2022/12/01 更新

写真a

トミハラ ケイ
冨原 圭
TOMIHARA Kei
所属
教育研究院 医歯学系 歯学系列 教授
歯学部 歯学科 教授
医歯学総合研究科 口腔生命科学専攻 口腔健康科学 教授
職名
教授
外部リンク

学位

  • 博士(医学) ( 2002年3月   札幌医科大学 )

研究分野

  • ライフサイエンス / 外科系歯学  / 口腔外科 口腔癌 腫瘍免疫学

経歴(researchmap)

  • 新潟大学大学院医歯学総合研究科   顎顔面口腔外科学分野   教授

    2021年7月 - 現在

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  • 富山大学学術研究部医学系   歯科口腔外科学   准教授

    2020年10月 - 2021年6月

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  • 富山大学大学院医学薬学教育部   歯科口腔外科学講座   准教授

    2017年6月 - 2020年9月

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  • 富山大学医学部附属病院   歯科口腔外科   講師

    2014年5月 - 2017年5月

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  • 富山大学医学部附属病院   歯科口腔外科   助教

    2013年4月 - 2014年3月

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  • 富山大学医学部附属病院   歯科口腔外科   医員

    2011年6月 - 2013年3月

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  • テキサス大学衛生科学センターサンアントニオ校   がん治療・研究センター   博士研究員

    2008年6月 - 2011年3月

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    国名:アメリカ合衆国

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  • 札幌医科大学   口腔外科学講座   医員

    2006年4月 - 2008年6月

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  • 札幌医科大学医学部附属病院   歯科臨床研修医

    2001年4月 - 2002年3月

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経歴

  • 新潟大学   教育研究院 医歯学系 歯学系列   教授

    2021年7月 - 現在

  • 新潟大学   医歯学総合研究科 口腔生命科学専攻 口腔健康科学   教授

    2021年7月 - 現在

  • 新潟大学   歯学部 歯学科   教授

    2021年7月 - 現在

学歴

  • 札幌医科大学医学部大学院 医学研究科

    2002年4月 - 2006年3月

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  • 新潟大学   歯学部   歯学科

    1995年4月 - 2001年3月

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所属学協会

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論文

  • Durable complete response to immunotherapy with anti-PD-1 antibody nivolumab in a patient with oral squamous cell carcinoma presenting with lung metastasis: A case report. 査読 国際誌

    Katsuhisa Sekido, Shuichi Imaue, Kei Tomihara, Hidetake Tachinami, Kentaro Yamagishi, Seisuke Okazawa, Atsushi Ikeda, Kumiko Fujiwara, Makoto Noguchi

    Clinical case reports   9 ( 9 )   e04545   2021年9月

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    記述言語:英語  

    Although the optimal treatment method for metastatic oral cancer remains largely unknown, the present case suggests that immunotherapy is a potentially promising alternative for metastatic oral cancer in which other therapies are no longer effective.

    DOI: 10.1002/ccr3.4545

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  • Dysregulation of Amphiregulin stimulates the pathogenesis of cystic lymphangioma. 国際誌

    Naofumi Yoshida, Seiji Yamamoto, Takeru Hamashima, Noriko Okuno, Naruho Okita, Shinjiro Horikawa, Masao Hayashi, Thanh Chung Dang, Quang Linh Nguyen, Koichi Nishiyama, Teruhiko Makino, Yoko Ishii, Kei Tomihara, Tadamichi Shimizu, Masabumi Shibuya, Makoto Noguchi, Masakiyo Sasahara

    Proceedings of the National Academy of Sciences of the United States of America   118 ( 19 )   2021年5月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Along with blood vessels, lymphatic vessels play an important role in the circulation of body fluid and recruitment of immune cells. Postnatal lymphangiogenesis commonly occurs from preexisting lymphatic vessels by sprouting, which is induced by lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C). However, the key signals and cell types that stimulate pathological lymphangiogenesis, such as human cystic lymphangioma, are less well known. Here, we found that mouse dermal fibroblasts that infiltrate to sponges subcutaneously implanted express VEGF-D and sushi, Von Willebrand factor type A, EGF, and pentraxin domain containing 1 (SVEP1) in response to PDGFRβ signal. In vitro, Pdgfrb knockout (β-KO) fibroblasts had reduced expression of VEGF-D and SVEP1 and overproduced Amphiregulin. Dysregulation of these three factors was involved in the cyst-like and uneven distribution of lymphatic vessels observed in the β-KO mice. Similarly, in human cystic lymphangioma, which is one of the intractable diseases and mostly occurs in childhood, fibroblasts surrounding cystic lymphatics highly expressed Amphiregulin. Moreover, fibroblast-derived Amphiregulin could induce the expression of Amphiregulin in lymphatic endothelial cells. The dual source of Amphiregulin activated EGFR expressed on the lymphatic endothelial cells. This exacerbation cascade induced proliferation of lymphatic endothelial cells to form cystic lymphangioma. Ultimately, excessive Amphiregulin produced by fibroblasts surrounding lymphatics and by lymphatic endothelial cells per se results in pathogenesis of cystic lymphangioma and will be a fascinating therapeutic target of cystic lymphangioma.

    DOI: 10.1073/pnas.2019580118

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  • Protumor role of estrogen receptor expression in oral squamous cell carcinoma cells. 査読 国際誌

    Rie Akyu Takei, Kei Tomihara, Manabu Yamazaki, Rohan Moniruzzaman, Wataru Heshiki, Katsuhisa Sekido, Hidetake Tachinami, Kotaro Sakurai, Amirmoezz Yonesi, Shuichi Imaue, Kumiko Fujiwara, Makoto Noguchi

    Oral surgery, oral medicine, oral pathology and oral radiology   132 ( 5 )   549 - 565   2021年4月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Accumulating evidence has demonstrated the protumor role of estrogen receptor (ER)-mediated signaling in multiple cancer types, which is distinct from this signaling in sex steroid-dependent organs. However, its role in oral squamous cell carcinoma (OSCC) remains unclear. STUDY DESIGN: We assessed the expression of ERα and ERβ in human OSCC tissues by immunohistochemistry and evaluated the expression of both receptors in OSCC cell lines by immunoblotting and flow cytometry. To further assess the contribution of ER-mediated signals to oral cancer progression, proliferation, invasion, and chemosensitivity, cell lines were stimulated with the ER agonist β-estradiol. RESULTS: Immunohistochemical analysis of OSCC tissues showed that ERβ was present in the cytoplasm and nuclei of OSCC cells. In contrast, ERα was not detected in any of the cases analyzed. Additionally, the proliferation and invasiveness of OSCC cells were significantly elevated following stimulation with β-estradiol. Chemotherapeutic agent-induced apoptosis of cancer cells was attenuated by pretreatment with β-estradiol. CONCLUSIONS: ER-mediated signaling plays a crucial role in oral cancer progression by facilitating the proliferation, invasion, and chemoresistance of OSCC cells, indicating its potential for developing novel targeted therapies for this type of cancer.

