PTGS2, immunolocalized ubiquitously in cochlear structures, including the lateral wall (the stria vascularis and spiral ligament), in the histological sections of aged cochleae. IBA1-positive macrophages were observed in the stria vascularis and spiral ligament in aged mice. Therefore, inflammatory and immune reactions are modulated in aged cochlear tissues with ARHL.

DOI： 10.1371/journal.pone.0258977

HPV E2, E4, E5 drive alternative carcinogenic pathways in HPV positive cancers. Reviewed International journal

Shuling Ren, Daria A Gaykalova, Theresa Guo, Alexander V Favorov, Elana J Fertig, Pablo Tamayo, Juan Luis Callejas-Valera, Mike Allevato, Mara Gilardi, Jessica Santos, Takahito Fukusumi, Akihiro Sakai, Mizuo Ando, Sayed Sadat, Chao Liu, Guorong Xu, Kathleen M Fisch, Zhiyong Wang, Alfredo A Molinolo, J Silvio Gutkind, Trey Ideker, Wayne M Koch, Joseph A Califano

Oncogene 39 ( 40 ) 6327 - 6339 2020.10

Language：English Publishing type：Research paper (scientific journal)

The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2/E4/E5, as well as association with lack of integration into the host genome. Models of the E2/E4/E5 carcinogenesis show p53 dependent enhanced proliferation in vitro, as well as increased susceptibility to induction of cancer in vivo. Whole genomic expression analysis of the E2/E4/E5 pharyngeal cancer subtype is defined by activation of the fibroblast growth factor receptor (FGFR) pathway and this subtype is susceptible to combination FGFR and mTOR inhibition, with implications for targeted therapy.

DOI： 10.1038/s41388-020-01431-8

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma. Reviewed International journal

Hideaki Hirai, Yuichiro Tada, Masato Nakaguro, Daisuke Kawakita, Yukiko Sato, Tomotaka Shimura, Kiyoaki Tsukahara, Satoshi Kano, Hiroyuki Ozawa, Kenji Okami, Yuichiro Sato, Chihiro Fushimi, Akira Shimizu, Isaku Okamoto, Soichiro Takase, Takuro Okada, Hiroki Sato, Yorihisa Imanishi, Kuninori Otsuka, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Takafumi Togashi, Yushi Ueki, Hisayuki Ota, Natsuki Saigusa, Hideaki Takahashi, Mizuo Ando, Makoto Urano, Toyoyuki Hanazawa, Toshitaka Nagao

Virchows Archiv : an international journal of pathology 477 ( 2 ) 291 - 299 2020.2

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1007/s00428-020-02777-w

A novel splice variant of LOXL2 promotes progression of human papillomavirus-negative head and neck squamous cell carcinoma. Reviewed International journal

Chao Liu, Theresa Guo, Akihiro Sakai, Shuling Ren, Takahito Fukusumi, Mizuo Ando, Sayed Sadat, Yuki Saito, Joseph A Califano

Cancer 126 ( 4 ) 737 - 748 2020.2

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequently diagnosed cancers worldwide. LOXL2 demonstrates alternative splicing events in patients with human papillomavirus (HPV)-negative HNSCC. The current study explored the role of a dominant LOXL2 variant in HPV-negative HNSCC. METHODS: Expression of the LOXL2 variant was analyzed using The Cancer Genome Atlas cohorts and validated using quantitative reverse transcriptase-polymerase chain reaction in a separate primary tumor set. The authors defined the effect of LOXL2 splice variants in assays for cell proliferation using a cell viability assay and colony formation assay. Cell migration and invasion were examined using a cell scratch assay and transwell cell migration and invasion assay in LOXL2 splice variant gain and loss of expression cells. Western blot analysis and gene set enrichment analysis were used to explore the potential mechanism of the LOXL2 splice variant in HPV-negative HNSCC. RESULTS: Expression of a novel LOXL2 variant was found to be upregulated in The Cancer Genome Atlas HPV-negative HNSCC, and confirmed in the separate primary tumor validation set. Analyses of loss and gain of function demonstrated that this LOXL2 variant enhanced proliferation, migration, and invasion in HPV-negative HNSCC cells and activated the FAK/AKT pathway. A total of 837 upregulated and 820 downregulated genes and 526 upregulated and 124 downregulated pathways associated with LOXL2 variant expression were identified using gene set enrichment analysis, which helped in developing a better understanding of the networks activated by this LOXL2 variant in patients with HPV-negative HNSCC. CONCLUSIONS: The novel LOXL2 variant can promote the progression of HPV-negative HNSCC, in part through FAK/AKT pathway activation, which may provide a new potential therapeutic target among patients with HPV-negative HNSCC.

DOI： 10.1002/cncr.32610

Cannabinoids promote progression of HPV positive head and neck squamous cell carcinoma via p38 MAPK activation. Reviewed International journal

Chao Liu, Sayed H Sadat, Koji Ebisumoto, Akihiro Sakai, Bharat A Panuganti, Shuling Ren, Yusuke Goto, Sunny Haft, Takahito Fukusumi, Mizuo Ando, Yuki Saito, Theresa Guo, Pablo Tamayo, Huwate Yeerna, William Kim, Jacqueline Hubbard, Andrew B Sharabi, J Silvio Gutkind, Joseph A Califano

Clinical cancer research : an official journal of the American Association for Cancer Research 26 ( 11 ) 2693 - 2703 2020.1

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: Human papilloma virus (HPV) related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV positive HNSCC. EXPERIMENTAL DESIGN: The expression of cannabinoid receptors CNR1 and CNR2 was analyzed using The Cancer Genome Atlas (TCGA) HNSCC data. We used agonists, antagonists, siRNAs or shRNA based models to explore the roles of CNR1 and CNR2 in HPV positive HNSCC cell lines and animal models. Cannabinoid downstream pathways involved were determined by Western blotting and analyzed in a primary HPV HNSCC cohort with single sample gene set enrichment analysis (ssGSEA) and the OncoGenome Positioning System (Onco-GPS). RESULTS: In TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV positive HNSCC compared with HPV negative HNSCC, and knockdown of CNR1/CNR2 expression inhibited proliferation in HPV positive HNSCC cell lines. Specific CNR1 and CNR2 activation as well as non-selective cannabinoid receptor activation in cell lines and animal models promoted cell growth, migration, and inhibited apoptosis through p38 MAPK pathway activation. CNR1/CNR2 antagonists suppressed cell proliferation and migration, and induced apoptosis. Using whole genome expression analysis in a primary HPV HNSCC cohort, we identified specific p38 MAPK pathway activation signature in tumors from HPV HNSCC patients with objective measurement of concurrent cannabinoid exposure. CONCLUSION: Cannabinoids can promote progression of HPV positive HNSCC through p38 MAPK pathway activation.

DOI： 10.1158/1078-0432.CCR-18-3301

Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing. Reviewed International journal

Akihiro Sakai, Mizuo Ando, Takahito Fukusumi, Shuling Ren, Chao Liu, Jesse Qualliotine, Sunny Haft, Sayed Sadat, Yuki Saito, Theresa W Guo, Guorong Xu, Roman Sasik, Kathleen M Fisch, J Silvio Gutkind, Elana J Fertig, Alfredo A Molinolo, Joseph A Califano

PloS one 15 ( 5 ) e0233380 2020

Language：English Publishing type：Research paper (scientific journal)

Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype. We identified 319 spliceosome genes and employed a discovery pipeline to identify 13 candidate spliceosome genes altered in HNSCC using The Cancer Genome Atlas (TCGA) HNSCC data. Phenotypic screens identified amplified and overexpressed CPSF1 as a target gene alteration that was validated in proliferation, colony formation, and apoptosis assays in cell line and xenograft systems as well as in primary HNSCC. We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models. Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.

DOI： 10.1371/journal.pone.0233380

Spinal solitary fibrous tumor of the neck: Next-generation sequencing-based analysis of genomic aberrations. Reviewed International journal

Mizuo Ando, Hiroshi Kobayashi, Aya Shinozaki-Ushiku, Hirotaka Chikuda, Yoshitaka Matsubayashi, Masafumi Yoshida, Yuki Saito, Shinji Kohsaka, Katsutoshi Oda, Kiyoshi Miyagawa, Hiroyuki Aburatani, Hiroyuki Mano, Tatsuya Yamasoba

Auris, nasus, larynx 47 ( 6 ) 1058 - 1063 2019.12

Language：English Publishing type：Research paper (scientific journal)

A solitary fibrous tumor (SFT) is a rare neoplasm with recurrent NAB2-STAT6 gene fusion. An SFT may develop almost anywhere throughout the body, including the head and neck region, and is characterized by a broad spectrum of malignancy. Here we present a case involving a 57-year-old male with a dumbbell-shaped SFT in the cervical spine that mimicked schwannoma. Repeated fine-needle aspiration cytology failed to establish a definitive diagnosis. Given that the tumor size increased significantly over a 10-month period, open biopsy was then performed. Though the biopsy result was inconclusive, a nonepithelial tumor, including sclerosing epithelioid fibrosarcoma or ossifying fibromyxoid tumor, was suspected. The tumor was then completely removed together with adjacent parts of C2 and C3 vertebrae and left vertebral artery via combined anterior and posterior approaches. Histologically, the tumor consisted of round cells with prominent stromal hyalinization and was immunohistochemically positive for STAT6, CD34, and cytokeratin. Finally, Todai OncoPanel, a next-generation sequencing-based molecular profiling system using formalin-fixed paraffin-embedded samples, demonstrated fusion transcript in which NAB2 exon 6 was fused to STAT6 exon 16 supporting the diagnosis of SFT, while whole-exome sequencing analysis detected no somatic mutations which were known to be oncogenic.

DOI： 10.1016/j.anl.2019.12.001

Rational genomic optimization of DNA detection for human papillomavirus type 16 in head and neck squamous cell carcinoma. Reviewed International journal

Yuki Saito, Alexander V Favorov, Michael Forman, Shuling Ren, Akihiro Sakai, Takahito Fukusumi, Chao Liu, Sayed Sadat, Mizuo Ando, Guorong Xu, Zubair Khan, John Pang, Alex Valsamakis, Kathleen M Fisch, Joseph A Califano

Head & neck 42 ( 4 ) 688 - 697 2019.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: We aimed to use genomic data for optimizing polymerase chain reaction (PCR) primer/probe sets for detection of human papillomavirus (HPV)-16 in body fluids of patients with HPV-related head and neck squamous cell carcinoma (HPV-HNSCC). METHODS: We used genomic HPV-HNSCC sequencing data from a single institutional and a TCGA cohort. Optimized primer/probe sets were designed and tested for analytical performance in CaSki HPV-16 genome and confirmed in salivary rinse samples from patients with HPV-HNSCC. RESULTS: The highest read density was observed between E5 and L2 regions. The E1 region contained a region that was universally present. Among candidate PCR primer/probe sets created, six reliably detected 30 HPV-16 copy number. In a CLIA certified laboratory setting, the combination of two novel primer/probe with E7 sets improved performance in salivary rinse samples with a sensitivity of 96% and specificity of 100%. CONCLUSIONS: PCR-based detection of HPV-16 DNA in HPV-HNSCC can be improved using rational genomic design.

DOI： 10.1002/hed.26041

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

Masato Nakaguro, Yukiko Sato, Yuichiro Tada, Daisuke Kawakita, Hideaki Hirai, Makoto Urano, Tomotaka Shimura, Kiyoaki Tsukahara, Satoshi Kano, Hiroyuki Ozawa, Kenji Okami, Yuichiro Sato, Chihiro Fushimi, Akira Shimizu, Soichiro Takase, Takuro Okada, Hiroki Sato, Yorihisa Imanishi, Kuninori Otsuka, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Takafumi Togashi, Yushi Ueki, Hisayuki Ota, Natsuki Saigusa, Hideaki Takahashi, Mizuo Ando, Toyoyuki Hanazawa, Toshitaka Nagao

The American journal of surgical pathology 44 ( 4 ) 526 - 535 2019.11

Language：English Publishing type：Research paper (scientific journal)

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; progression-free 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 high-risk (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.

DOI： 10.1097/PAS.0000000000001413

High CT attenuation values relative to the brainstem may predict squamous cell carcinoma arising from inverted papilloma. Reviewed International journal

Sanami Azuma, Shu Kikuta, Masafumi Yoshida, Mizuo Ando, Kenji Kondo, Tatsuya Yamasoba

Acta oto-laryngologica 139 ( 11 ) 1030 - 1037 2019.11

Language：English Publishing type：Research paper (scientific journal)

Background: A diagnostic indicator for differentiating squamous cell carcinomas (SCCs) from inverted papillomas (IPs) has not been established. Objectives: This study aimed to evaluate whether CT attenuation values relative to those of the brainstem (relative CT number) could be useful in differentiating IPs from SCCs. Material and Methods: Consecutive patients who were pathologically diagnosed with IP or SCC between 2007 and 2017 were retrospectively identified. Relative CT numbers were compared between the two patient groups. The factors with predictive power for differentiating IPs from SCCs were identified by univariate and multivariate logistic regression analyses. Results: Fifty-four sinonasal tumour cases were finally analysed (IP, 25 cases; SCC, 29 cases). Relative CT numbers were significantly higher in SCC than in IP (p < .001). The univariate logistic regression analysis showed BMI, relative CT number, and disease duration to have predictive value for differentiating IPs from SCCs. In the multivariate logistic regression analysis, only the relative CT number had predictive value for distinguishing IP from SCC (odds ratio, 1.97), with a relative CT number of ≥1.4 being significantly associated with SCC. Conclusions: High relative CT numbers could potentially be used to identify SCCs, and their measurement could provide a basis for differentiating IPs from SCCs.

