Faculty Profiles - Ando Mizuo

Papers - Ando Mizuo

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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

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