    DOI: 10.1016/j.oooo.2021.04.006

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  • CD36 expression on oral squamous cell carcinoma cells correlates with enhanced proliferation and migratory activity. 査読 国際誌

    Kotaro Sakurai, Kei Tomihara, Manabu Yamazaki, Wataru Heshiki, Rohan Moniruzzaman, Katsuhisa Sekido, Hidetake Tachinami, Atsushi Ikeda, Shuichi Imaue, Kumiko Fujiwara, Makoto Noguchi

    Oral diseases   26 ( 4 )   745 - 755   2020年5月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: Recent studies have demonstrated the pro-tumour role of CD36 in multiple cancer types. However, its role has not been well elucidated in oral squamous cell carcinoma (OSCC). Here, we aimed to evaluate the role of CD36 in proliferation and migration of OSCC cells. METHODS: Human OSCC cell lines HSC-2, HSC-3, HSC-4 and Ca9-22 were assessed for proliferation by staining with the cell proliferation marker Ki-67. We also assessed migration activity, and the expression of cell adhesion molecules such as E-cadherin and β-catenin and platelet-derived growth factor receptors (PDGFRs) of CD36-positive cells. RESULTS: CD36-positive cells showed increased expression of Ki-67 and migration activity compared with CD36-negative cells. Moreover, CD36-positive cells showed reduced expression of E-cadherin and β-catenin, whereas the expression of PDGFRs increased compared with that in CD36-negative cells. CONCLUSIONS: Our results strongly suggest that CD36 has an important role in facilitating the proliferation and migration activity of OSCC cells, indicating its usefulness in the diagnosis of high-grade tumour and targeted therapy of oral cancer.

    DOI: 10.1111/odi.13210

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  • Alterations in composition of immune cells and impairment of anti-tumor immune response in aged oral cancer-bearing mice. 査読 国際誌

    Katsuhisa Sekido, Kei Tomihara, Hidetake Tachinami, Wataru Heshiki, Kotaro Sakurai, Rohan Moniruzzaman, Shuichi Imaue, Kumiko Fujiwara, Makoto Noguchi

    Oral oncology   99   104462 - 104462   2019年12月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: Aging has been suggested to be associated with immune dysregulation. An understanding of alterations in the host immunity with advancing age is, therefore, important for designing immune therapy for elderly cancer patients. In this context, not much is known about age-associated alterations in the immune system in oral cancer. METHODS: To evaluate age-associated alterations in the immune system, which might affect anti-tumor immune responses in oral cancer, we performed a comparative analysis of the proportion of different immune cells, the proliferative capacity of T cell compartment, and the response against immune therapies targeting immune check point molecules between young and aged oral cancer-bearing mice. RESULTS: The proportion of immune regulatory cells, such as regulatory T cells and myeloid derived suppressor cells, was significantly increased in aged mice compared to that in young mice. Moreover, the expression of PD-1 and CTLA-4 on both CD4+ and CD8+ T cells was elevated in aged mice compared to that in young mice, and the proliferative abilities of CD4+ and CD8+ T cells derived from aged mice were significantly reduced following stimulation of T-cell receptors. Moreover, tumor growth was significantly enhanced in aged mice compared to that in young mice. However, immunotherapies targeting PD-1, CTLA-4, and PD-L1 resulted in faster tumor regression in aged mice than in young mice. CONCLUSIONS: Together, our results indicate that age-associated alterations in the immune system are directly associated with the impairment of anti-tumor immunity in aged mice bearing oral cancer, and might facilitate the progression of the tumor.

    DOI: 10.1016/j.oraloncology.2019.104462

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  • Combination of 5-aminosalicylic acid and hyperthermia synergistically enhances apoptotic cell death in HSC-3 cells due to intracellular nitric oxide/peroxynitrite generation. 査読 国際誌

    Rohan Moniruzzaman, Mati Ur Rehman, Qing-Li Zhao, Paras Jawaid, Yohei Mitsuhashi, Kotaro Sakurai, Wataru Heshiki, Ryohei Ogawa, Kei Tomihara, Jun-Ichi Saitoh, Kyo Noguchi, Takashi Kondo, Makoto Noguchi

    Cancer letters   451   58 - 67   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The repurposing of existing FDA-approved non-cancer drugs is a potential source of new treatment options for cancer patients. An anti-inflammatory drug, 5-aminosalicylic acid (5-ASA), has been clinically used to treat inflammatory bowel disease. Hyperthermia (HT) is widely applicable addendum therapy with the existing cancer treatment modalities. Here, we addressed how 5-ASA combined with HT induces lethal effects in human oral squamous cell carcinoma (OSCC) HSC-3 cells. We found that 5-ASA/HT combination significantly inhibited the viability of HSC-3 cells, while cytotoxic effects in primary human dermal fibroblast cells were minor. Apoptotic endpoints were significantly increased by the 5-ASA/HT combined treatment, as evidenced by presence of Annexin V-FITC/PI positive cells, loss of MMP, Bcl-2/Bax ratio alteration, and increased Fas, cleaved Bid, and caspase expression. Interestingly, the enhancement of apoptosis was reversed in the presence of ON/ONOO- scavengers. These findings indicate that the combination treatment enhances apoptosis via ON/ONOO- mediated ER stress-Ca2+-mitochondria signaling and caspase-dependent apoptotic pathways. Our findings provide novel evidence that the combination of 5-ASA and HT is a promising approach for the enhancement of apoptosis; it may serve as an effective strategy for treating human OSCC.

    DOI: 10.1016/j.canlet.2019.03.004

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  • Differences of tumor-recruiting myeloid cells in murine squamous cell carcinoma influence the efficacy of immunotherapy combined with a TLR7 agonist and PD-L1 blockade. 査読 国際誌

    Hidetake Tachinami, Naoto Nishii, Yulong Xia, Yoshihisa Kashima, Tatsukuni Ohno, Shigenori Nagai, Lixin Li, Walter Lau, Kei Tomihara, Makoto Noguchi, Miyuki Azuma

    Oral oncology   91   21 - 28   2019年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: The immune status of the tumor microenvironment has a marked impact on clinical outcomes. Here we examined the immune environments of tumor-infiltrating leukocytes (TILes) in two murine models of squamous cell carcinoma and compared the effects of immunotherapeutic agents, including a TLR7 agonist and an immune checkpoint inhibitor, and a chemotherapeutic agent, gemcitabine, in these models. MATERIALS AND METHODS: TILes from NR-S1- and SCCVII-grafted mice were analyzed by flow cytometry. NR-S1-inoculated mice received resiquimod (a synthetic TLR7 agonist), an anti-PD-L1 antibody, or both, and tumor growth and TILs were examined. Gemcitabine was administered to deplete CD11b+ cells. RESULTS: More than 50% of TILes from NR-S1- and SCCVII-inoculated mice were CD11b+Gr-1+ cells. A major fraction of NR-S1 CD11b+ cells was Ly6GhighLy6Clow-negaF4/80- tumor-associated neutrophils (TANs) and the majority of SCCVII CD11b+ cells were Ly6GlowLy6C-F4/80+ tumor-associated macrophages. NR-S1 TANs did not express MHC class II and CD86, but did express reactive oxygen species and PD-L1. Resiquimod, alone and in combination with an anti-PD-L1 antibody, did not regress NR-S1 tumors, but the combination increased the CD8/regulatory T cell-ratio, and IFN-γ and PD-1 expression in CD8+ TILes. Pre-administration of low-dose gemcitabine prior to the combination treatment suppressed the progression of NR-S1 tumors. CONCLUSIONS: NR-S1 tumors with abundant recruitment of TANs were resistant to treatments with a TLR7 agonist, alone and in combination with PD-1 blockade, and required an additional gemcitabine treatment. The phenotype and status of tumor-infiltrating CD11b+ myeloid cells may influence the efficacy of immunotherapeutic agents.