DOI： 10.1080/00016489.2019.1659515

Mutation of chromatin regulators and focal hotspot alterations characterize human papillomavirus-positive oropharyngeal squamous cell carcinoma. Reviewed International journal

Sunny Haft, Shuling Ren, Guorong Xu, Adam Mark, Kathleen Fisch, Theresa W Guo, Zubair Khan, John Pang, Mizuo Ando, Chao Liu, Akihiro Sakai, Takahito Fukusumi, Joseph A Califano

Cancer 125 ( 14 ) 2423 - 2434 2019.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Human papillomavirus (HPV)-associated oropharyngeal cancer is a disease clinically and biologically distinct from smoking-related head and neck squamous cell carcinoma (HNSCC). Despite its rapidly increasing incidence, the mutational landscape of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) remains understudied. METHODS: This article presents the first mutational analysis of the 46 HPV+ OPSCC tumors within the newly expanded cohort of 530 HNSCC tumors from The Cancer Genome Atlas. A separate exome sequencing analysis was also performed for 46 HPV+ OPSCCs matched to their normal lymphocyte controls from the Johns Hopkins University cohort. RESULTS: There was a strikingly high 33% frequency of mutations within genes associated with chromatin regulation, including mutations in lysine methyltransferase 2C (KMT2C), lysine methyltransferase 2D (KMT2D), nuclear receptor binding SET domain protein 1 (NSD1), CREB binding protein (CREBBP), E1A-associated protein p300 (EP300), and CCCTC-binding factor (CTCF). In addition, the commonly altered genes phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) and fibroblast growth factor receptor 3 (FGFR3) showed distinct domain-specific hotspot mutations in comparison with their HPV- counterparts. PIK3CA showed a uniquely high rate of mutations within the helicase domain, and FGFR3 contained a predominance of hotspot S249C alterations that were not found in HPV- HNSCC. CONCLUSIONS: This analysis represents one of the largest studies to date of HPV+ OPSCC and lends novel insight into the genetic landscape of this biologically distinct disease, including a high rate of mutations in histone- and chromatin-modifying genes, which may offer novel therapeutic targets.

DOI： 10.1002/cncr.32068

Use of intensity-modulated radiation therapy for nasopharyngeal cancer in Japan: analysis using a national database. Reviewed International journal

Ryoko Rikitake, Yoichiro Tsukada, Mizuo Ando, Masafumi Yoshida, Momoko Iwamoto, Tatsuya Yamasoba, Takahiro Higashi

Japanese journal of clinical oncology 49 ( 7 ) 639 - 645 2019.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Intensity-modulated radiation therapy (IMRT) yields better outcomes and fewer toxicities for radiation therapy (RT) of head and neck cancers (HNCs), including nasopharyngeal cancer (NPC). IMRT is the standard RT treatment and has been widely adopted in Western countries to treat HNCs. However, its uptake in clinical practice among NPC patients has never been studied. METHODS: We investigated the use of IMRT for NPC using data from a nationwide cancer registry to describe the use of IMRT among NPC patients in Japan. We analyzed the data of patients with HNC, including NPC, who underwent IMRT between 2012 and 2014, as recorded in the hospital-based cancer registries linked with insurance claims. We calculated the proportion of patients with NPC who underwent IMRT at each hospital. To evaluate the use of IMRT for NPC, the IMRT use for NPC was compared with the proportion of patients with prostate cancer who underwent IMRT. RESULTS: Among 508 patients with NPC who underwent RT at one of 87 hospitals, 348 (69%) underwent IMRT. This proportion gradually increased between 2012 and 2014 (62%, 64% and 77%). Meanwhile, 4790 patients with prostate cancer (90%) underwent IMRT. Although some hospitals where IMRT was performed treated many patients with NPC, the proportion of patients with NPC who were treated with IMRT was low. CONCLUSIONS: IMRT has not been widely adopted in Japan for treating NPC. Barriers for adopting its use should be identified to close the gap between the standard and actual medical practice in Japan.

DOI： 10.1093/jjco/hyz042

Caloric restriction reduces basal cell proliferation and results in the deterioration of neuroepithelial regeneration following olfactotoxic mucosal damage in mouse olfactory mucosa. Reviewed International journal

Iwamura H, Kondo K, Kikuta S, Nishijima H, Kagoya R, Suzukawa K, Ando M, Fujimoto C, Toma-Hirano M, Yamasoba T

Cell and tissue research 378 ( 2 ) 175 - 193 2019.6

Language：English Publishing type：Research paper (scientific journal)

The effects of caloric restriction (CR) on cell dynamics and gene expression in the mouse olfactory neuroepithelium are evaluated. Eight-week-old male C57BL/6 mice were fed either control pellets (104 kcal/week) or CR pellets (67 kcal/week). The cytoarchitecture of the olfactory neuroepithelium in the uninjured condition and its regeneration after injury by an olfactotoxic chemical, methimazole, were compared between mice fed with the control and CR diets. In the uninjured condition, there were significantly fewer olfactory marker protein (OMP)-positive olfactory receptor neurons and Ki67-positive proliferating basal cells at 3 months in the CR group than in the control group. The number of Ki67-positive basal cells increased after methimazole-induced mucosal injury in both the control and the CR groups, but the increase was less robust in the CR group. The recovery of the neuroepithelium at 2 months after methimazole administration was less complete in the CR group than in the control group. These histological changes were region-specific. The decrease in the OMP-positive neurons was prominent in the anterior region of the olfactory mucosa. Gene expression analysis using a DNA microarray and quantitative real-time polymerase chain reaction demonstrated that the expression levels of two inflammatory cytokines, interleukin-6 and chemokine ligand 1, were elevated in the olfactory mucosa of the CR group compared with the control group. These findings suggest that CR may be disadvantageous to the maintenance of the olfactory neuroepithelium, especially when it is injured.

DOI： 10.1007/s00441-019-03047-1

Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers. Reviewed International journal

Mizuo Ando, Yuki Saito, Guorong Xu, Nam Q Bui, Kate Medetgul-Ernar, Minya Pu, Kathleen Fisch, Shuling Ren, Akihiro Sakai, Takahito Fukusumi, Chao Liu, Sunny Haft, John Pang, Adam Mark, Daria A Gaykalova, Theresa Guo, Alexander V Favorov, Srinivasan Yegnasubramanian, Elana J Fertig, Patrick Ha, Pablo Tamayo, Tatsuya Yamasoba, Trey Ideker, Karen Messer, Joseph A Califano

Nature communications 10 ( 1 ) 2188 - 2188 2019.5

Language：English Publishing type：Research paper (scientific journal)

Although promoter-associated CpG islands have been established as targets of DNA methylation changes in cancer, previous studies suggest that epigenetic dysregulation outside the promoter region may be more closely associated with transcriptional changes. Here we examine DNA methylation, chromatin marks, and transcriptional alterations to define the relationship between transcriptional modulation and spatial changes in chromatin structure. Using human papillomavirus-related oropharyngeal carcinoma as a model, we show aberrant enrichment of repressive H3K9me3 at the transcriptional start site (TSS) with methylation-associated, tumor-specific gene silencing. Further analysis identifies a hypermethylated subtype which shows a functional convergence on MYC targets and association with CREBBP/EP300 mutation. The tumor-specific shift to transcriptional repression associated with DNA methylation at TSSs was confirmed in multiple tumor types. Our data may show a common underlying epigenetic dysregulation in cancer associated with broad enrichment of repressive chromatin marks and aberrant DNA hypermethylation at TSSs in combination with MYC network activation.

DOI： 10.1038/s41467-019-09937-w

4E-BP1 Is a Tumor Suppressor Protein Reactivated by mTOR Inhibition in Head and Neck Cancer. Reviewed International journal

Wang Z, Feng X, Molinolo AA, Martin D, Vitale-Cross L, Nohata N, Ando M, Wahba A, Amornphimoltham P, Wu X, Gilardi M, Allevato M, Wu V, Steffen DJ, Tofilon P, Sonenberg N, Califano J, Chen Q, Lippman SM, Gutkind JS

Cancer research 79 ( 7 ) 1438 - 1450 2019.4

Language：English Publishing type：Research paper (scientific journal)

Aberrant activation of the PI3K-mTOR signaling pathway occurs in >80% of head and neck squamous cell carcinomas (HNSCC), and overreliance on this signaling circuit may in turn represent a cancer-specific vulnerability that can be exploited therapeutically. mTOR inhibitors (mTORi) promote tumor regression in genetically defined and chemically induced HNSCC animal models, and encouraging results have been recently reported. However, the mTOR-regulated targets contributing to the clinical response have not yet been identified. Here, we focused on EIF4E-BP1 (4E-BP1), a direct target of mTOR that serves as key effector for protein synthesis. A systematic analysis of genomic alterations in the PIK3CA-mTOR pathway in HNSCC revealed that 4E-BP1 is rarely mutated, but at least one 4E-BP1 gene copy is lost in over 35% of the patients with HNSCC, correlating with decreased 4E-BP1 protein expression. 4E-BP1 gene copy number loss correlated with poor disease-free and overall survival. Aligned with a tumor-suppressive role, 4e-bp1/2 knockout mice formed larger and more lesions in models of HNSCC carcinogenesis. mTORi treatment or conditional expression of a mutant 4E-BP1 that cannot be phosphorylated by mTOR was sufficient to disrupt the translation-initiation complex and prevent tumor growth. Furthermore, CRISPR/Cas9-targeted 4E-BP1 HNSCC cells resulted in reduced sensitivity to mTORi in vitro and in vivo. Overall, these findings indicate that in HNSCC, mTOR persistently restrains 4E-BP1 via phosphorylation and that mTORi can restore the tumor-suppressive function of 4E-BP1. Our findings also support 4E-BP1 expression and phosphorylation status as a mechanistic biomarker of mTORi sensitivity in patients with HNSCC. SIGNIFICANCE: These findings suggest that EIF4E-BP1 acts as a tumor suppressor in HNSCC and that 4E-BP1 dephosphorylation mediates the therapeutic response to mTORi, providing a mechanistic biomarker for future precision oncology trials.

DOI： 10.1158/0008-5472.CAN-18-1220

Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin-fixed paraffin-embedded specimens. Reviewed International journal

Shinji Kohsaka, Kenji Tatsuno, Toshihide Ueno, Masaaki Nagano, Aya Shinozaki-Ushiku, Tetsuo Ushiku, Daiya Takai, Masachika Ikegami, Hiroshi Kobayashi, Hidenori Kage, Mizuo Ando, Keisuke Hata, Hiroki Ueda, Shogo Yamamoto, Shinya Kojima, Kumiko Oseto, Keisuke Akaike, Yoshiyuki Suehara, Takuo Hayashi, Tsuyoshi Saito, Fumiyuki Takahashi, Kazuhisa Takahashi, Kazuya Takamochi, Kenji Suzuki, Satoshi Nagayama, Yoshinao Oda, Koshi Mimori, Soichiro Ishihara, Yutaka Yatomi, Takahide Nagase, Jun Nakajima, Sakae Tanaka, Masashi Fukayama, Katsutoshi Oda, Masaomi Nangaku, Kohei Miyazono, Kiyoshi Miyagawa, Hiroyuki Aburatani, Hiroyuki Mano

Cancer science 110 ( 4 ) 1464 - 1479 2019.4

Language：English Publishing type：Research paper (scientific journal)

Tumor molecular profiling is becoming a standard of care for patients with cancer, but the optimal platform for cancer sequencing remains undetermined. We established a comprehensive assay, the Todai OncoPanel (TOP), which consists of DNA and RNA hybridization capture-based next-generation sequencing panels. A novel method for target enrichment, named the junction capture method, was developed for the RNA panel to accurately and cost-effectively detect 365 fusion genes as well as aberrantly spliced transcripts. The TOP RNA panel can also measure the expression profiles of an additional 109 genes. The TOP DNA panel was developed to detect single nucleotide variants and insertions/deletions for 464 genes, to calculate tumor mutation burden and microsatellite instability status, and to infer chromosomal copy number. Clinically relevant somatic mutations were identified in 32.2% (59/183) of patients by prospective TOP testing, signifying the clinical utility of TOP for providing personalized medicine to cancer patients.

