Faculty Profiles - Ando Mizuo

Papers - Ando Mizuo

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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

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