    DOI: 10.1016/j.oraloncology.2019.02.014

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  • Roles of intracellular and extracellular ROS formation in apoptosis induced by cold atmospheric helium plasma and X-irradiation in the presence of sulfasalazine. 査読 国際誌

    Rohan Moniruzzaman, Mati Ur Rehman, Qing-Li Zhao, Paras Jawaid, Yohei Mitsuhashi, Shuichi Imaue, Kumiko Fujiwara, Ryohei Ogawa, Kei Tomihara, Jun-Ichi Saitoh, Kyo Noguchi, Takashi Kondo, Makoto Noguchi

    Free radical biology & medicine   129   537 - 547   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sulfasalazine (SSZ) is a well-known anti-inflammatory drug and also an inhibitor of the cystine-glutamate antiporter that is known to reduce intracellular glutathione (GSH) level and increase cellular oxidative stress, indicating its anti-tumor potential. However, the combination of SSZ with other physical modalities remains unexplored. Here, the effects of SSZ on cold atmospheric helium plasma (He-CAP), which produces approximately 24 x higher concentration of hydroxyl radicals (. OH) compared to X-irradiation (IR) in aqueous solution, and on IR-induced apoptosis in human leukemia Molt-4 cells were studied to elucidate the mechanism of apoptosis enhancement. Both the Annexin V-FITC/PI and DNA fragmentation assay revealed that pre-treatment of cells with SSZ significantly enhanced He-CAP and IR-induced apoptosis. Similar enhancement was observed during the loss of mitochondrial membrane potential, intracellular Ca2+ ions, and mitochondria- and endoplasmic reticulum-related proteins. The concentration of intracellular reactive oxygen species (ROS) was much higher in He-CAP treated cells than in X-irradiated cells. On the other hand, strong enhancement of Fas expression and caspase-8 and -3 activities were only observed in X-irradiated cells. It might be possible that the higher concentration of intracellular and extracellular ROS suppressed caspase activities and Fas expression in He-CAP-treated cells. Notably, pretreating the cells with an antioxidant N-acetyl-L-cysteine (NAC) dramatically decreased apoptosis in cells treated by He-CAP, but not by IR. These results suggest that IR-induced apoptosis is due to specific and effective ROS distribution since intracellular ROS formation is marginal and the high production of ROS inside and outside of cells plays unique roles in He-CAP induced apoptosis. We conclude that our data provides efficacy and mechanistic insights for SSZ, which might be helpful for establishing SSZ as a future sensitizer in He-CAP or IR therapy for cancer.

    DOI: 10.1016/j.freeradbiomed.2018.10.434

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  • Different PDGF Receptor Dimers Drive Distinct Migration Modes of the Mouse Skin Fibroblast. 査読 国際誌

    Kohta Yamada, Takeru Hamashima, Yoko Ishii, Seiji Yamamoto, Noriko Okuno, Naofumi Yoshida, Moe Yamada, Ting Ting Huang, Norifumi Shioda, Kei Tomihara, Toshihiko Fujimori, Hisashi Mori, Kohji Fukunaga, Makoto Noguchi, Masakiyo Sasahara

    Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology   51 ( 3 )   1461 - 1479   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIMS: The migration of mesenchymal cells is a fundamental cellular process that has been implicated in many pathophysiological conditions and is induced by chemoattractants such as platelet-derived growth factors (PDGFs). However, the regulatory mechanisms shaping this migration remain to be elucidated. METHODS: Here, we prepared mouse skin fibroblasts inactivated for different PDGF receptor genes and systematically measured their chemotactic responses within a gradient of different chemoattractants. RESULTS: We found that PDGFRαβ and PDGFRββ dimers were strong inducers of random and directionally-persistent migration, respectively, that was sustained for up to 24 h. MAPK and PI3K were necessary to mediate random and directional migration, respectively. Directional migration was accompanied by abundant ventral stress fiber formation and consistent cell shape with less frequent formation of branch-like processes. CONCLUSION: This is the first systematic study that characterized the chemotaxis mediated by three-different types of PDGFR dimers in mesenchymal cell migration. Our data demonstrate that PDGFR dimer formation is the critical step to determine the specific mode of fibroblast chemotaxis, while the accompanying cytoskeletal remodeling might contribute to migration persistence.

    DOI: 10.1159/000495594

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  • Cold atmospheric helium plasma causes synergistic enhancement in cell death with hyperthermia and an additive enhancement with radiation. 査読 国際誌

    Rohan Moniruzzaman, Mati Ur Rehman, Qing-Li Zhao, Paras Jawaid, Keigo Takeda, Kenji Ishikawa, Masaru Hori, Kei Tomihara, Kyo Noguchi, Takashi Kondo, Makoto Noguchi

    Scientific reports   7 ( 1 )   11659 - 11659   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cold atmospheric plasmas (CAPs) have been proposed as a novel therapeutic method for its anti-cancer potential. However, its biological effects in combination with other physical modalities remain elusive. Therefore, this study examined the effects of cold atmospheric helium plasma (He-CAP) in combination with hyperthermia (HT) 42 °C or radiation 5 Gy. Synergistic enhancement in the cell death with HT and an additive enhancement with radiation were observed following He-CAP treatment. The synergistic effects were accompanied by increased intracellular reactive oxygen species (ROS) production. Hydrogen peroxide (H2O2) and superoxide (O2•-) generation was increased immediately after He-CAP treatment, but fails to initiate cell death process. Interestingly, at late hour's He-CAP-induced O2•- generation subsides, however the combined treatment showed sustained increased intracellular O2•- level, and enhanced cell death than either treatment alone. He-CAP caused marked induction of ROS in the aqueous medium, but He-CAP-induced ROS seems insufficient or not completely incorporated intra-cellularly to activate cell death machinery. The observed synergistic effects were due to the HT effects on membrane fluidity which facilitate the incorporation of He-CAP-induced ROS into the cells, thus results in the enhanced cancer cell death following combined treatment. These findings would be helpful when establishing a therapeutic strategy for CAP in combination with HT or radiation.

    DOI: 10.1038/s41598-017-11877-8

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  • Enhanced expression of PD-L1 in oral squamous cell carcinoma-derived CD11b(+)Gr-1(+) cells and its contribution to immunosuppressive activity. 査読 国際誌

    Hiroki Fuse, Kei Tomihara, Wataru Heshiki, Manabu Yamazaki, Rie Akyu-Takei, Hidetake Tachinami, Ken-Ichiro Furukawa, Kotaro Sakurai, Moniruzzaman Rouwan, Makoto Noguchi

    Oral oncology   59   20 - 29   2016年8月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cancer is often associated with dysregulation of both the humoral and cellular immune response, which in some instances is believed to result from changes in immune cell populations. For example, immunosuppressive CD11b(+)Gr-1(+) myeloid-derived suppressor cells have been shown to proliferate in the tumor microenvironment and surrounding tissues, highlighting the relationship between tumor growth and impairment of the immune response. However, the role of myeloid-derived suppressor cells in cancer progression has not been fully characterized because these cells are heterogeneous with properties influenced by the type and location of the tumor. Here, we show that CD11b(+)Gr-1(+) cells are elevated in the peripheral blood, spleen, and tumor of mice with oral squamous cell carcinoma. The phenotype and function of these cells varied depending on the tissue of origin. In particular, CD11b(+)Gr-1(+) cells in tumors expressed PD-L1 more abundantly than those in other tissues. Accordingly, CD11b(+)Gr-1(+) cells from tumors, but not from the spleen, suppressed T cell proliferation in vitro. The results suggest that tumor-derived or immune factors result in the accumulation of phenotypically and functionally diverse populations of CD11b(+)Gr-1(+) cells in mice with oral squamous cell carcinoma. The data also indicate that PD-L1 expression in CD11b(+)Gr-1(+) cells contributes to immune suppression, implying that targeting both myeloid-derived suppressor cells and PD-L1 would be an effective immunotherapeutic strategy against oral cancer.