DOI： 10.1111/cas.13968

All-Exon TP53 Sequencing and Protein Phenotype Analysis Accurately Predict Clinical Outcome after Surgical Treatment of Head and Neck Squamous Cell Carcinoma. Reviewed International journal

Kobayashi K, Yoshimoto S, Matsumoto F, Ando M, Murakami N, Omura G, Fukasawa M, Matsumoto Y, Matsumura S, Akamatsu M, Hiraoka N, Eigitsu R, Mori T

Annals of surgical oncology 26 ( 7 ) 2294 - 2303 2019.3

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: This study elucidates the clinical impact of surgical treatment of head and neck squamous cell carcinoma (HNSCC) based on a detailed search of all exons of the TP53 gene and p53 protein phenotypic analysis using formalin-fixed paraffin-embedded (FFPE) specimens. METHODS: Clinically well-annotated FFPE specimens from 317 patients with HNSCC treated by surgery were examined by all-exon TP53 sequencing using a next-generation sequencer and p53 protein phenotype by immunohistochemistry. After excluding human papillomavirus-associated oropharyngeal carcinomas, two risk categories were classified as "p53 adverse function" and "p53 favorable function" based on TP53 mutation status and p53 protein phenotype. Mutation in PIK3CA, AKT, and HRAS was also evaluated by target sequence. Cox proportional hazards regression models were used for statistical analysis of clinical outcomes. Receiver operating characteristic curve analysis was used to determine the optimal surgical margin cutoff for local recurrence. Local control rates were compared between the risk groups using Fisher's exact test. RESULTS: Multivariate analysis identified "p53 adverse function" as an independent poor predictor of overall survival, local control, and distant metastasis-free survival. In oral cavity cancer, the optimal surgical margin cutoff associated with local recurrence was 6 mm. In patients with surgical margin > 6 mm, the "p53 adverse function" group demonstrated significantly higher local recurrence rate than the "p53 favorable function" group. PIK3CA, AKT, or HRAS mutation did not correlate with improved overall survival. CONCLUSIONS: All-exon TP53 sequencing and p53 protein phenotype analysis using FFPE specimens can accurately predict clinical outcomes.

DOI： 10.1245/s10434-019-07287-x

Discovery and development of differentially methylated regions in human papillomavirus-related oropharyngeal squamous cell carcinoma. Reviewed International journal

Shuling Ren, Daria Gaykalova, Jennifer Wang, Theresa Guo, Ludmila Danilova, Alexander Favorov, Elana Fertig, Justin Bishop, Zubair Khan, Emily Flam, Piotr T Wysocki, Peter DeJong, Mizuo Ando, Chao Liu, Akihiro Sakai, Takahito Fukusumi, Sunny Haft, Sayed Sadat, Joseph A Califano

International journal of cancer 143 ( 10 ) 2425 - 2436 2018.11

Language：English Publishing type：Research paper (scientific journal)

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) exhibits a different composition of epigenetic alterations. In this study, we identified differentially methylated regions (DMRs) with potential utility in screening for HPV-positive OPSCC. Genome wide DNA methylation was measured using methyl-CpG binding domain protein-enriched genome sequencing (MBD-seq) in 50 HPV-positive OPSCC tissues and 25 normal tissues. Fifty-one DMRs were defined with maximal methylation specificity to cancer samples. The Cancer Genome Atlas (TCGA) methylation array data was used to evaluate the performance of the proposed candidates. Supervised hierarchical clustering of 51 DMRs found that HPV-positive OPSCC had significantly higher DNA methylation levels compared to normal samples, and non-HPV-related head and neck squamous cell carcinoma (HNSCC). The methylation levels of all top 20 DNA methylation biomarkers in HPV-positive OPSCC were significantly higher than those in normal samples. Further confirmation using quantitative methylation specific PCR (QMSP) in an independent set of 24 HPV-related OPSCCs and 22 controls showed that 16 of the 20 candidates had significant higher methylation levels in HPV-positive OPSCC samples compared with controls. One candidate, OR6S1, had a sensitivity of 100%, while 17 candidates (KCNA3, EMBP1, CCDC181, DPP4, ITGA4, BEND4, ELMO1, SFMBT2, C1QL3, MIR129-2, NID2, HOXB4, ZNF439, ZNF93, VSTM2B, ZNF137P and ZNF773) had specificities of 100%. The prediction accuracy of the 20 candidates rang from 56.2% to 99.8% by receiver operating characteristic analysis. We have defined 20 highly specific DMRs in HPV-related OPSCC, which can potentially be applied to molecular-based detection tests and improve disease management.

DOI： 10.1002/ijc.31778

Characterization of Alternative Splicing Events in HPV-Negative Head and Neck Squamous Cell Carcinoma Identifies an Oncogenic DOCK5 Variant. Reviewed International journal

Chao Liu, Theresa Guo, Guorong Xu, Akihiro Sakai, Shuling Ren, Takahito Fukusumi, Mizuo Ando, Sayed Sadat, Yuki Saito, Zubair Khan, Kathleen M Fisch, Joseph Califano

Clinical cancer research : an official journal of the American Association for Cancer Research 24 ( 20 ) 5123 - 5132 2018.10

Language：English Publishing type：Research paper (scientific journal)

Purpose: Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide, and alternative splicing is considered to play important roles in tumor progression. Our study is designed to identify alternative splicing events (ASEs) in human papillomavirus (HPV)-negative HNSCC.Experimental Design: RNA sequencing data of 407 HPV-negative HNSCC and 38 normal samples were obtained from The Cancer Genome Atlas (TCGA), and splice junctions were discovered using MapSplice. Outlier analysis was used to identify significant splicing junctions between HPV-negative HNSCC and normal samples. To explore the functional role of the identified DOCK5 variant, we checked its expression with qRT-PCR in a separate primary tumor validation set and performed proliferation, migration, and invasion assays.Results: A total of 580 significant splicing events were identified in HPV-negative HNSCC, and the most common type of splicing events was an alternative start site (33.3%). The prevalence of a given individual ASE among the tumor cohort ranged from 9.8% and 64.4%. Within the 407 HPV-negative HNSCC samples in TCGA, the number of significant ASEs differentially expressed in each tumor ranged from 17 to 290. We identified a novel candidate oncogenic DOCK5 variant confirmed using qRT-PCR in a separate primary tumor validation set. Loss- and gain-of-function experiments indicated that DOCK5 variant promoted proliferation, migration, and invasion of HPV-negative HNSCC cells, and patients with higher expression of DOCK5 variant showed decreased overall survival.Conclusions: Analysis of ASEs in HPV-negative HNSCC identifies multiple alterations likely related to carcinogenesis, including an oncogenic DOCK5 variant. Clin Cancer Res; 24(20); 5123-32. ©2018 AACR.

DOI： 10.1158/1078-0432.CCR-18-0752

Postoperative mechanical bowel obstruction after pharyngolaryngectomy for hypopharyngeal cancer: Retrospective analysis using a Japanese inpatient database. Reviewed International journal

Sayaka Suzuki, Hideo Yasunaga, Hiroki Matsui, Kiyohide Fushimi, Mizuo Ando, Tatsuya Yamasoba

Head & neck 40 ( 7 ) 1548 - 1554 2018.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Data have been limited on donor-site mechanical bowel obstruction after pharyngolaryngectomy with free jejunum graft reconstruction. METHODS: Using a nationwide Japanese inpatient database, we extracted data on patients who underwent pharyngolaryngectomy for hypopharyngeal cancer between July 2007 and March 2014. A Cox proportional hazard model was used to determine the association between background characteristics and the occurrence of mechanical bowel obstruction. RESULTS: Among the 3320 eligible patients from 332 hospitals, 108 patients (3.3%) developed mechanical bowel obstruction after a median 88 (interquartile range 26-217) postoperative days. Multivariable Cox regression analysis revealed that older age (≥60 years old) was independently associated with an increased risk of mechanical bowel obstruction, whereas sex, body mass index [BMI], smoking status, comorbidity at admission, blood transfusion, history of surgery, and hospital type were not. CONCLUSION: In pharyngolaryngectomy, careful attention should be paid to the risk of abdominal complications and, thus, to the graft choice, especially in elderly patients.

DOI： 10.1002/hed.25139

Radiotherapy alone and with concurrent chemotherapy for nasopharyngeal carcinoma Reviewed

Atsuto Katano, Wataru Takahashi, Hideomi Yamashita, Kentaro Yamamoto, Mizuo Ando, Masafumi Yoshida, Yuki Saito, Osamu Abe, Keiichi Nakagawa

Medicine (United States) 97 ( 18 ) e0502 2018.5

Publishing type：Research paper (scientific journal)

Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. We sought to evaluate clinical outcomes and toxicities of radiation therapy (RT) alone compared to RT with concurrent chemotherapy (CCT) for nasopharyngeal carcinoma (NPC) treatment. We conducted a retrospective review of consecutive patients with biopsy-proven nonmetastatic NPC who underwent RT at our institution. From May 2001 to April 2015; 62 newly diagnosed NPC patients were treated with three-dimensional conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT) with or without CCT. The patients were classified as follows: 8% stage I, 15% stage II, 32% stage III, and 45% stage IVA/IVB. A total of 76% of tumors were World Health Organization types II or III. Acute and late toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0. Overall survival (OS), progression-free survival (PFS), locoregional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS) were analyzed. The median follow-up period for living patients was 53 months. The median actual delivered dose was 70 Gy with a range of 28 to 70 Gy in fraction sizes of 2 Gy. The estimated 5-year OS, PFS, LRPFS, and DMFS rates were 72.7%, 59.8%, 77.9%, and 84.2%, respectively. The use of CCT was a predictive factor of significantly better OS and PFS, whereas stage IV was a significant predictor of poor OS and PFS. The most severe acute toxicities included Grade 3 mucositis in 56% and Grade 3 dermatitis in 8%. Subset analysis revealed that Grade 2 xerostomia was significantly lower in the IMRT (23%) group than in the 3D-CRT (52%) group (P = .02). RT yielded favorable outcomes. CCT was associated with longer PFS and OS than RT alone.

DOI： 10.1097/MD.0000000000010502

The NOTCH4-HEY1 Pathway Induces Epithelial-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma. Reviewed International journal

Takahito Fukusumi, Theresa W Guo, Akihiro Sakai, Mizuo Ando, Shuling Ren, Sunny Haft, Chao Liu, Panomwat Amornphimoltham, J Silvio Gutkind, Joseph A Califano

Clinical cancer research : an official journal of the American Association for Cancer Research 24 ( 3 ) 619 - 633 2018.2

Language：English Publishing type：Research paper (scientific journal)

Purpose: Recently, several comprehensive genomic analyses demonstrated NOTCH1 and NOTCH3 mutations in head and neck squamous cell carcinoma (HNSCC) in approximately 20% of cases. Similar to other types of cancers, these studies also indicate that the NOTCH pathway is closely related to HNSCC progression. However, the role of NOTCH4 in HNSCC is less well understood.Experimental Design: We analyzed NOTCH4 pathway and downstream gene expression in the TCGA data set. To explore the functional role of NOTCH4, we performed in vitro proliferation, cisplatin viability, apoptosis, and cell-cycle assays. We also compared the relationships among NOTCH4, HEY1, and epithelial-mesenchymal transition (EMT)-related genes using the TCGA data set and in vitro assays.Results:HEY1 is specifically upregulated in HNSCC compared with normal tissues in the TCGA data set. NOTCH4 is more significantly related to HEY1 activation in HNSCC in comparison with other NOTCH receptors. NOTCH4 promotes cell proliferation, cisplatin resistance, inhibition of apoptosis, and cell-cycle dysregulation. Furthermore, NOTCH4 and HEY1 upregulation resulted in decreased E-cadherin expression and increased Vimentin, Fibronectin, TWIST1, and SOX2 expression. NOTCH4 and HEY1 expression was associated with an EMT phenotype as well as increased invasion and cell migration.Conclusions: In HNSCC, the NOTCH4-HEY1 pathway is specifically upregulated, induces proliferation and cisplatin resistance, and promotes EMT. Clin Cancer Res; 24(3); 619-33. ©2017 AACR.

DOI： 10.1158/1078-0432.CCR-17-1366

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

Tomotaka Shimura, Yuichiro Tada, Hideaki Hirai, Daisuke Kawakita, Satoshi Kano, Kiyoaki Tsukahara, Akira Shimizu, Soichiro Takase, Yorihisa Imanishi, Hiroyuki Ozawa, Kenji Okami, Yuichiro Sato, Yukiko Sato, Chihiro Fushimi, Hideaki Takahashi, Takuro Okada, Hiroki Sato, Kuninori Otsuka, Yoshihiro Watanabe, Akihiro Sakai, Koji Ebisumoto, Takafumi Togashi, Yushi Ueki, Hisayuki Ota, Mizuo Ando, Shinji Kohsaka, Toyoyuki Hanazawa, Hideaki Chazono, Yoshiyuki Kadokura, Hitome Kobayashi, Toshitaka Nagao

Oncotarget 9 ( 2 ) 1852 - 1867 2018.1

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.18632/oncotarget.22927

The prognostic value of TP53 mutations in hypopharyngeal squamous cell carcinoma Reviewed

Go Omura, Mizuo Ando, Yasuhiro Ebihara, Yuki Saito, Kenya Kobayashi, Osamu Fukuoka, Ken Akashi, Masafumi Yoshida, Takahiro Asakage, Tatsuya Yamasoba

BMC Cancer 17 ( 1 ) 898 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：BioMed Central Ltd.

