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• Biomarkers for Predicting Anti-Programmed Cell Death-1 Antibody Treatment Effects in Head and Neck Cancer.

  Katsunori Tanaka, Hitoshi Hirakawa, Mikio Suzuki, Teruyuki Higa, Shinya Agena, Narumi Hasegawa, Junko Kawakami, Masatomo Toyama, Tomoyo Higa, Hidetoshi Kinjyo, Norimoto Kise, Shunsuke Kondo, Hiroyuki Maeda, Taro Ikegami

  Current oncology (Toronto, Ont.)   30 ( 6 ) 5409 - 5424   2023.06 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  In recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC), survival outcomes are significantly better in patients who receive anti-programmed cell death-1 (PD-1) monoclonal antibody therapy than in those who receive standard therapy. However, there is no established biomarker that can predict the anti-PD-1 antibody treatment effect and immune-related adverse events (irAEs) in these patients. This study investigated the inflammatory and nutritional status in 42 patients with R/M-HNSCC and programmed cell death ligand-1 (PD-L1) polymorphisms (rs4143815 and rs2282055) in 35 of the 42 patients. The 1- and 2-year overall survival was 59.5% and 28.6%, respectively; the 1- and 2-year first progression-free survival was 19.0% and 9.5%, respectively, and the respective second progression-free survival was 50% and 27.8%. Performance status and inflammatory and nutritional status (assessed by the geriatric nutritional risk index, modified Glasgow prognostic score, and prognostic nutritional index) were identified as significant indicators of survival outcomes in multivariate analysis. Patients with ancestral alleles in PD-L1 polymorphisms had less frequent irAEs. Performance status and inflammatory and nutritional status before treatment were closely related to survival outcomes after PD-1 therapy. These indicators can be calculated using routine laboratory data. PD-L1 polymorphisms may be biomarkers for predicting irAEs in patients receiving anti-PD-1 therapy.

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• Human papillomavirus infection and EGFR exon 20 insertions in sinonasal inverted papilloma and squamous cell carcinoma

  Hitoshi Hirakawa, Taro Ikegami, Norimoto Kise, Hidetoshi Kinjyo, Shunsuke Kondo, Shinya Agena, Narumi Hasegawa, Junko Kawakami, Hiroyuki, Maeda, Mikio Suzuki

  Journal of Personalized Medicine   13 ( 4 ) 657   2023.04 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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• Development of Antibodies against HPV-6 and HPV-11 for the Study of Laryngeal Papilloma.

  Taro Ikegami, Norimoto Kise, Hidetoshi Kinjyo, Shunsuke Kondo, Mikio Suzuki, Narutoshi Tsukahara, Akikazu Murakami, Asanori Kiyuna, Shinya Agena, Katsunori Tanaka, Narumi Hasegawa, Junko Kawakami, Akira Ganaha, Hiroyuki Maeda, Hitoshi Hirakawa

  Viruses   13 ( 10 )   2021.10 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Laryngeal papilloma (LP), which is associated with infection by human papillomavirus (HPV)-6 or -11, displays aggressive growth. The precise molecular mechanism underlying the tumorigenesis of LP has yet to be uncovered. Building on our earlier research into HPV-6, in this study, the viral gene expression of HPV-11 was investigated by quantitative PCR and DNA/RNA in situ hybridization. Additionally, newly developed antibodies against the E4 protein of HPV-6 and HPV-11 were evaluated by immunohistochemistry. The average viral load of HPV-11 in LP was 1.95 ± 0.66 × 105 copies/ng DNA, and 88% of HPV mRNA expression was found to be E4, E5a, and E5b mRNAs. According to RNA in situ hybridization, E4 and E5b mRNAs were expressed from the middle to upper part of the epithelium. E4 immunohistochemistry revealed a wide positive reaction in the upper cell layer in line with E4 mRNA expression. Other head and neck lesions with HPV-11 infection also showed a positive reaction in E4 immunohistochemistry. The distribution pattern of HPV DNA, viral mRNA, and E4 protein in LP with HPV-11 infection was quite similar to that of HPV-6. Therefore, it might be possible to apply these E4-specific antibodies in other functional studies as well as clinical applications, including targeted molecular therapies in patients with HPV-6 and HPV-11 infection.

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• Coordinated Expression of HPV-6 Genes with Predominant E4 and E5 Expression in Laryngeal Papilloma.

  Taro Ikegami, Hitoshi Hirakawa, Narutoshi Tsukahara, Akikazu Murakami, Norimoto Kise, Asanori Kiyuna, Takayoshi Kosugi, Shinya Agena, Hidetoshi Kinjyo, Narumi Hasegawa, Masatomo Touyama, Shunsuke Kondo, Hiroyuki Maeda, Mikio Suzuki, Akira Ganaha

  Microorganisms   9 ( 3 )   2021.03 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  Laryngeal papilloma (LP) associated with human papillomavirus (HPV)-6 or -11 infection shows aggressive growth. However, the detailed molecular mechanism of virus-driven tumorigenesis has not been uncovered fully. HPV-6 viral gene expression and dynamic alterations were investigated with in situ localization of viral DNA and RNA in 13 patients with HPV-6-infected laryngeal papilloma. The average viral load was 4.80 × 105 ± 1.86 × 105 copies/ng DNA. E4, E5a, and E5b mRNAs accounted for 96% of the expression of 9 mRNAs. The alteration of viral DNA load during recurrence paralleled the mRNA expression levels, and the expression of all mRNAs showed a similar curve. E4, E5a, and E5b were expressed in the middle to upper part of the epithelium and were co-expressed in the same cells. E4 immunohistochemistry demonstrated an extensively positive reaction in the upper cell layer in accordance with E4 mRNA expression. These results suggest that individual viral genes are coordinately expressed for viral replication, virus release, and immunosurveillance avoidance. The newly developed E4-specific monoclonal antibody can be applied to further functional studies and clinical applications such as targeted molecular therapies.

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• Raptor and rictor expression in patients with human papillomavirus-related oropharyngeal squamous cell carcinoma.

  Shunsuke Kondo, Hitoshi Hirakawa, Taro Ikegami, Takayuki Uehara, Shinya Agena, Jin Uezato, Hidetoshi Kinjyo, Noritomo Kise, Yukashi Yamashita, Katsunori Tanaka, Narumi Hasegawa, Asanori Kiyuna, Hiroyuki Maeda, Mikio Suzuki, Akira Gahana

  BMC cancer   21 ( 1 ) 87 - 87   2021.01 [ Peer Review Accepted ]

  Type of publication: Research paper (scientific journal)

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  BACKGROUND: Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC). METHODS: The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC. RESULTS: The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression. CONCLUSIONS: These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.

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