    DOI: 10.1016/j.oraloncology.2016.05.012

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  • Constitutive Activation of Caspase-3 in Non-Apoptotic Oral Squamous Cell Carcinoma Cells 査読

    Wataru Heshiki, Kei Tomihara, Manabu Yamazaki, Naoya Arai, Kenji Nakamori, Makoto Noguchi

    Journal of Cancer Science & Therapy   07 ( 02 )   2015年

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    担当区分:責任著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:OMICS Publishing Group  

    DOI: 10.4172/1948-5956.1000328

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  • Gemcitabine chemotherapy induces phenotypic alterations of tumor cells that facilitate antitumor T cell responses in a mouse model of oral cancer. 査読 国際誌

    Kei Tomihara, Hiroki Fuse, Wataru Heshiki, Rie Takei, Bin Zhang, Naoya Arai, Kenji Nakamori, Makoto Noguchi

    Oral oncology   50 ( 5 )   457 - 67   2014年5月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVES: Gemcitabine (GEM) is a pyrimidine nucleoside analogue that is a new chemotherapeutic agent used for treating various cancers. Because accumulating evidence indicates that GEM may activate host immune responses, its potential as an immune modulator in cancer chemotherapy has generated considerable interest. MATERIALS AND METHODS: In the present study, we investigated the antitumor effects of GEM using a mouse oral cancer model using immunological analyses. We examined apoptotic cell death of tumor cells with GEM treatment both in vitro and in vivo. We also investigated whether in vivo administration of GEM affected the distributions of immune cells, tumor-cell surface expression levels of immune accessory molecules and T cell immune responses in tumor-bearing mice. RESULTS: GEM induced significant oral cancer-cell apoptosis in vitro, and in vivo GEM administration markedly attenuated established mouse tumor growth. In vivo GEM administration decreased the numbers of both myeloid-derived suppressor cells (MDSCs) and B cells in tumor-bearing mice and enhanced dendritic cell maturation. Moreover, GEM treatment upregulated tumor-cell surface expressions of several immune accessory molecules and adhesion molecules, including CD80, CD86, CD40, ICAM-1, VCAM-1, and P-selectin. Remarkably, these tumor cells augmented tumor specific T-cell responses. CONCLUSION: These results suggest that GEM can induce host antitumor immune responses, which would facilitate antitumor effects in the treatment of oral cancer.

    DOI: 10.1016/j.oraloncology.2014.01.013

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  • CD44 and SSEA-4 positive cells in an oral cancer cell line HSC-4 possess cancer stem-like cell characteristics. 査読 国際誌

    Zenko Noto, Toshiko Yoshida, Motonori Okabe, Chika Koike, Moustafa Fathy, Hiroaki Tsuno, Kei Tomihara, Naoya Arai, Makoto Noguchi, Toshio Nikaido

    Oral oncology   49 ( 8 )   787 - 95   2013年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Cancer may be derived from cancer stem-like cells (CSCs), which are tumor-initiating cells that have properties similar to those of stem cells. Identification and isolation of CSCs needs to be improved further. MATERIALS AND METHODS: CSCs markers were examined in human oral cancer cell lines by flow cytometry. The stem cell properties of subpopulations expressing different markers were assessed further by in vitro sphere formation assays, expression of stemness genes, drug resistance assays, and the ability to form tumors in nude mice. RESULTS: We demonstrated that CSCs could be isolated by the cell surface markers CD44 and stage-specific embryonic antigen-4 (SSEA-4). CD44+SSEA-4+ cells exhibited cancer stem-like properties, including extensive self-renewal into the bulk of cancer cells. In vivo xenograft experiments indicated that CD44+SSEA-4+ cells exhibit the highest tumorigenic capacity compared with the remaining subpopulations and parental cells. Double-positive cells for CD44 and SSEA-4 exhibited preferential expression of some stemness genes and were more resistant to the anticancer drugs, cisplatin and 5-fluorouracil (5-FU). In addition, cells expressing CD44 and SSEA-4 were detected in all tumor specimens analyzed, while coexpression of CD44 and SSEA-4 was not detectable in normal oral mucosa. CONCLUSION: Our findings suggest that CD44+SSEA-4+ cells exhibit the characteristics of CSCs in oral squamous cell carcinoma and provide a target for the development of more effective therapies.

    DOI: 10.1016/j.oraloncology.2013.04.012

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  • Optimization of immunotherapy in elderly cancer patients. 査読 国際誌

    Kei Tomihara, Tyler J Curiel, Bin Zhang

    Critical reviews in oncogenesis   18 ( 6 )   573 - 83   2013年

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Increasing evidence has revealed the incidence of cancer augments with aging, which could be attributed to a multitude of age-associated changes including the dysregulation of the immune system. Although many reports demonstrate the efficacy of cancer immunotherapies in numerous preclinical studies, most experiments have been performed in young animals. Studies from our group and others show that cancer immunotherapy could be ineffective in old mice, even though the same therapeutic treatment works efficiently in young mice. Given that cancer occurs mostly in the elderly, we should take age-associated immune dysregulation into consideration to achieve the effectiveness of immunotherapeutic interventions in the old. Understanding both age-related and tumor-related immune alterations might be equally important in improving the effectiveness of immunotherapy. This article reviews a number of age-associated immune alterations with specific attention given to the impact on antitumor responses, and also discusses possible strategies for optimization of immunotherapeutic interventions in the elderly.

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  • Aging-associated B7-DC+ B cells enhance anti-tumor immunity via Th1 and Th17 induction. 査読 国際誌

    Kei Tomihara, Takako Shin, Vincent J Hurez, Hideo Yagita, Drew M Pardoll, Bin Zhang, Tyler J Curiel, Tahiro Shin

    Aging cell   11 ( 1 )   128 - 38   2012年2月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Because most patients with cancer are aged and because immunological functions are altered during aging, it is important to account for aging-associated immunological alterations in the design of new cancer immunotherapies. We thus compared immune populations in young and aged mice and found that B7-DC(+) (PD-L2/CD273) B cells, a minor population in young mice, were significantly increased in aged mice. Induction of both Th1 and Th17 cells was significantly augmented by B7-DC(+) B cells from aged mice, and this effect was blocked with anti-B7-DC antibodies in vitro and in vivo. Moreover, retardation of tumor growth in aged mice was largely B7-DC dependent. Tumor growth in young mice was significantly inhibited by immunization with B7-DC(+) B cells from aged mice owing to increased induction of tumor antigen-specific cytotoxic T lymphocytes. These data indicate that B7-DC(+) B cells could play an important role in aging-associated cancer immunopathology as well as in other aging-associated diseases and further suggest that B7-DC(+) B cells have potential for future cancer immunotherapy.