Background: TP53 is the most frequently mutated gene in human cancers. Previous studies reported that TP53 mutations correlated with poor prognoses in patients with head and neck squamous cell carcinoma (HNSCC). However, the relationship between TP53 mutations and hypopharyngeal squamous cell carcinoma (HPSCC) is not known. The current study aimed to evaluate TP53 mutation status as a predictive biomarker in patients with HPSCC. Methods: We retrospectively reviewed the clinical charts of 57 HPSCC patients treated with initial surgery between 2008 and 2014. TP53 mutation status was determined by Sanger sequencing, and patients were classified into wild-type, missense mutation, and truncating mutation groups. Additionally, p53 expression was determined using immunohistochemistry in surgical specimens. Results: TP53 mutations were identified in 39 (68%) patients. The 3-year disease-specific survival (DSS) rate of wild-type, missense mutation, and truncating mutation group were 94%, 61%, and 43%, respectively. The TP53 mutation group displayed significantly worse DSS and overall survival rates than the wild-type group (P = 0.01 and P = 0.007, respectively). Multivariate analyses revealed that the presence of TP53 mutations and ≥4 metastatic lymph nodes were independent adverse prognostic factors for HPSCC. p53 immunopositivity was detected in 22 patients, including 5 (28%) and 17 (71%) patients in the wild-type and missense mutation groups, whereas none of the patients with truncating mutation exhibited p53 immunopositivity (P = 0.0001). Conclusion: The TP53 mutation status correlated with poor prognosis in surgically treated HPSCC patients. Specifically, truncating mutations which were not detected by p53 immunohistochemistry were predictive of worst survival.

DOI： 10.1186/s12885-017-3913-1

Prognostic value of ALDH2 polymorphism for patients with oropharyngeal cancer in a Japanese population Reviewed

Hirotaka Shinomiya, Hitomi Shinomiya, Mie Kubo, Yuki Saito, Masafumi Yoshida, Mizuo Ando, Masanori Teshima, Naoki Otsuki, Naomi Kiyota, Ryohei Sasaki, Kenichi Nibu

PLOS ONE 12 ( 12 ) e0187992 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Background
Half of Japanese possess a polymorphism of aldehyde dehydrogenase 2(ALDH2), while few white individuals possess this mutation. The purpose of this study was to investigate the possibility of ALDH2 polymorphism as a prognostic factor for oropharyngeal cancer (OPC) among Japanese population.
Methods
We analyzed 82 Japanese patients with OPC treated between 2006 and 2011. The median observation period was 50 months. P16-staining and ALDH2 polymorphisms were investigated. To examine the frequencies of second primary pharyngeal and esophageal cancers (SPPEC), 37 Japanese patients with OPC treated at Tokyo University Hospital were included for statistical analysis.
Results
Statistically significant differences were noted in OS among sex, age, N classification, and p16 (p = 0.045, 0.024, 0.020, 0.007, respectively). In addition, OS and DSS rates of the patients with heterozygous ALDH2 tended to be worse than those of the patients with homozygous ALDH2 (p = 0.21, 0.086, respectively). Of note, OS and DSS of the patients with p16-negative OPC and heterozygous ALDH2 was significant poorer than those of the patients with p16-positive OPC (p = 0.002, 0.006, respectively), while there was no significant difference in OS and DSS between patients with p16-positive OPC and patients with p16-negative OPC and homozygous ALDH2.
Conclusions
ALDH2 polymorphism might be a promising prognostic factor for Japanese patients with p16-negative OPC.

DOI： 10.1371/journal.pone.0187992

The impact of elevated C-reactive protein level on the prognosis for oro-hypopharynx cancer patients treated with radiotherapy Reviewed

Atsuto Katano, Wataru Takahashi, Hideomi Yamashita, Kentaro Yamamoto, Mizuo Ando, Masafumi Yoshida, Yuki Saito, Osamu Abe, Keiichi Nakagawa

SCIENTIFIC REPORTS 7 ( 1 ) 17805 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

The purpose of this study was to investigate an association between the prognosis for oro-hypopharynx squamous cell carcinoma treated with radiation therapy and the pre-therapeutic level of C-reactive protein (CRP). Patient with oro-hypopharyngeal squamous cell carcinoma who underwent definitive radiotherapy in our institution from January 2002 to August 2016 were enrolled. The patient were divided into elevated CRP (over 0.3 mg/dl) group and normal CRP groups, according to pre-treatment serum levels. There were 276 evaluable patients, and the median follow up was 41 months, ranging from 2 to 171 months. The 3-year OS and CSS for all enrolled patients were 67.0% and 72.8%, respectively. The OS and CSS rates were significantly worse in the elevated CRP group than in the normal CRP group, according to Kaplan-Meier survival curves analysed by a Log-rank test (p = 0.005 and p < 0.001, respectively). Multivariate analyses indicated that serum CRP levels remained independent predictors for both OS (HR: 1.588, p = 0.022) and CSS (HR: 1.989, p = 0.005). The pre-treatment CRP level is an independent predictor of treatment prognosis in patients with oro-hypopharyngeal cancer who underwent definitive radiotherapy. Especially, it is curious that an elevated CRP serum level is a significant predictor of loco-regional recurrence.

DOI： 10.1038/s41598-017-18233-w

Current status of superficial pharyngeal squamous cell carcinoma in Japan Reviewed

Ryoko Rikitake, Mizuo Ando, Yuki Saito, Seiichi Yoshimoto, Tatsuya Yamasoba, Takahiro Higashi

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 22 ( 5 ) 826 - 833 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

To investigate the status and treatment of superficial pharyngeal squamous cell carcinoma in Japan.
We analyzed all cases diagnosed between 2011 and 2013, as recorded in the national database of hospital-based cancer registries. We extracted data on patient sex, age, tumor locations, histology, presentation routes, initial treatments, and TNM stages. Additionally, we compared the characteristics of pharyngeal carcinoma to those of esophageal cancer.
A total of 16,521 oropharyngeal and hypopharyngeal cancers from 409 institutions were included. Diagnosis of Tis tumors was infrequent, and both cancers were likely to be diagnosed at an advanced stage (n = 866, 5.3%). Tis diseases were the most commonly detected during follow-up examinations for other diseases (n = 608, 70%). While more oropharyngeal Tis patients were men compared to T1-4 patients (88 vs 82%, respectively), hypopharyngeal cancer patients comprised an equally high proportion of men (94 vs 92%, respectively). The most common location of oropharyngeal Tis tumors was the posterior wall (32%), whereas T1-4 tumors were most commonly found on the lateral wall (36%). In hypopharyngeal cancer, both Tis and T1-4 were most commonly located in the pyriform sinus (62%). The proportion of Tis tumors diagnosed at individual institutions showed a positive correlation with the number of endoscopic treatments (r = 0.32, P < 0.001) and the number of esophageal cancer cases (r = 0.37, P < 0.001).
Our national database study elucidated the current characteristics of superficial pharyngeal squamous cell carcinoma patients in Japan. Further improvements in early diagnosis and standardized treatments are warranted.

DOI： 10.1007/s10147-017-1135-9

Prognostic value of lymphovascular invasion of the primary tumor in hypopharyngeal carcinoma after total laryngopharyngectomy Reviewed

Yuki Saito, Go Omura, Kazuo Yasuhara, Ryoko Rikitake, Ken Akashi, Osamu Fukuoka, Masafumi Yoshida, Mizuo Ando, Takahiro Asakage, Tatsuya Yamasoba

HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK 39 ( 8 ) 1535 - 1543 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Background. We aimed to determinate the prognostic value of lymphovascular invasion in the specimens resected during total laryngopharyngectomy for hypopharyngeal carcinoma.
Methods. Patients who underwent total laryngopharyngectomy at our institution between 2004 and 2014 were included in this study and retrospectively analyzed. We then discriminated for vascular invasion and lymphatic invasion of the primary tumor in all cases.
Results. We reviewed 135 records (120 men and 15 women; age range, 36-84 years). Tumors with lymphatic invasion tended to be associated with more metastatic lymph nodes and extracapsular spread (ECS) of metastatic lymph nodes. Tumors with vascular invasion tended to be associated with nonpyriform sinus locations. In a multivariate analysis, nonpyriform sinus locations, >3 metastatic lymph nodes, and vascular invasion remained significant prognostic factors for overall survival (OS); in recursive partitioning analysis, ECS and vascular invasion remained important categorical variables for OS.
Conclusion. Vascular invasion is a strong prognostic biomarker for advanced hypopharyngeal carcinoma. (C) 2017 Wiley Periodicals, Inc.

DOI： 10.1002/hed.24705

Prolonged denervation induces remodeling of nasal mucosa in rat model of posterior nasal neurectomy Reviewed

Hironobu Nishijima, Kenji Kondo, Makiko Toma-Hirano, Shu Kikuta, Mizuo Ando, Rumi Ueha, Tatsuya Yamasoba

INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY 7 ( 7 ) 670 - 678 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Background: The posterior nasal nerve is the dominant source of the parasympathetic, sympathetic, and sensory fibers that innervate the nasal respiratory mucosa. Therefore, a posterior nasal neurectomy (PNN) induces denervation of the nasal mucosa and relieves the nasal symptoms of intractable rhinitis. PNN depletes nerve fibers, choline acetyltransferase, and neuropeptides in nasal respiratory mucosa, and reduces nasal secretion. However, the histological and symptomatic changes over an extended period after PNN remain unknown.
Methods: Using a rat model of PNN via the transorbital approach, we investigated chronological changes of nasal morphology, innervation, and secretion over a 48-week postoperative period after PNN.
Results: The respiratory nasal mucosa exhibited squamous metaplasia, lymphocyte and plasma cell infiltration, basement membrane thickening, loss of cilia, and hyperplasia of the mucus gland in thickened epithelium with increased connective tissue from24 weeks after PNN. These changes resemble the characteristics of remodeling in chronic rhinosinusitis. DNA microarray and quantitative polymerase chain reaction analysis revealed that mucin 5ac, interleukin 13, and brain-derived neurotrophic factor messenger RNA ( mRNA) were upregulated in PNN-treatedmucosa compared to untreated mucosa. During this period, nerve fibers including sensory, sympathetic, and parasympathetic fibers gradually reinnervated the mucosa from 12 weeks after PNN. However, nasal secretion was decreased even at 48 weeks after PNN probably due to the prolonged absence of choline acetyltransferase.
Conclusion: Prolonged denervation induces remodeling of the nasal mucosa. Although the depleted nerves were partially reinnervated a few months after PNN, nasal secretion was still suppressed, partly due to a sustained deficiency of acetylcholine synthesis. (C) 2017 ARS-AAOA, LLC.

DOI： 10.1002/alr.21952

Survival impact of local extension sites in surgically treated patients with temporal bone squamous cell carcinoma Reviewed

Go Omura, Mizuo Ando, Yuki Saito, Osamu Fukuoka, Ken Akashi, Masafumi Yoshida, Akinobu Kakigi, Takahiro Asakage, Tatsuya Yamasoba

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 22 ( 3 ) 431 - 437 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Objectives Temporal bone squamous cell carcinoma (TSCC) is a rare malignancy. Due to its low incidence rate, studies involving TSCC treatment are limited. The aim of this study is to define the prognostic factors of surgery for TSCC by evaluating our clinical experience.
Methods We reviewed the clinical charts of patients presenting at the University of Tokyo Hospital between 2001 and 2014 and identified 33 patients with TSCC who had been treated with surgery as initial curative treatment.
Results Lateral and subtotal temporal bone resections were performed in 17 and 16 patients, respectively. The 5-year disease-specific and overall survival rate were 71 and 62%, respectively. The significant poor prognostic factors were pathological T4 (P = 0.03), dural invasion (P = 0.008), temporomandibular joint invasion (P = 0.04), and a positive surgical margin (P = 0.009).
Conclusion We demonstrated that the outcome of curative surgery for TSCC as initial treatment was favorable. However, because of the difficulty to ensure an adequate or clear surgical margin due to anatomical complexity, the surgical indication for T4 TSCC with temporomandibular joint invasion should be reconsidered.

DOI： 10.1007/s10147-016-1076-8

Association between ear-picking habits and carcinoma of external auditory canal Reviewed

Ryohei Ishiura, Takuya Iida, Akinobu Kakigi, Mizuo Ando, Masafumi Yoshida, Yuki Saito, Tatsuya Yamasoba, Isao Koshima

Japanese Journal of Head and Neck Cancer 43 ( 1 ) 76 - 78 2017

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Society for Head and Neck Cancer

Carcinoma of the external auditory canal (EAC) is a very rare disease. Although a relationship between frequent ear-picking and EAC carcinoma has been suspected, no statistical analysis has been reported. We retrospectively reviewed ear-picking habit in patients with carcinoma of EAC and in healthy Japanese people and statistically analyzed the data. As a result, in the“ younger ( under 50 years old)” group, both“ frequency” and“ materials” showed a significant difference between the patients and the healthy population( p=0.0021 and p=0.0012, respectively). Ear-picking more than once a day and with hard materials might be risk factors for carcinoma of EAC in the younger generation.