    DOI: 10.1111/j.1474-9726.2011.00764.x

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  • Antigen-specific immunity and cross-priming by epithelial ovarian carcinoma-induced CD11b(+)Gr-1(+) cells. 査読 国際誌

    Kei Tomihara, Miao Guo, Takako Shin, Xiuhua Sun, Sara M Ludwig, Michael J Brumlik, Bin Zhang, Tyler J Curiel, Tahiro Shin

    Journal of immunology (Baltimore, Md. : 1950)   184 ( 11 )   6151 - 60   2010年6月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Both innate and adaptive immune systems are considered important for cancer prevention, immunosurveillance, and control of cancer progression. It is known that, although both systems initially eliminate emerging tumor cells efficiently, tumors eventually escape immune attack by a variety of mechanisms, including differentiation and recruitment of immunosuppressive CD11b(+)Gr-1(+) myeloid suppressor cells into the tumor microenvironment. However, we show that CD11b(+)Gr-1(+) cells found in ascites of epithelial ovarian cancer-bearing mice at advanced stages of disease are immunostimulatory rather than being immunosuppressive. These cells consist of a homogenous population of cells that morphologically resemble neutrophils. Moreover, like dendritic cells, immunostimulatory CD11b(+)Gr-1(+) cells can strongly cross-prime, augmenting the proliferation of functional CTLs via signaling through the expression of costimulatory molecule CD80. Adoptive transfer of these immunostimulatory CD11b(+)Gr-1(+) cells from ascites of ovarian cancer-bearing mice results in the significant regression of s.c. tumors even without being pulsed with exogenous tumor Ag prior to adoptive transfer. We now show for the first time that adaptive immune responses against cancer can be augmented by these cancer-induced granulocyte-like immunostimulatory myeloid (CD11b(+)Gr-1(+)) cells, thereby mediating highly effective antitumor immunity in an adoptive transfer model of immunity.

    DOI: 10.4049/jimmunol.0903519

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  • Costimulator B7-DC attenuates strong Th2 responses induced by Nippostrongylus brasiliensis. 査読 国際誌

    Kenji Ishiwata, Naohiro Watanabe, Miao Guo, Kei Tomihara, Michael J Brumlik, Hideo Yagita, Drew Pardoll, Lieping Chen, Tahiro Shin

    Journal of immunology (Baltimore, Md. : 1950)   184 ( 4 )   2086 - 94   2010年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The caliber and magnitude of T cell responses are regulated by costimulatory molecules following the engagement of TCRs and MHC molecules. B7-DC has the highest homology with B7-H1 in the B7 family, and both of them bind an immunoregulatory molecule, programmed death 1. Previous studies have demonstrated that B7-DC stimulates T cell proliferation and CTL generation, which sharply contrasts the inhibitory role of B7-H1. Th2 cytokines prompt B7-DC expression, which in turn enhances Th1 responses. In this study, we used an intestinal nematode, Nippostrongylus brasiliensis, to induce strong Th2 responses and to evaluate B7-DC function under Th2-polarizing conditions in vivo. By either blocking B7-DC expression during N. brasiliensis infection or by examining N. brasiliensis-infected B7-DC knockout mice, we observed enhanced eosinophilia, the overproduction of serum IgE, and increased Th2 cytokine production along with decreased Th1 cytokine production (particularly IFN-gamma production), indicating that B7-DC inhibits Th2 responses. Our results further demonstrate that the inhibition of Th2 responses by B7-DC occurs independently of programmed death 1 but conceivably acts through an as yet unknown alternative receptor that enhances Th1 responses. Although the deficiency of B7-DC expression that enhanced the production of IL-13 paradoxically resulted in better protection against N. brasiliensis infection, our results show that B7-DC plays an important role in bolstering a robust Th1 response that is required for effective antiviral and anticancer immunity, even under a strong Th2-polarizing environment induced by N. brasiliensis infection.

    DOI: 10.4049/jimmunol.0804051

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  • Sendai viral vector mediated angiopoietin-1 gene transfer for experimental ischemic limb disease. 査読 国際誌

    Jianhua Huang, Makoto Inoue, Mamoru Hasegawa, Kei Tomihara, Toshihiro Tanaka, Jiahua Chen, Hirofumi Hamada

    Angiogenesis   12 ( 3 )   243 - 9   2009年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sendai virus vector is emerging as a promising vector for gene therapy, and angiopoietin-1 (Ang-1) has been reported to improve the blood flow recovery in the ischemic limb or heart. In this study, we constructed a human Ang-1-expressing Sendai viral vector (SeVhAng-1) and injected it into the ischemic limb of rats. We found that SeVhAng-1 improved the blood flow recovery and increased the capillary density of the ischemic limb, compared with the controls. We also found that SeVhAng-1 increased p-Akt during the early period of limb ischemia, and decreased apoptosis in ischemic limb. It suggests that SeVhAng-1 may serve as a potential therapeutic tool in ischemic limb disease.

    DOI: 10.1007/s10456-009-9144-6

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  • A single-institute phase I/II trial combining nedaplatin dose escalation with a fixed dose of docetaxel for induction chemotherapy of oral squamous cell carcinoma. 査読 国際誌

    Akihiro Miyazaki, Junichi Kobayashi, Takashi Yamamoto, Yukie Kido, Kanako Takemura, Masato Abe, Kei Tomihara, Hironari Dehari, Kenji Nakamori, Itaru Nagai, Hiroyoshi Hiratsuka

    Oral oncology   44 ( 5 )   471 - 6   2008年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The purpose of this clinical trial was to assess the toxicity and efficacy of docetaxel plus nedaplatin induction chemotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). Twenty-one patients were enrolled in this phase I/II clinical study. The toxicities, response rates, and the maximum tolerated dose of nedaplatin that could be safely given preoperatively were assessed. Patients received escalating doses of nedaplatin (60, 70, 80, 90 mg/m2) combined with a fixed dose of docetaxel (60 mg/m2) on day one. Dose-limiting toxicity (DLT), grade 4 leukopenia lasting for two days or more, was seen in one patient at dose level 3; no other DLT was observed at any dose level. The overall response rate was 66.7%. The response rate was 100% at nedaplatin dose level 4, while that at dose level 1 was low (33.3%). Given these results, the recommended dose of nedaplatin in this regimen combined with fixed dose docetaxel (60 mg/m2) was determined to be 90 mg/m2. Docetaxel 60 mg/m2 plus nedaplatin 90 mg/m2 induction chemotherapy can be recommended for patients with locally advanced oral squamous cell carcinoma. Based on these results, an early phase II clinical study using this dose level was conducted; docetaxel plus nedaplatin induction chemotherapy appears to be a useful regimen for the treatment of OSCC. A late phase II clinical study is warranted.

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  • Gene transfer of CD40-ligand to dendritic cells stimulates interferon-γ production to induce growth arrest and apoptosis of tumor cells 査読

    K Tomihara, K Kato, Y Masuta, K Nakamura, H Uchida, K Sasaki, T Tanaka, J Huang, H Hiratsuka, H Hamada

    Gene Therapy   15 ( 3 )   203 - 213   2008年2月

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    担当区分:筆頭著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Springer Science and Business Media LLC  

    DOI: 10.1038/sj.gt.3303056

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    その他リンク: http://www.nature.com/articles/3303056

  • Gene transfer of noncleavable cell surface mutants of human CD154 induces the immune response and diminishes systemic inflammatory reactions. 査読 国際誌

    Yukari Masuta, Kazunori Kato, Kei Tomihara, Kiminori Nakamura, Katsunori Sasaki, Satoshi Takahashi, Hirofumi Hamada

    Journal of immunotherapy (Hagerstown, Md. : 1997)   30 ( 7 )   694 - 704   2007年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    CD154 (CD40-ligand) is a critical transmembrane molecule with potent immune-stimulatory properties that is used in clinical applications of gene therapy for leukemia and lymphoma. However, CD154 is cleaved into a soluble form, and high levels of sCD154 contribute to systemic inflammatory and cardiovascular diseases, suggesting a deleterious side effect of CD154 gene therapy. In this study, we engineered noncleavable mutants of human CD154 with point mutations to develop a potentially less toxic molecule in vivo. In contrast to wild-type CD154 (CD154-WT) subsequently released as sCD154, both mutants CD154-M3 and CD154-M4 were resistant to cleavage in tumor cells. Also, CD40-expressing leukemia B cells transfected with CD154-M3 mutant were highly effective stimulators in a mixed lymphocyte-leukemia reaction, indicating that CD154-M3 mutant did not lose biologic activity. In mice transplanted with tumors expressing CD154-WT, we found increased plasma levels of human sCD154 followed by various systemic inflammatory reactions such as glomerulonephritis and an increased number of infiltrating mononuclear cells in the liver. However, CD154-M3 mutant did not induce any systemic inflammatory effects in vivo. As such, the noncleavable mutant of CD154 is fully capable of inducing the immune response with less toxic properties and is a useful tool for CD154 immune gene therapy.

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  • Gene transfer of the CD40-ligand to human dendritic cells induces NK-mediated antitumor effects against human carcinoma cells. 査読 国際誌

    Kei Tomihara, Kazunori Kato, Yukari Masuta, Kiminori Nakamura, Toshihiro Tanaka, Hiroyoshi Hiratsuka, Hirofumi Hamada

    International journal of cancer   120 ( 7 )   1491 - 8   2007年4月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The CD40-ligand (CD40L) is a key molecule for the activation of dendritic cells (DCs), followed by the induction of DC maturation and cytokine production. Here we found that DC infected with adenovirus vector encoding human CD40L (CD40L-DC) displayed significantly higher levels of immune accessory molecules and IL-12 production than did uninfected cells, and that CD40L-DC produced much higher levels of IFN-gamma. To investigate whether CD40L-DC-derived these soluble factors could stimulate NK cells without physical cell-to-cell contact, we cocultured NK cells with CD40L-DC in transwell culture plates. NK cells showed up-regulated cytotoxic activity toward various squamous oral cell carcinoma (OSC-70, HSC-2, HSC-3), and we determined that both IL-12 and IFN-gamma contributed to the CD40L-DC-mediated NK cell activation. NK cells stimulated with CD40L-DC resulted in the induction of the cell surface expression of TRAIL, the production of IFN-gamma and intracellular accumulation of granzyme B. The cytotoxic activity of NK cells stimulated with CD40L-DC could be mostly inhibited by neutralizing antibody for TRAIL and completely abrogated by the combination of antibody and exocytosis inhibitor, indicating that this was mainly mediated by a TRAIL-TRAIL-receptor interaction and granule exocytosis. Moreover, CD40L-DC-activated NK cells could induce up-regulation of a death-receptor TRAIL-R2 (DR5) and down-regulation of a decoy receptor TRAIL-R3 (DcR1) on carcinoma cells. Overall, these results have revealed that CD40L-DC could activate an innate immune reaction by stimulating NK cells followed by carcinoma cells, supporting that administration of CD40L-DC may have potential as an anticancer therapy.

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  • Carcinoembryonic antigen-targeted selective gene therapy for gastric cancer through FZ33 fiber-modified adenovirus vectors. 査読 国際誌

    Toshihiro Tanaka, Jianhua Huang, Sachie Hirai, Motomu Kuroki, Masahide Kuroki, Naoki Watanabe, Kei Tomihara, Kazunori Kato, Hirofumi Hamada

    Clinical cancer research : an official journal of the American Association for Cancer Research   12 ( 12 )   3803 - 13   2006年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: A major problem when using the adenoviral vectors for gene therapy applications is thought to be related to low transduction efficiency in cancer cells or to side effects in normal cells. There is an urgent requirement to improve the specificity of gene delivery in the context of cancer gene therapy. EXPERIMENTAL DESIGN: We constructed a genetically modified adenovirus incorporating an IgG Fc-binding motif from the Staphylococcus protein A, Z33, within the HI loop (Adv-FZ33). A remarkable degree of targeted gene delivery to gastric cancer cells was obtained with Adv-FZ33 with the fully human anti-carcinoembryonic antigen (CEA) monoclonal antibody, C2-45. RESULTS: In vitro LacZ or EGFP gene expression after Adv-FZ33 infection via C2-45 was 20 times higher than control monoclonal antibody in MKN-45 at 1,000 viral particles/cell. We generated Ax3CAUP-FZ33 (UP-FZ33), which is an Adv-FZ33 derivative vector expressing a therapeutic gene (i.e., Escherichia coli uracil phosphoribosyltransferase), which converts 5-fluorouracil (5-FU) directly to 5-fluoro-UMP. UP-FZ33 with C2-45 enhanced the cytotoxicity of 5-FU by 10.5-fold in terms of IC(50) against MKN-45 compared with control IgG4. In a nude mouse peritoneal dissemination model, tumor growth in mice treated with UP-FZ33/C2-45/5-FU was significantly suppressed, and tumor volumes were less than one-fourth of those of the control IgG4 group (P < 0.05). The median survival time of the UP-FZ33/C2-45/5-FU group was significantly longer than those treated with PBS or 5-FU only (P < 0.01). CONCLUSIONS: These data suggest that CEA-targeted FZ33 mutant adenovirus-mediated gene delivery offers a strong and selective therapeutic modality against CEA-producing cancers.

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  • Bcl-xL gene transfer inhibits Bax translocation and prolongs cardiac cold preservation time in rats. 査読 国際誌

    Jianhua Huang, Kiminori Nakamura, Yoshinori Ito, Takeshi Uzuka, Masayuki Morikawa, Sachie Hirai, Kei Tomihara, Toshihiro Tanaka, Yukari Masuta, Keiji Ishii, Kazunori Kato, Hirofumi Hamada

    Circulation   112 ( 1 )   76 - 83   2005年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Apoptosis is an important cause of early graft loss after heart transplantation. Bcl-xL was reported to protect the heart against normothermic ischemia and reperfusion injury. In this study, we determined whether overexpression of Bcl-xL could inhibit tissue injury resulting from prolonged cold preservation followed by warm reperfusion of heart transplants. METHODS AND RESULTS: Lewis rat hearts were transduced with an adenovirus vector harboring Bcl-xL cDNA (AxCAhBclxL) 4 days before collection of tissue. After preservation in University of Wisconsin solution at 4 degrees C for 24 hours, the heart was either perfused with a Langendorff device ex vivo or used for heterotopic heart transplantation in vivo. Bcl-xL gene transfer significantly reduced the infarct size (23.0+/-2.6% versus 47.7+/-7.0% in saline control and 48.6+/-6.1% in vector control, P<0.01) after 2-hour reperfusion at 37 degrees C with the Langendorff device and significantly decreased creatine kinase release (0.82+/-0.27 IU, versus 1.57+/-0.33 and 1.50+/-0.37 IU in saline and vector controls, respectively; P<0.05). In heart transplantation, overexpression of Bcl-xL inhibited Bax translocation from the cytosol to the mitochondria, resulting in decreased cytochrome c release from the mitochondria; it also significantly decreased cardiac cell apoptosis and improved graft survival rate after long cold preservation, followed by warm reperfusion. CONCLUSIONS: Bcl-xL gene transfer inhibited the translocation of Bax and prolonged the cold preservation time of cardiac transplants. This may be a potential therapeutic method in clinical practice.