DOI： 10.5981/jjhnc.43.76

Association of the upregulated expression of focal adhesion kinase with poor prognosis and tumor dissemination in hypopharyngeal cancer Reviewed

Go Omura, Mizuo Ando, Yuki Saito, Kenya Kobayashi, Masafumi Yoshida, Yasuhiro Ebihara, Kaori Kanaya, Chisato Fujimoto, Takashi Sakamoto, Kenji Kondo, Takahiro Asakage, Tatsuya Yamasoba

HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK 38 ( 8 ) 1164 - 1169 2016.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

BackgroundFocal adhesion kinase (FAK) plays an important role in tumor metastasis. The purpose of this study was to evaluate the significance of FAK expression in surgically treated patients with hypopharyngeal cancer.
MethodsWe retrospectively reviewed the clinical charts of patients treated at our institution between 2004 and 2012 and identified 87 patients with hypopharyngeal cancer. FAK expression status was retrospectively evaluated using immunohistochemistry.
ResultsFAK-positive patients displayed significantly worse disease-specific survival than FAK-negative patients (p=.001). Multivariate analyses revealed that FAK positivity and extracapsular spread (ECS) were independent, significant adverse prognostic factors. Furthermore, FAK positivity significantly correlated with the number of metastatic lymph nodes (p=.048), and FAK-positive patients displayed a higher incidence of distant metastases (p=.009).
ConclusionThe current study demonstrated that upregulated FAK expression correlates with poor prognosis and tumor dissemination in surgically treated patients with hypopharyngeal cancer. (c) 2016 Wiley Periodicals, Inc. Head Neck 38:1164-1169, 2016

DOI： 10.1002/hed.24176

Induction Chemotherapy for p16 Positive Oropharyngeal Squamous Cell Carcinoma. Reviewed International journal

Yuki Saito, Mizuo Ando, Go Omura, Kazuo Yasuhara, Masafumi Yoshida, Wataru Takahashi, Tatsuya Yamasoba

Laryngoscope investigative otolaryngology 1 ( 2 ) 28 - 32 2016.4

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVES/HYPOTHESIS: We aimed to determine the effectiveness of induction chemotherapy for treating p16-positive oropharyngeal cancer in our department. STUDY DESIGN: This was a retrospective case series to assess treatment effectiveness. METHODS: We administered induction chemotherapy to patients with stage III to IV oropharyngeal p16-positive squamous cell carcinoma between 2008 and 2013. Induction chemotherapy was administered using combinations of docetaxel, cisplatin, and 5-fluorouracil. We measured the survival rates using the Kaplan-Meier method and log-rank test. RESULTS: We reviewed 23 patients (18 men and 5 women; age, 42-79 years). Induction chemotherapy resulted in partial or complete remission (20 patients) and in stable (2 patients) or progressive (1 patient) disease. In partial or complete remission, subsequent radiotherapy was performed in 16 patients, chemoradiotherapy in two, and transoral resection in two. In stable or progressive disease, subsequent open surgery was performed. Overall, one patient died of cervical lymph node metastasis, one died of kidney cancer, and one died of myocardial infarction. Event-free, distant-metastasis-free survival was present for 20 patients. The 3-year disease-specific survival was 95%; the overall survival was 87%. Two patients required gastrostomies during chemoradiotherapy and three required tracheotomies, but these were closed in all patients. CONCLUSION: The therapeutic response to induction chemotherapy for p16-positive oropharyngeal cancer was good. Partial or complete remission was achieved in almost 90% patients, and control of local and distant metastases was possible when it was followed by radiotherapy alone or with transoral resection of the primary tumor. A multicenter study is required to confirm these findings. LEVEL OF EVIDENCE: 4.

DOI： 10.1002/lio2.18

Mutational Landscape and Antiproliferative Functions of ELF Transcription Factors in Human Cancer Reviewed

Mizuo Ando, Masahito Kawazu, Toshihide Ueno, Daizo Koinuma, Koji Ando, Junji Koya, Keisuke Kataoka, Takahiko Yasuda, Hiroyuki Yamaguchi, Kazutaka Fukumura, Azusa Yamato, Manabu Soda, Eirin Sai, Yoshihiro Yamashita, Takahiro Asakage, Yasushi Miyazaki, Mineo Kurokawa, Kohei Miyazono, Stephen D. Nimer, Tatsuya Yamasoba, Hiroyuki Mano

CANCER RESEARCH 76 ( 7 ) 1814 - 1824 2016.4

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

ELF4 (also known as MEF) is a member of the ETS family of transcription factors. An oncogenic role for ELF4 has been demonstrated in hematopoietic malignancies, but its function in epithelial tumors remains unclear. Here, we show that ELF4 can function as a tumor suppressor and is somatically inactivated in a wide range of human tumors. We identified a missense mutation affecting the transactivation potential of ELF4 in oral squamous cell carcinoma cells. Restoration of the transactivation activity through introduction of wild-type ELF4 significantly inhibited cell proliferation in vitro and tumor xenograft growth. Furthermore, we found that ELF1 and ELF2, closely related transcription factors to ELF4, also exerted anti-proliferative effects in multiple cancer cell lines. Mutations in ELF1 and ELF2, as in ELF4, were widespread across human cancers, but were almost all mutually exclusive. Moreover, chromatin immunoprecipitation coupled with high-throughput sequencing revealed ELF4-binding sites in genomic regions adjacent to genes related to cell-cycle regulation and apoptosis. Finally, we provide mechanistic evidence that the antiproliferative effects of ELF4 were mediated through the induction of HRK, an activator of apoptosis, and DLX3, an inhibitor of cell growth. Collectively, our findings reveal a novel subtype of human cancer characterized by inactivating mutations in the ELF subfamily of proteins, and warrant further investigation of the specific settings where ELF restoration may be therapeutically beneficial.

DOI： 10.1158/0008-5472.CAN-14-3816

Comorbidity as predictor poor prognosis for patients with advanced head and neck cancer treated with major surgery Reviewed

Go Omura, Mizuo Ando, Yuki Saito, Kenya Kobayashi, Tatsuya Yamasoba, Takahiro Asakage

HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK 38 ( 3 ) 364 - 369 2016.3

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

BackgroundThe impact of comorbidities on patients with advanced head and neck cancer treated with major surgery has not been reported before.
MethodsWe retrospectively reviewed clinical charts between 2004 and 2011 at our institution and identified 185 patients with clinical stage III to IV head and neck cancer treated with major surgery. Comorbidities were scored using the Adult Comorbidity Evaluation-27 (ACE-27) index manual.
ResultsPatients with ACE-27 2 had significantly worse overall survival (OS) and disease-specific survival (DSS) than those with ACE-27 1 (p<.0001 and p=.0047, respectively). Multivariate analyses revealed that ACE-27 2 and extracapsular spread (ECS) were independently significant adverse prognostic factors for OS and DSS. In addition, patients with ACE-27 2 had a higher incidence of distant metastases (p=.0057).
ConclusionThe current study suggests that comorbidities may predict poor prognosis and development of distant metastases for patients with advanced head and neck cancer treated with major surgery. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 364-369, 2016

DOI： 10.1002/hed.23897

Human Papillomavirus 16 Physical Status and the TP53 Codon 72 Polymorphism in Japanese HPV-Positive Oropharyngeal Cancer Patients Reviewed

Yuki Saito, Mizuo Ando, Chisato Fujimoto, Go Omura, Kenya Kobayashi, Takahiro Asakage, Tatsuya Yannasoba

ORL-JOURNAL FOR OTO-RHINO-LARYNGOLOGY HEAD AND NECK SURGERY 78 ( 1 ) 46 - 54 2016

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Background: In human papillomavirus (HPV)-induced carcinogenesis, the arginine (Arg) allele of the TP53 codon 72 polymorphism binds more efficiently to the HPV E6 oncoprotein than the proline (Pro) allele. We investigated the physical status of HPV-16 DNA and the TP53 codon 72 polymorphism in oropharyngeal squamous cell carcinoma (OPSCC). Methods: Tumor samples from 70 p16-positive OPSCC patients were tested for HPV-16 physical status by examining the E2 and E6 open reading frames. The TP53 codon 72 polymorphism was screened by direct sequencing. Results: Of 70 patients, 53 were E6 positive, 29 had integrated forms of HPV-16 DNA, and 24 had mixed or episomal forms. Furthermore, 44 carried the Arg/Arg or Arg/Pro genotype, 3 carried the Pro/Pro genotype, and in 6 patients we were unable to obtain sequencing data. Conclusions: HPV-16 physical status was heterogeneous in our OPSCC patients. Most OPSCC patients had the TP53 Arg/Arg or Arg/Pro genotype. (C) 2016 S. Karger AG, Basel

DOI： 10.1159/000442354

Clinical Value of the Epstein-Barr Virus and p16 Status in Patients with Nasopharyngeal Carcinoma: A Single-Centre Study in Japan Reviewed

Yuki Saito, Tetsuo Ushiku, Go Omura, Kazuo Yasuhara, Masafumi Yoshida, Wataru Takahashi, Mizuo Ando, Masashi Fukayama, Tatsuya Yamasoba

ORL-JOURNAL FOR OTO-RHINO-LARYNGOLOGY HEAD AND NECK SURGERY 78 ( 6 ) 334 - 343 2016

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Background: The clinical significance of the Epstein-Barr virus (EBV) status and p16 expression was unknown in nasopharyngeal carcinoma (NPC). Methods: We retrospectively studied our pathology database for 13 years to determine the prevalence of EBV and p16 expression and their association with prognosis in cases of NPC. We performed immunohistochemistry for the p16 protein and in situ hybridization (ISH) for EBV-encoded small RNAs and human papillomavirus (HPV) DNA. Results: Of the 43 patients with NPC, 27 (63%), 6 (14%), and 10 (23%) cases were EBV positive, EBV negative with keratinization, and EBV negative without keratinization, respectively. No cases were HPV positive by ISH. Among the 21 EBV-positive tumours that were tested for p16, only 2 tumours were p16 positive. The keratinization-positive group included only males, typically > 60 years of age (5 of 6) and with T4 tumours (3 of 6). In contrast, the EBV-positive cohort tended to be younger (< 60 years, 13 of 27) and have progressive N-stage tumours (N2-3, 14 of 27). The keratinization and EBV-negative cohort included predominantly males (9 of 10) who were likely p16 negative (4 of 10) and smokers (7 of 10). Multivariate analysis confirmed that keratinization was an independent prognostic factor for progression-free survival. Conclusion: In areas, such as Japan, that are nonendemic for both EBV and HPV, the causality of NPC appears to be more heterogeneous. (C) 2017 S. Karger AG, Basel

DOI： 10.1159/000455901

Maxillary carcinosarcoma: Identification of a novel MET mutation in both carcinomatous and sarcomatous components through next generation sequencing Reviewed

Mizuo Ando, Yuki Saito, Teppei Morikawa, Go Omura, Kenya Kobayashi, Ken Akashi, Masafumi Yoshida, Yasuhiro Ebihara, Chisato Fujimoto, Masashi Fukayama, Tatsuya Yamasoba, Takahiro Asakage

HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK 37 ( 12 ) E179 - E185 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Background. Carcinosarcoma is a rare tumor with biphasic growth of the carcinomatous and sarcomatous components. Prognosis is generally poor and characterization of the molecular mechanisms may provide information for the development of novel antitumor agents and biomarkers.
Methods and Results. We present the case of 66-year-old man with a complaint of nasal obstruction. He was diagnosed with maxillary carcinosarcoma and coexisting papilloma. He underwent multimodal treatment but died of uncontrolled local disease 10 months after the initial presentation. Genetic testing using next-generation sequencing (NGS) revealed that both the carcinomatous and sarcomatous components carried a somatic mutation in the conserved domain of the mesenchymal-epithelial transition factor (MET) proto-oncogene.
Conclusion. Our observation highlighted the importance of the MET gene in the oncogenesis of maxillary carcinosarcoma and is indicative of the common clonal origin of both malignant components. This suggested a possibility of treating MET mutation-positive carcinosarcomas with c-MET inhibitors. (C) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/hed.24043

Retrospective study of laryngeal preservation treatment for hypopharyngeal carcinoma with transoral resection or induction chemotherapy Reviewed

Takahiro Asakage, Mizuo Ando, Masafumi Yoshida, Yuki Saito, Go Omura, Tatsuya Yamasoba

Journal of Otolaryngology of Japan 118 ( 9 ) 1118 - 1123 2015.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Oto-Rhino-Laryngological Society of Japan Inc.

We have performed transoral surgical resection for patients with T1/T2 hypopharyngeal cancer and induction chemotherapy with docetaxel for patients with T2/T3 disease. The patients were analyzed in order to determine the current situation of larynx preservation in patients with hypopharyngeal cancer. The data of a total of 83 patients with hypopharyngeal cancer were analyzed retrospectively. The primary subsites were: pyriform sinus (PS) in 61 patients, posterior wall (PW) in 13 patients, and postcricoid (PC) in 9 patients. The number of patients classified as having T1, T2, T3 and T4 disease were 14, 29, 23 and 17, respectively. The main therapies employed in the patients were as follows: transoral surgical resection plus radiation therapy for Tl disease, radiation therapy, induction chemotherapy, and partial resection for T2 disease, induction chemotherapy, radiation therapy, and pharyngo-laryngoesophagectomy for T3 disease, and pharyngo-laryngoesophagectomy plus induction chemotherapy for T4 disease. The 5-year larynx preservation rates in the patients with T1, T2, T3 and T4 disease were 100%, 73%, 39% and 35%, respectively. Our method was able to improve the larynx preservation rate without having any adverse effect on the survival rate. However, the strength of treatment for T 3 disease needs to be improved, because a large number of recurrences and deaths due to the primary disease were encountered in this patient group.