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  • Clinical Application of Hyperdry Amniotic Membrane in Cleft Palate Repair. 国際誌

    Kumiko Fujiwara, Hiroaki Tsuno, Motonori Okabe, Toshiko Yoshida, Shuichi Imaue, Kei Tomihara, Naoya Arai, Makoto Noguchi

    The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association   10556656221075937 - 10556656221075937   2022年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    OBJECTIVE: To examine the safety and efficacy of hyperdry amniotic membrane (HDAM) for wound closure after palatoplasty in cleft palate patients. METHODS: HDAMs were prepared by washing and drying under infrared rays and microwaves at temperatures less than 60°C using a hyperdrying device. A total of 16 cleft palate patients (8 males, 8 females), aged 1 to 3 years (mean age 1 year 9 months), received one-stage pushback palatoplasty. The remaining raw wound after surgery was covered by an HDAM and a plastic cover plate. The cover plate was removed 1 week after surgery and parameters including temperature, feeding, allergic reactions, postoperative bleeding, re-epithelialization, wound dehiscence, and infection were monitored during the follow-up period of 31.2 months. RESULTS: All patients could adequately ingest at 5 days postoperation and after removal of the cover plate. None of the patients had a persistent fever or allergic reactions. Ingestion was feasible immediately in all patients, and no postoperative bleeding was observed during ingestion. No secondary hemorrhages were observed during follow-up. No postoperative wound dehiscence on the midline of the palate was observed. No infections were observed after the removal of the cover plate. No patients suffered from severe scar formation or contracture of the wound in the follow-up period. Hemorrhage, undue epithelialization, and scar contracture did not occur in any patient. The mean evaluation score was 7.75 points. CONCLUSION: HDAM can be used safely and effectively for wound closure following palatoplasty in cleft palate infants. Future studies testing the safety of patient's own amnion for palatoplasty, are required.

    DOI: 10.1177/10556656221075937

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  • [Neutrophil-to-Lymphocyte Ratio(NLR)as a Predictive Indicator of the Response to Nivolumab in Patients with Oral Squamous Cell Carcinoma].

    Hidetake Tachinami, Kei Tomihara, Atsushi Ikeda, Katsuhisa Sekido, Kotaro Sakurai, Shuichi Imaue, Kumiko Fujiwara, Ryuji Hayashi, Makoto Noguchi

    Gan to kagaku ryoho. Cancer & chemotherapy   48 ( 12 )   1485 - 1490   2021年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: The immune checkpoint inhibitor (ICI) nivolumab has revolutionized the treatment for recurrent or metastatic advanced oral cancer. Because the response rate remains low, the identification of predictive indicators of the response to nivolumab is among the most critical issues. The neutrophil-to-lymphocyte ratio(NLR)is a potential predictive marker of the response to nivolumab in patients with various cancer types. However, the utility of the NLR as a biomarker for predicting the response of oral cancer patients to ICIs is poorly understood. PATIENTS AND METHODS: In this retrospective cohort study, we evaluated the association between NLR and nivolumab treatment outcome in 13 patients diagnosed with recurrent or metastatic oral squamous cell carcinoma(OSCC)treated with nivolumab at the Toyama University Hospital between December 2017 and December 2019. RESULTS: Complete response(CR)and partial response(PR)rates of 38.5%(5/13)and 0% (0/13), respectively, were observed in responders; stable disease(SD)and progressive disease(PD)rates of 7.7%(1/13) and 53.8%(7/13), respectively, were observed in non-responders. After nivolumab treatment, the median NLR among responders decreased to 3.3(3.0-3.9)from 4.1(3.7-4.3)during pre-treatment assessment and increased from 5.6(3.2- 9.2)at pre-treatment to 9.4(5.3-17.9)among non-responders. Moreover, patients with higher NLRs(≥5)in the post- treatment group had a significantly worse overall survival than those with lower NLRs(<5). Specifically, patients with a higher post-treatment NLR(≥10)had significantly worse outcomes for post-nivolumab salvage chemotherapy. CONCLUSION: The NLR could be a useful marker for predicting the treatment response to nivolumab or post-nivolumab salvage chemotherapy in OSCC patients.

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  • Central mucoepidermoid carcinoma of the maxilla developing from a calcifying odontogenic cyst: A rare case report. 国際誌

    Megumi Isshiki-Murakami, Hidetake Tachinami, Kei Tomihara, Akira Noguchi, Katsuhisa Sekido, Shuichi Imaue, Kumiko Fujiwara, Johji Imura, Makoto Noguchi

    Clinical case reports   9 ( 10 )   e04928   2021年10月

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    記述言語:英語  

    Intraosseous mucoepidermoid carcinoma of the jaw is a rare lesion that has been suggested to originate from the odontogenic epithelium. We report an unusual case of central mucoepidermoid carcinoma in an 18-year-old Japanese man with an odontogenic cyst.

    DOI: 10.1002/ccr3.4928

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  • Sarcoidosis of the mandibular condyle manifesting as a temporomandibular joint arthrosis: A rare case report 査読

    Sayaka Hori (Wakao), Kei Tomihara, Katsuhisa Sekido, Hidetake Tachinami, Shuichi Imaue, Kumiko Fujiwara, Makoto Noguchi

    Oral Science International   18 ( 3 )   229 - 232   2021年9月

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    担当区分:責任著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1002/osi2.1095

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    その他リンク: https://onlinelibrary.wiley.com/doi/full-xml/10.1002/osi2.1095

  • Mini-microform cleft lip with complete cleft alveolus and palate: A case report. 査読 国際誌

    Kumiko Fujiwara, Mitsuna Yoshida, Naomi Nakamichi, Satoru Saitoh, Mayu Takaichi, Risa Ishizaka, Kei Tomihara, Makoto Noguchi

    Congenital anomalies   61 ( 4 )   133 - 137   2021年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cleft lip and cleft alveolus are caused by incomplete fusion of the frontonasal and maxillary prominences. However, milder forms of cleft lip are rarely accompanied by cleft alveolus. Here, we report a rare case of mini-microform cleft lip with complete cleft alveolus and cleft palate. No findings suggestive of cleft lip were evident on initial examination. However, three-dimensional facial measurements confirmed the presence of cleft lip despite no evidence of orbicularis oris muscle (OOM) rupture on ultrasonography. Collapsed nostril, as observed in this case, is usually associated with OOM rupture. However, it can also be caused by skeletal abnormalities, such as cleft alveolus. Three-dimensional facial measurements and ultrasonography can assist in accurate diagnosis when visual examination is ambiguous.