DOI： 10.3950/jibiinkoka.118.1118

Prognostic value of p16 expression irrespective of human papillomavirus status in patients with oropharyngeal carcinoma Reviewed

Yuki Saito, Masafumi Yoshida, Go Omura, Kenya Kobayashi, Chisato Fujimoto, Mizuo Ando, Takashi Sakamoto, Takahiro Asakage, Tatsuya Yamasoba

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 ( 9 ) 828 - 836 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

In a previous study, we reported the value of p16 expression and alcohol consumption in oropharyngeal carcinoma in Japan. We now report the clinical significance of human papillomavirus status and p16 expression in oropharyngeal carcinoma in Japan.
Over a 9-year period, a retrospective case comparison study of the pathology database was conducted at the University of Tokyo to identify tumor samples of oropharyngeal carcinoma. We performed immunohistochemistry for the p16 protein, in situ hybridization for human papillomavirus-deoxyribonucleic acid and polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 in oropharyngeal carcinoma in Japanese patients. We evaluated the human papillomavirus status in patients with oropharyngeal carcinoma to determine its prevalence and association with prognosis. We defined human papillomavirus(+) and human papillomavirus(-) oropharyngeal carcinoma cohorts as those with and without polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 or in situ hybridization-human papillomavirus.
In oropharyngeal carcinoma, the prevalences of p16(+)human papillomavirus(+), p16(+)human papillomavirus(-), p16(-)human papillomavirus(+) and p16(-)human papillomavirus(-) were 32% (48/150), 7% (10/150), 2% (3/150) and 59% (89/150), respectively. Low tobacco and alcohol consumption, tonsil or base of tongue localization, but not age, were associated with p16(+)human papillomavirus(+). Low alcohol consumption was associated with p16(+)human papillomavirus(-). There was a significant difference in overall survival between p16(+)human papillomavirus(-) and p16(-)human papillomavirus(-) (P = 0.03). In multivariate Cox regression models, p16 was the independent prognostic factor, regardless of human papillomavirus status.
p16 expression was a reliable prognostic biomarker regardless of human papillomavirus status.

DOI： 10.1093/jjco/hyv085

Nerve Growth Factor Signals as Possible Pathogenic Biomarkers for Perineural Invasion in Adenoid Cystic Carcinoma Reviewed

Kenya Kobayashi, Mizuo Ando, Yuki Saito, Kenji Kondo, Go Omura, Aya Shinozaki-Ushiku, Masashi Fukayama, Takahiro Asakage, Tatsuya Yamasoba

OTOLARYNGOLOGY-HEAD AND NECK SURGERY 153 ( 2 ) 218 - 224 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE PUBLICATIONS LTD

Objective The molecular mechanisms underlying perineural invasion (PNI)a characteristic pathological feature of adenoid cystic carcinoma (ACC)remain largely unclear. Recently, nerve growth factor (NGF) has been implicated in perineural invasion in certain malignancies. Overexpression of Myb related to the MYB-NFIB fusion gene in ACC has also been correlated with perineural invasion and survival. However, this concept is controversial. The aim of this study was to examine the expression of NGF together with its receptors, tropomyosin receptor kinase A (TrkA) and p75NRT, and Myb in ACC and assess their relationship with perineural invasion and survival.
Study Design Case series with chart review.
Setting The University of Tokyo Hospital.
Subjects and Methods We retrospectively analyzed 37 patients with ACC surgically treated from 1991 to 2011. We examined expression levels of NGF, TrkA, p75NRT, and Myb in the ACC specimens and their correlations with PNI and prognosis.
Results NGF, TrkA, p75NRT, and Myb overexpression rates were 65%, 65%, 30%, and 62%, respectively. Pearson product-moment correlation coefficient revealed a strong correlation between NGF/TrkA immunostaining and PNI (NGF: r = 0.68, P < .0001; TrkA: r = 0.53, P = .0007). Moreover, NGF overexpression was significantly associated with worse 8-year local control rate (27% vs 80%, P = .005). However, p75NRT and Myb expression was related to neither perineural invasion nor survival.
Conclusion Our findings demonstrated that NGF and TrkA overexpression, but not Myb and p75NRT overexpression, may contribute to PNI and thus cause local recurrence in patients with ACC.

DOI： 10.1177/0194599815584762

Disease control and clinicopathological prognostic factors of total pharyngolaryngectomy for hypopharyngeal cancer: a single-center study Reviewed

Go Omura, Mizuo Ando, Yuki Saito, Kenya Kobayashi, Tatsuya Yamasoba, Takahiro Asakage

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 20 ( 2 ) 290 - 297 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Total pharyngolaryngectomy (TPL) is a conventional and standard surgical method for locoregional control of advanced hypopharyngeal cancer (HPC). This study aimed to define the clinicopathological prognostic factors of TPL by evaluating our surgical experience of TPL in the treatment of HPCs.
We retrospectively reviewed the clinical charts of patients with HPC who were treated between 1995 and 2011 at the University of Tokyo Hospital and enrolled 119 patients who underwent TPL as an initial curative treatment.
The mean follow-up period was 46 months (range, 2-164 months). The 5-year overall survival (OS), disease-specific survival (DSS), locoregional control rates, and relapse-free survival for all patients were 44, 53, 76, and 50 %, respectively. In multivariate analysis, the number of a parts per thousand yen4 metastatic lymph nodes (LNs) was a significant poor prognostic factor for both OS and DSS (p = 0.03 and p = 0.01). Patients with moderate to severe comorbidities had poor prognoses for OS (p = 0.002). In addition, patients with the number of a parts per thousand yen4 metastatic LNs had a higher incidence of distant metastases (p < 0.0001).
The locoregional control rate following TPL was acceptable and the number of metastatic LNs was associated with the incidence of distant metastases.

DOI： 10.1007/s10147-014-0709-z

Frequent copy gain of the MET gene in hypopharyngeal and laryngeal cancer in Japanese population. Reviewed

Akashi K, Ebihara Y, Omura G, Saito Y, Yoshida M, Ando M, Asakage T, Yamasoba T, Murakami Y

Journal of Cancer Therapy ( 6 ) 1093 - 1102 2015

Salvage Surgery for Local Residual or Recurrent Pharyngeal Cancer After Radiotherapy or Chemoradiotherapy Reviewed

Go Omura, Yuki Saito, Mizuo Ando, Kenya Kobayashi, Yasuhiro Ebihara, Tatsuya Yamasoba, Takahiro Asakage

LARYNGOSCOPE 124 ( 9 ) 2075 - 2080 2014.9

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Objectives/Hypothesis: Local residual or recurrent pharyngeal cancer after definitive radiotherapy (RT) or chemoradiotherapy (CRT) is correlated to poor prognosis. We analyzed the efficacy of salvage surgery for patients with local residual or recurrent pharyngeal cancer after RT or CRT.
Study Design: Retrospective clinical study with chart review.
Methods: Between 2001 and 2011, we treated 207 patients with resectable pharyngeal cancer, including 98 patients with oropharyngeal cancer (OPC) and 109 patients with hypopharyngeal cancer (HPC) who received definitive RT or CRT. Local residual or recurrence developed in 59 patients (23 with OPC; 36 with HPC), of whom 42 (18 with OPC; 24 with HPC) underwent salvage surgery. These 42 patients were investigated in this study.
Results: The initial treatments were RT; RT with induction chemotherapy (IC); and concurrent CRT in 12, 9, and 21 patients, respectively. The median radiation dose was 70 Gy. The 3-year disease-specific survival rate after salvage surgery was 40% (median, 26 months). The significant prognostic factors were stage IV prior to initial therapy (P=.049), development of concurrent local and regional relapse (P=.02), and OPC (P=.04).
Conclusions: The efficacy of salvage surgery for local residual or recurrent pharyngeal cancer was limited. Oropharynx origin, stage IV prior to initial therapy, and concurrent regional relapses were significantly poor prognostic factors. Salvage surgery for HPC is worth challenging aggressively. Conversely, the indication of salvage surgery for OPCs should be carefully considered because of its low cure rate.

DOI： 10.1002/lary.24695

Negative Human Papillomavirus Status and Excessive Alcohol Consumption are Significant Risk Factors for Second Primary Malignancies in Japanese Patients with Oropharyngeal Carcinoma Reviewed

Yuki Saito, Yasuhiro Ebihara, Tetsuo Ushiku, Go Omura, Kenya Kobayashi, Mizuo Ando, Takashi Sakamoto, Masashi Fukayama, Tatsuya Yamasoba, Takahiro Asakage

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 44 ( 6 ) 564 - 569 2014.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

To determine the clinical significance of human papillomavirus subclinical infection in patients with oropharyngeal squamous cell carcinoma in Japan.
Over a 9-year period, a retrospective case comparison study of the pathology database was conducted at the University of Tokyo to identify samples of oropharyngeal squamous cell carcinoma. We performed in situ hybridization for human papillomavirus-DNA to identify subclinical human papillomavirus infections among patients with oropharyngeal squamous cell carcinoma. Second primary malignancies were classified as synchronous, if identified within 6 months of the diagnosis of the first tumor, or metachronous, if identified after this 6-month period. Univariate and multivariate analyses using logistic stepwise regression models were performed to identify factors associated with synchronous and metachronous second primary malignancy.
Of the 150 patients with oropharyngeal squamous cell carcinoma, 14% (21/150) and 20.7% (31/150) developed synchronous and metachronous second primary malignancies, respectively. Esophageal carcinoma was the most frequent second primary malignancy (10/21 for synchronous and 10/31 for metachronous second primary malignancies). The prevalence of oropharyngeal squamous cell carcinoma positive for human papillomavirus was 31% (47/150). Multivariate analysis identified alcohol consumption as a significant unfavorable risk factor for the occurrence of synchronous second primary malignancy, and either a human papillomavirus-negative status or N0 classification was a significant unfavorable risk factor for the occurrence of metachronous second primary malignancy.
Evaluation of the human papillomavirus status may help identify patients at risk for metachronous second primary malignancy. Upper gastrointestinal endoscopy is very important in the diagnosis of oropharyngeal squamous cell carcinoma among heavy drinkers in Japan.

DOI： 10.1093/jjco/hyu042

Leukemic evolution of donor-derived cells harboring IDH2 and DNMT3A mutations after allogeneic stem cell transplantation Reviewed

T. Yasuda, T. Ueno, K. Fukumura, A. Yamato, M. Ando, H. Yamaguchi, M. Soda, M. Kawazu, E. Sai, Y. Yamashita, M. Murata, H. Kiyoi, T. Naoe, H. Mano

LEUKEMIA 28 ( 2 ) 426 - 428 2014.2

Clinical Features of Human Papilloma Virus-Related Head and Neck Squamous Cell Carcinoma of an Unknown Primary Site Reviewed

Kenya Kobayashi, Yuki Saito, Go Omura, Mizuo Ando, Takashi Sakamoto, Tatsuya Yamasoba, Takahiro Asakage

ORL-JOURNAL FOR OTO-RHINO-LARYNGOLOGY HEAD AND NECK SURGERY 76 ( 3 ) 137 - 146 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Purpose: Head and neck squamous cell carcinoma of an unknown primary site (HNSCCUP) is a heterogeneous group of tumors that includes the human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma. To investigate the relationship between HNSCCUP and HPV, we reviewed p16 overexpression and HPV DNA in lymph node metastases and examined their correlation with the primary site and clinical features. Materials and Methods: Thirty-three patients with HNSCCUP were retrospectively studied. Dissected neck metastases were analyzed for p16 overexpression by immunohistochemistry, and the presence of HPV DNA was investigated by in situ hybridization. Results: Of the 33 patients, 8 (24%) exhibited p16 overexpression. p16-positive lymph node metastases contained significantly more HPV DNA and were most frequently associated with occult primary lesions in the oropharynx and a favorable prognosis. Patients with a lower alcohol consumption, only level II/III metastasis, and cystic lymph node metastasis tended to have p16 overexpression. Conclusions: This is the first report on the relationship of HNSCCUP with p16 and HPV DNA status in Asian patients. In total, 24% of the HNSCCUP patients were p16 positive. p16 overexpression in neck metastasis was predictive of both an occult primary lesion in the oropharynx and an association with HPV infection. Alcohol consumption, location, and features of neck metastasis were correlated with p16 expression. (C) 2014 S. Karger AG, Basel

DOI： 10.1159/000363190

High incidence of null-type mutations of the TP53 gene in Japanese patients with head and neck squamous cell carcinoma Reviewed

Ebihara Y, Iwai M, Ito T, Omura G, Saito Y, Yoshida M, Ando M, Asakage T, Yamasoba T, Murakami Y

Journal of Cancer Therapy 5 664 - 671 2014

STK10 missense mutations associated with anti-apoptotic function Reviewed

Kazutaka Fukumura, Yoshihiro Yamashita, Masahito Kawazu, Eirin Sai, Shin-Ichiro Fujiwara, Naoya Nakamura, Kengo Takeuchi, Mizuo Ando, Kohei Miyazono, Toshihide Ueno, Keiya Ozawa, Hiroyuki Mano

Oncology Reports 30 ( 4 ) 1542 - 1548 2013.10

Language：English Publishing type：Research paper (scientific journal) Publisher：4

Peripheral T-cell lymphoma (PTCL) is an aggressive lymphoma with a 5-year overall survival rate of &lt
30%. To identify carcinogenesis-related genes in PTCL, we conducted high-throughput resequencing of target-captured cDNA in a PTCL specimen, revealing a total of 19 missense mutations among 18 independent genes. One of such substitutions, c.2201G&gt
A in STK10 cDNA, replaces an arginine residue to a histidine (R634H) in the encoded protein. Of note, while wild-type STK10 suppresses NF-κ
B activity and potentiates dexamethasone-induced apoptosis, the R634H change significantly decreases such pro-apoptotic activity. This c.2201G&gt
A change of STK10 was also identified in another PTCL specimen, but now registered as a single nucleotide polymorphism in the latest dbSNP database. Furthermore, other somatic mutations of STK10 have been reported, and we now reveal that some of them (L85P and K277E) have more profound anti-apoptotic effects compared to R634H. These results suggest that STK10 functions as a tumor suppressor gene, and that dysfunction of STK10 activity either through polymorphism or somatic mutations may confer anti-apoptotic effects contributing to carcinogenesis.

DOI： 10.3892/or.2013.2605

Cancer-associated missense mutations of caspase-8 activate nuclear factor-kappa B signaling Reviewed

Mizuo Ando, Masahito Kawazu, Toshihide Ueno, Kazutaka Fukumura, Azusa Yamato, Manabu Soda, Yoshihiro Yamashita, Young L. Choi, Tatsuya Yamasoba, Hiroyuki Mano

CANCER SCIENCE 104 ( 8 ) 1002 - 1008 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a 5-year survival rate of similar to 50%. With the use of a custom cDNA-capture system coupled with massively parallel sequencing, we have now investigated transforming mechanisms for this malignancy. The cDNAs of cancer-related genes (n = 906) were purified from a human HNSCC cell line (T3M-1 Cl-10) and subjected to high-throughput resequencing, and the clinical relevance of non-synonymous mutations thus identified was evaluated with luciferase-based reporter assays. A CASP8 (procaspase-8) cDNA with a novel G-to-C point mutation that results in the substitution of alanine for glycine at codon 325 was identified, and the mutant protein, CASP8 (G325A), was found to activate nuclear factor-kappa B (NF-kappa B) signaling to an extent far greater than that achieved with the wild-type protein. Moreover, forced expression of wild-type CASP8 suppressed the growth of T3M-1 Cl-10 cells without notable effects on apoptosis. We further found that most CASP8 mutations previously detected in various epithelial tumors also increase the ability of the protein to activate NF-kappa B signaling. Such NF-kappa B activation was shown to be mediated through the COOH-terminal region of the second death effector domain of CASP8. Although CASP8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regard to activation of NF-kappa B signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC.

DOI： 10.1111/cas.12191

Cancer-associated missense mutations of caspase-8 activate nuclear factor-κB signaling Reviewed

Mizuo Ando, Masahito Kawazu, Toshihide Ueno, Kazutaka Fukumura, Azusa Yamato, Manabu Soda, Yoshihiro Yamashita, Young L. Choi, Tatsuya Yamasoba, Hiroyuki Mano

Cancer Science 104 ( 8 ) 1002 - 1008 2013.8

Language：English Publishing type：Research paper (scientific journal) Publisher：8

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a 5-year survival rate of ~50%. With the use of a custom cDNA-capture system coupled with massively parallel sequencing, we have now investigated transforming mechanisms for this malignancy. The cDNAs of cancer-related genes (n = 906) were purified from a human HNSCC cell line (T3M-1 Cl-10) and subjected to high-throughput resequencing, and the clinical relevance of non-synonymous mutations thus identified was evaluated with luciferase-based reporter assays. A CASP8 (procaspase-8) cDNA with a novel G-to-C point mutation that results in the substitution of alanine for glycine at codon 325 was identified, and the mutant protein, CASP8 (G325A), was found to activate nuclear factor-κB (NF-κB) signaling to an extent far greater than that achieved with the wild-type protein. Moreover, forced expression of wild-type CASP8 suppressed the growth of T3M-1 Cl-10 cells without notable effects on apoptosis. We further found that most CASP8 mutations previously detected in various epithelial tumors also increase the ability of the protein to activate NF-κB signaling. Such NF-κB activation was shown to be mediated through the COOH-terminal region of the second death effector domain of CASP8. Although CASP8 mutations associated with cancer have been thought to promote tumorigenesis as a result of attenuation of the proapoptotic function of the protein, our results now show that most such mutations, including the novel G325A identified here, separately confer a gain of function with regard to activation of NF-κB signaling, indicating another role of CASP8 in the transformation of human malignancies including HNSCC. © 2013 Japanese Cancer Association.

DOI： 10.1111/cas.12191

Transforming mutations of RAC guanosine triphosphatases in human cancers Reviewed

Masahito Kawazu, Toshihide Ueno, Kenji Kontani, Yoshitaka Ogita, Mizuo Ando, Kazutaka Fukumura, Azusa Yamato, Manabu Soda, Kengo Takeuchi, Yoshio Miki, Hiroyuki Yamaguchi, Takahiko Yasuda, Tomoki Naoe, Yoshihiro Yamashita, Toshiaki Katada, Young Lim Choi, Hiroyuki Mano

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110 ( 8 ) 3029 - 3034 2013.2

Language：English Publishing type：Research paper (scientific journal) Publisher：NATL ACAD SCIENCES

Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities. Whereas HRAS, NRAS, and KRAS frequently acquire transforming missense mutations in human cancer, little is known of the oncogenic roles of other small GTPases, including Ras-related C3 botulinum toxin substrate (RAC) proteins. We show that the human sarcoma cell line HT1080 harbors both NRAS(Q61K) and RAC1(N92I) mutant proteins. Whereas both of these mutants were able to transform fibroblasts, knockdown experiments indicated that RAC1(N92I) may be the essential growth driver for this cell line. Screening for RAC1, RAC2, or RAC3 mutations in cell lines and public databases identified several missense mutations for RAC1 and RAC2, with some of the mutant proteins, including RAC1(P29S), RAC1(C157Y), RAC2(P29L), and RAC2(P29Q), being found to be activated and transforming. P29S, N92I, and C157Y mutants of RAC1 were shown to exist preferentially in the GTP-bound state as a result of a rapid transition from the GDP-bound state, rather than as a result of a reduced intrinsic GTPase activity. Activating mutations of RAC GTPases were thus found in a wide variety of human cancers at a low frequency; however, given their marked transforming ability, the mutant proteins are potential targets for the development of new therapeutic agents.

DOI： 10.1073/pnas.1216141110

喉頭癌に対する予防的頸部郭清術の検討 Reviewed

齊藤祐毅, 小村豪, 吉田昌史, 安藤瑞生, 蝦原康宏, 朝蔭孝宏, 山岨達也

頭頸部外科 22 ( 3 ) 323 - 326 2013.2

Language：Japanese Publisher：(NPO)日本頭頸部外科学会

2005年1月から2011年12月までの7年間に喉頭癌に対し一次治療として根治手術を行った53症例を検討対象とした。男性44例、女性9例、年齢は46歳～87歳(中央値70歳)、観察期間は4～80ヵ月(中央値24ヵ月)、声門上癌36例、声門癌15例、声門下癌2例であった。潜在リンパ節転移率は声門癌N0で6.7%、声門上癌N0で30%、声門上癌N1、N2bの対側頸部で20%であった。予防的頸部廓清術は声門癌N0には不要で声門上癌N0には適応があると考えられた。N1、N2bの対側頸部の頸部郭清術の適応は今後の検討課題と考えられた。郭清範囲は患側のLevel II～IIIで充分な可能性が示唆された。(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J04210&link_issn=&doc_id=20130311410013&doc_link_id=10.5106%2Fjjshns.22.323&url=https%3A%2F%2Fdoi.org%2F10.5106%2Fjjshns.22.323&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Salvage surgery for recurrence of hypopharyngeal carcinoma after definitive radiotherapy or chemoradio-therapy Reviewed

Go Omura, Yuki Saito, Masahumi Yoshida, Mizuo Ando, Yasuhiro Ebihara, Takahiro Asakage

Japanese Journal of Head and Neck Cancer 39 ( 1 ) 55 - 59 2013

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japan Society for Head and Neck Cancer

The aim of this study was to analyze the efficacy of salvage surgery for patients with recurrent hypopharyngeal carcinoma after definitive radiotherapy (RT) or chemoradiotherapy (CRT). From April 2001 to August 2010, 101 patients with hypopharyngeal carcinoma underwent definitive RT or CRT at the University of Tokyo Hospital. Local recurrence developed in 35 patients (35%), of whom 24 patients underwent salvage surgery. The types of surgical procedures were as follows: total pharyngolaryngectomy: 20, partial pharyngectomy: 3, and endoscopic pharyngo-laryngo surgery (ELPS): 1. Three-year overall survival after salvage surgery was 60%. The median survival period was 38 months. Among these patients, postoperative complications occurred in 11 patients (46%). Salvage surgery for recurrent hypopharyngeal carcinoma after definitive RT or CRT is effective for not only for the patients' quality of life, but also for the improvement of prognosis.

DOI： 10.5981/jjhnc.39.55

Other Link： https://search.jamas.or.jp/default/link?pub_year=2013&ichushi_jid=J04195&link_issn=&doc_id=20130507330010&doc_link_id=10.5981%2Fjjhnc.39.55&url=https%3A%2F%2Fdoi.org%2F10.5981%2Fjjhnc.39.55&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

Oncogenic MAP2K1 mutations in human epithelial tumors Reviewed

Young Lim Choi, Manabu Soda, Toshihide Ueno, Toru Hamada, Hidenori Haruta, Azusa Yamato, Kazutaka Fukumura, Mizuo Ando, Masahito Kawazu, Yoshihiro Yamashita, Hiroyuki Mano

CARCINOGENESIS 33 ( 5 ) 956 - 961 2012.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

The scirrhous subtype of gastric cancer is a highly infiltrative tumor with a poor outcome. To identify a transforming gene in this intractable disorder, we constructed a retroviral complementary DNA (cDNA) expression library from a cell line (OCUM-1) of scirrhous gastric cancer. A focus formation assay with the library and mouse 3T3 fibroblasts led to the discovery of a transforming cDNA, encoding for MAP2K1 with a glutamine-to-proline substitution at amino acid position 56. Interestingly, treatment with a MAP2K1-specific inhibitor clearly induced cell death of OCUM-1 but not of other two cells lines of scirrhous gastric cancer that do not carry MAP2K1 mutations, revealing the essential role of MAP2K1(Q56P) in the transformation mechanism of OCUM-1 cells. By using a next-generation sequencer, we further conducted deep sequencing of the MAP2K1 cDNA among 171 human cancer specimens or cell lines, resulting in the identification of one known (D67N) and four novel (R47Q, R49L, I204T and P306H) mutations within MAP2K1. The latter four changes were further shown to confer transforming potential to MAP2K1. In our experiments, a total of six (3.5%) activating mutations in MAP2K1 were thus identified among 172 of specimens or cell lines for human epithelial tumors. Given the addiction of cancer cells to the elevated MAP2K1 activity for proliferation, human cancers with such MAP2K1 mutations are suitable targets for the treatment with MAP2K1 inhibitors.

DOI： 10.1093/carcin/bgs099

High-throughput resequencing of target-captured cDNA in cancer cells Reviewed

Toshihide Ueno, Yoshihiro Yamashita, Manabu Soda, Kazutaka Fukumura, Mizuo Ando, Azusa Yamato, Masahito Kawazu, Young Lim Choi, Hiroyuki Mano

CANCER SCIENCE 103 ( 1 ) 131 - 135 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

The recent advent of whole exon (exome)-capture technology, coupled with second-generation sequencers, has made it possible to readily detect genomic alterations that affect encoded proteins in cancer cells. Such target resequencing of the cancer genome, however, fails to detect most clinically-relevant gene fusions, given that such oncogenic fusion genes are often generated through intron-to-intron ligation. To develop a resequencing platform that simultaneously captures point mutations, insertions-deletions (indels), and gene fusions in the cancer genome, we chose cDNA as the input for target capture and extensive resequencing, and we describe the versatility of such a cDNA-capture system. As a test case, we constructed a custom target-capture system for 913 cancer-related genes, and we purified cDNA fragments for the target gene set from five cell lines of CML. Our target gene set included Abelson murine leukemia viral oncogene homolog 1 (ABL1), but it did not include breakpoint cluster region (BCR); however, the sequence output faithfully detected reads spanning the fusion points of these two genes in all cell lines, confirming the ability of cDNA capture to detect gene fusions. Furthermore, computational analysis of the sequence dataset successfully identified non-synonymous mutations and indels, including those of tumor protein p53 (TP53). Our data might thus support the feasibility of a cDNA-capture system coupled with massively parallel sequencing as a simple platform for the detection of a variety of anomalies in protein-coding genes among hundreds of cancer specimens. (Cancer Sci 2012; 103: 131-135)

DOI： 10.1111/j.1349-7006.2011.02105.x

High-throughput resequencing of target-captured cDNA in cancer cells Reviewed

Toshihide Ueno, Yoshihiro Yamashita, Manabu Soda, Kazutaka Fukumura, Mizuo Ando, Azusa Yamato, Masahito Kawazu, Young Lim Choi, Hiroyuki Mano

Cancer Science 103 ( 1 ) 131 - 135 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：1

The recent advent of whole exon (exome)-capture technology, coupled with second-generation sequencers, has made it possible to readily detect genomic alterations that affect encoded proteins in cancer cells. Such target resequencing of the cancer genome, however, fails to detect most clinically-relevant gene fusions, given that such oncogenic fusion genes are often generated through intron-to-intron ligation. To develop a resequencing platform that simultaneously captures point mutations, insertions-deletions (indels), and gene fusions in the cancer genome, we chose cDNA as the input for target capture and extensive resequencing, and we describe the versatility of such a cDNA-capture system. As a test case, we constructed a custom target-capture system for 913 cancer-related genes, and we purified cDNA fragments for the target gene set from five cell lines of CML. Our target gene set included Abelson murine leukemia viral oncogene homolog 1 (ABL1), but it did not include breakpoint cluster region (BCR)
however, the sequence output faithfully detected reads spanning the fusion points of these two genes in all cell lines, confirming the ability of cDNA capture to detect gene fusions. Furthermore, computational analysis of the sequence dataset successfully identified non-synonymous mutations and indels, including those of tumor protein p53 (TP53). Our data might thus support the feasibility of a cDNA-capture system coupled with massively parallel sequencing as a simple platform for the detection of a variety of anomalies in protein-coding genes among hundreds of cancer specimens. © 2011 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2011.02105.x

Genetic analysis of the TP53 and EGFR genes in head and neck cancers Reviewed

Yasuhiro Ebihara, Miwako Iwai, Masafumi Yoshida, Mizuo Ando, Takahiro Asakage, Tatsuya Yamasoba, Yoshinori Murakami

Japanese Journal of Head and Neck Cancer 37 ( 1 ) 1 - 6 2011

Language：Japanese Publishing type：Research paper (scientific journal)

To identify useful molecular markers for the treatment of head and neck cancers (HNCs), mutations of the TP53 and EGFR genes were analyzed in 56 HNCs, including 39 head and neck squamous cell carcinomas (HNSCCs). No EGFR mutation was observed in the fragments of exons 18-21. By contrast, 17 of 39 (44%) HNSCCs, as well as 3 of 6 cases (50%) with salivary gland carcinoma showed TP53 mutation in the fragments of exons 5-9. The incidence of nonsense mutation was 47%, which was higher than that in previous reports in other countries, suggesting the presence of etiological factors characteristic to Japanese patients. Further clinical assessment, including drug response and prognosis, is required in HNSCCs carrying the null-type mutation of TP53.

DOI： 10.5981/jjhnc.37.1

Metastases to the lingual nodes in tongue cancer: A pitfall in a conventional neck dissection Reviewed

Mizuo Ando, Masao Asai, Takayuki Ono, Yukihiro Nakanishi, Takahiro Asakage, Tatsuya Yamasoba

AURIS NASUS LARYNX 37 ( 3 ) 386 - 389 2010.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

Some classical textbooks of anatomy provided a detailed description of the lingual nodes, which are small inconstant lymph nodes in the floor-of-mouth and the upper neck. The clinical importance of these lymph nodes in cancer therapy. however, has been underestimated so far. We previously reported an extremely poor prognosis of oral tongue cancer patients who had lesions at the root of the lingual artery and assumed that metastases in occult lingual nodes might be responsible for such lesions. This case report clearly demonstrates the distinctive draining course of the lateral lingual nodes, which may potentially be left untreated by a neck dissection. A 63-year-old Japanese male with T2 squamous cell carcinoma of the oral tongue showed multiple metastatic involvements of the lateral lingual nodes; three nodes in close contact with the sublingual gland, and one node at the root of the lingual artery. A systematic inspection of lymph nodes along the draining course of the lateral lingual nodes should be included, because a neck dissection in continuity with the primary tumor (a pull-through approach) is still inadequate for the removal of the lymph nodes at the root of the lingual artery. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.anl.2009.10.001

A clinical study of glottic carcinoma Reviewed

Kazuki Miyano, Mizuo Ando, Masafumi Yoshida, Yasuhiro Ebihara, Takahiro Asakage, Atsuro Terahara, Kazuki Miyano

Toukeibu Gan 36 ( 3 ) 322 - 326 2010

Language：English Publishing type：Research paper (scientific journal)

A clinical study was made of 179 patients with previously untreated glottic carcinoma registered in our department between 1998 and 2004. In our facility, T1 glottic cancer was treated by radiotherapy, T2 glottic cancer by radiotherapy or chemoradiotherapy using low-dose CDDP, and T3 and T4 glottic cancer by laryngectomy. The five-year cause-specific survival rate for glottic carcinoma was 95.1%, 96.5% for stage I, 96.6% for stage II, 92.9% for stage III, and 68.6% for stage IV. The five-year local control rate for early glottic carcinoma treated by radiotherapy was 83.1% for T1a, 60.7% for T1b, and 62.5% for T2. In T2 cases, the local control rate was 49.2% for treatment by radiotherapy, and 83.6% for low-dose CDDP with radiotherapy. Low-dose CDDP with radiotherapy contributes to high local control rate in T2 cases. © 2010, Japan Society for Head and Neck Cancer. All rights reserved.

DOI： 10.5981/jjhnc.36.322

Metastatic Neck Disease Beyond the Limits of a Neck Dissection: Attention to the 'Para-hyoid' Area in T1/2 Oral Tongue Cancer Reviewed

Mizuo Ando, Masao Asai, Takahiro Asakage, Waichiro Oyama, Masahisa Saikawa, Mitsuo Yamazaki, Masakazu Miyazaki, Toru Ugumori, Hiroyuki Daiko, Ryuichi Hayashi

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 39 ( 4 ) 231 - 236 2009.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

We evaluated patients with small oral tongue cancer suffering from recurrence, which develops in the intervening area between the primary site and the neck. Lesions in the area around the cornu of the hyoid bone ('para-hyoid' area) often involve the hypoglossal nerve and the root of the lingual artery, resulting in treatment failure and death.
A 10-year retrospective chart review was conducted of 248 oral tongue cancer patients with small primary tumors (T1/2). No patients who underwent postoperative radiotherapy (PORT) were included.
After excluding those who had local failure or developed new primary lesions, 6.3% of the patients were noted to have a para-hyoid lesion. A similar incidence was observed between the patients with and without previous neck dissection, 6.9% and 5.7%, respectively. All but one patient died due to uncontrolled neck disease.
Recurrent para-hyoid lesions could occur, irrespective of a previous neck dissection. In other words, the para-hyoid area is beyond the limits of a neck dissection. Once a para-hyoid lesion becomes clinically evident, it seems difficult to salvage. Therefore, a careful inspection of the area should be included intraoperatively in any type of neck dissection (i.e. elective or therapeutic) for patients with oral tongue cancer. This may be the key to improving the regional control rate of patients with small oral tongue cancer. We believe that some patients will benefit from more aggressive treatment of the neck, although PORT seems unnecessary for the majority of the patients with limited neck disease.

DOI： 10.1093/jjco/hyp001

Recurrent Cancer of the Parotid Gland: How Well Does Salvage Surgery Work for Locoregional Failure? Reviewed

Kenya Kobayashi, Kazunari Nakao, Masafumi Yoshida, Mizuo Ando, Yasuhiro Ebihara, Takahiro Asakage, Tatsuya Yamasoba

ORL-JOURNAL FOR OTO-RHINO-LARYNGOLOGY AND ITS RELATED SPECIALTIES 71 ( 5 ) 239 - 243 2009

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Purpose: Many articles have discussed the clinical features of previously untreated parotid cancer, but the clinical characteristics and treatment of recurrent parotid cancer have not yet been fully described. Materials: We retrospectively reviewed 20 patients with recurrent parotid cancer and analyzed the therapeutic strategies and the prognostic factors. Results: Twelve patients (60%) underwent definitive surgery, including 3 who underwent skull base surgery. The 5-year overall survival (OS) and 5-year disease-free survival (DFS) in the surgery group were 66.7 and 64.1%. In the definitive surgery group, the presence of lymph node metastasis and high-grade malignant histopathology were associated with a poor prognosis (p < 0.01). On the other hand, the presence of facial palsy at presentation, the surgical margin, the time of relapse and the T stage did not affect the DFS in our series. Conclusions: The results suggest that aggressive definitive surgery may be justified for the treatment of recurrent parotid cancer. The presence of lymph node metastasis and the histopathological malignancy grade are poor prognostic factors for OS and DFS. Copyright (C) 2009 S. Karger AG, Basel

DOI： 10.1159/000236013

Mucoepidermoid carcinoma of the thyroid gland showing marked ciliation suggestive of its pathogenesis Reviewed

Mizuo Ando, Yukihiro Nakanishi, Masao Asai, Akiko Maeshima, Yoshihiro Matsuno

PATHOLOGY INTERNATIONAL 58 ( 11 ) 741 - 744 2008.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Mucoepidermoid carcinoma of the thyroid gland is a rare tumor first described by Rhatigan et al. in 1977. Its pathogenesis is still controversial. With regard to its most likely origin, some authors have suggested that it arises directly from follicular epithelium whereas others have proposed that it arises from ultimobranchial body (diverticulum from the fourth pharyngeal pouch) remnants, also known as solid cell nests (SCN). Herein is reported a unique case of thyroid mucoepidermoid carcinoma. The patient, a 67-year-old man, presented with a non-tender thyroid mass and vocal cord fixation. The tumor was poorly defined, necessitating subtotal thyroidectomy with composite resection of the adjacent structures. Pathologically, the tumor cells had characteristics of mucoepidermoid carcinoma, along with layers of columnar cells showing marked ciliation resembling respiratory-type epithelium, suggesting that this rare tumor had originated from SCN. p63 immunopositivity in the tumor provided additional evidence for the pathogenesis.

DOI： 10.1111/j.1440-1827.2008.02303.x

(2) T2 lateral oropharyngeal carcinoma

Ando, M.

Otolaryngology - Head and Neck Surgery (Tokyo) 80 ( 2 ) 2008

Clinical analysis of lateral wall oropharyngeal carcinoma - A retrospective study of 32 cases Reviewed

Yasuhiro Ebihara, Masafumi Yoshida, Mizuo Ando, Kazunari Nakao, Takahiro Asakage, Atsurou Terahara, Isao Koushima

Toukeibu Gan 34 ( 4 ) 526 - 529 2008

Language：English Publishing type：Research paper (scientific journal)

We analyzed 32 cases of lateral wall oropharyngeal carcinoma treated at our institution retrospectively. Five-year overall and disease-specific survival rates were 50% and 62%, respectively. The 5-year locoregional control rate was 57%, and including salvage therapy it was improved up to 62%. It was difficult to control locoregional tumor with surgery in far-advanced cases where the tumor had invaded the nasopharynx or larynx. There is a possibility of salvage if the recurrence is solitary, but a case with multiple recurrence is difficult to salvage. © 2008, Japan Society for Head and Neck Cancer. All rights reserved.

DOI： 10.5981/jjhnc.34.526

First Panic Attack Episodes in Head and Neck Cancer Patients Who Have Undergone Radical Neck Surgery

Shimizu, K., Kinoshita, H., Akechi, T., Uchitomi, Y., Andoh, M.

Journal of Pain and Symptom Management 34 ( 6 ) 2007

Mucosa-associated lymphoid tissue lymphoma presented as diffuse swelling of the parotid gland Reviewed

M Ando, M Matsuzaki, T Murofushi

AMERICAN JOURNAL OF OTOLARYNGOLOGY 26 ( 4 ) 285 - 288 2005.7

Language：English Publishing type：Research paper (scientific journal) Publisher：W B SAUNDERS CO

Mucosa-associated lymphoid tissue (MALT) lymphoma is a distinct subtype of lymphoma. Parotid MALT lymphoma is a rare tumor that is hard to diagnose by fine-needle aspiration cytology. Therefore, partial parotidectomy is often required for a pathological diagnosis. We report a case of MALT lymphoma presented as unilateral diffuse swelling of the parotid gland, who was diagnosed by partial parotidectomy and underwent radiotherapy. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.amjoto.2005.01.011

Computer-Guided Surgery in Head and Neck Lesions

Ando, M.

Otolaryngology - Head and Neck Surgery (Tokyo) 76 ( 1 ) 2004

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