    DOI: 10.1111/cga.12415

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  • Total paranasal sinus aplasia with multiple impacted teeth: A case report 査読

    Mayu Takaichi, Kei Tomihara, Ryuichi Terashima, Hiroyuki Ichijo, Yuichi Kamisaki, Kumiko Fujiwara, Makoto Noguchi

    JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY MEDICINE AND PATHOLOGY   33 ( 2 )   158 - 160   2021年3月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Paranasal sinus aplasia is a rare condition. Here, we report an extremely rare case of total paranasal sinus aplasia accompanied by 18 impacted teeth. A 77-year old man presented with a complaint of diffuse swelling in the anterior maxilla. Radiographs revealed well-demarcated radiolucent cystic lesions in the swollen maxilla. However, 14 teeth were impacted in the maxilla, and 4 were impacted in the mandible. Furthermore, paranasal sinuses were completely obliterated. The patient then underwent cystectomy and five impacted anterior maxillary teeth were extracted under general anesthesia. Furthermore, no systemic diseases, including metabolic and endocrine abnormalities, and bone diseases including osteogenesis imperfecta, which may have resulted in total paranasal sinus aplasia, were identified. The patient is healthy with no maxillary osteitis 1 year after cystectomy. To our knowledge, three cases of total paranasal sinus aplasia have been reported thus far (in English); however, no studies have reported cases of total paranasal aplasia with multiple impacted teeth. Therefore, while computed tomography is required to detect total paranasal sinus aplasia, maxillary sinus aplasia can be detected through panoramic radiography in general dental practice; hence, dental practitioners should consider the possibility, since paranasal sinus aplasia may result from severe systemic diseases or syndromes. (C) 2020 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.ajoms.2020.09.012

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  • A case of anti-laminin 332 mucous membrane pemphigoid manifesting as desquamative gingivitis 査読

    Sahoko Imai Maeda, Kumiko Fujiwara, Kei Tomihara, Manabu Yamazaki, Shuichi Imaue, Makoto Noguchi

    ORAL SCIENCE INTERNATIONAL   18 ( 1 )   73 - 77   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Anti-laminin 332 mucous membrane pemphigoid (MMP) is characterized by circulating anti-laminin 332 autoantibodies, with a high risk of concurrent malignant neoplasms. We report a case of anti-laminin 332 MMP manifesting as a desquamative gingivitis. A 45-year-old woman experienced painful erythema and occasional bullous lesions on the gingiva despite good oral hygiene and plaque control. Intraoral examination revealed gingival inflammation with desquamation. Biopsy showed subepithelial cleft formation suggesting a subepidermal blister. Direct immunofluorescence revealed the deposition of IgG and IgA in the epithelium. Accordingly, we diagnosed anti-laminin 332 MMP and treated with systemic corticosteroids. The oral lesion resolved after 3 months.

    DOI: 10.1002/osi2.1073

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  • Astaxanthin ameliorates cisplatin‐induced damage in normal human fibroblasts 査読

    Momoho Yamaguchi, Kei Tomihara, Wataru Heshiki, Kotaro Sakurai, Katsuhisa Sekido, Hidetake Tachinami, Rohan Moniruzzaman, Sayaka Inoue, Kumiko Fujiwara, Makoto Noguchi

    Oral Science International   16 ( 3 )   171 - 177   2019年12月

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    担当区分:責任著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1002/osi2.1031

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  • Clinical application and evaluation of hyperdried human amniotic membrane for the surgical repair of oral mucosal defects 査読

    Hiroaki Tsuno, Motonori Okabe, Kumiko Fujiwara, Risa Ishizaka, Kei Tomihara, Toshiko Yoshida, Toshio Nikaido, Makoto Noguchi

    ORAL SCIENCE INTERNATIONAL   16 ( 2 )   69 - 74   2019年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    The amniotic membrane is highly biocompatible, possesses anti-inflammatory properties, and has been used for reconstructive surgeries in various areas. However, there have been persistent problems related to its preparation, storage, and sterilization. Hyperdried human amniotic membrane (HD-AM) was developed at the Toyama University to resolve these problems of fresh amnion. The aim of this study was to evaluate the clinical effects of the surgical repair of oral mucosal defects by using HD-AM. In total, 29 patients with oral precancerous lesions or early-stage cancer were included. After resection of the oral lesions, surgical defects of the oral mucosa were covered with HD-AM in 15 patients (HD-AM group) and with commercial collagen graft material in 14 patients (CGM group). Postoperative pain, feeding state, epithelialization, the scarring of the wound, and oral function were evaluated. The postoperative medication period of nonsteroidal anti-inflammatory drug use was significantly shorter (P = 0.0457) and the recovery period for resumption of oral feeding was also significantly earlier (P = 0.0414) in the HD-AM group than in the CGM group, without specific complications. HD-AM reduced the postoperative inflammation; it can be used as a novel dressing material for the surgical repair of oral mucosal defects.

    DOI: 10.1002/osi2.1003

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  • Severe stomatitis caused by misuse of methotrexate in an elderly patient with chronic rheumatoid arthritis 査読

    Kohta Yamada, Kei Tomihara, Manabu Yamazaki, Makoto Noguchi

    JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY MEDICINE AND PATHOLOGY   31 ( 4 )   284 - 287   2019年7月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Methotrexate (MTX) is an antifolate that has been used as a chemotherapeutic agent for the treatment of neoplasm, such as leukemia and osteosarcoma. Moreover, MTX is also commonly used for treatment of chronic rheumatoid arthritis (RA). Here, we report a case of severe stomatitis in a patient with RA, which was caused by misuse of MTX. An 83-year-old female patient visited our department with the chief complaint of oral mucosal pain, accompanied by extreme fatigue. Severe stomatitis lesions were observed throughout her oral mucosa. Moreover, blood examination revealed pancytopenia. The patient reported a history of RA, and had been prescribed MTX since 2004. Although 6 mg MTX should be used twice per week, the patient mistakenly used MTX every day following her last consultation, for a period of 1 month. These findings led to a diagnosis of severe stomatitis, pancytopenia, and sepsis, all induced by misuse of MTX. Ultimately, she was treated with blood transfusion, antibiotics, and intravenous hyper alimentation, as well as administration of granulocyte colony-stimulating factor.MTX for the treatment of RA should be carefully managed to limit the risk of its misuse, especially in elderly patients, because of the severity and potential lethality of symptoms.

    DOI: 10.1016/j.ajoms.2018.06.009

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  • An intraosseous malignant peripheral nerve sheath tumor in the mandible of a patient with neurofibromatosis type 1 査読

    Mayu Takaichi, Kei Tomihara, Kumiko Fujiwara, Shuichi Imaue, Shigeharu Miwa, Makoto Noguchi

    ORAL SCIENCE INTERNATIONAL   15 ( 2 )   86 - 89   2018年7月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas that originate in peripheral nerves or neurilemma cells. Here, we report an extremely rare case of an intraosseous MPNST in the mandible of a patient with neurofibromatosis type 1 (NF1). A 57-year-old woman with a history of NF1 was referred to our hospital because she had abnormal sensations at her left mandible. She was diagnosed with MPNST and underwent radical resection, although local recurrence and multiple metastases were detected during follow-up. Despite receiving palliative radiotherapy, the patient died at 13 months after the initial diagnosis. (C) 2018 Japanese Stomatological Society. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/S1348-8643(18)30007-7

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  • Successful control of opioid-refractory cancer pain with methadone in a patient with advanced oral squamous cell carcinoma: A case report 査読

    Katsuhisa Sekido, Kei Tomihara, Hideyo Horikawa, Hidetake Tachinami, Nozomu Murakami, Makoto Noguchi

    Oral Science International   15 ( 2 )   78 - 80   2018年7月

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    担当区分:責任著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    DOI: 10.1016/s1348-8643(18)30004-1

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  • Oral squamous cell carcinoma in a patient with scimitar syndrome 査読

    Katsuhisa Sekido, Kei Tomihara, Kumiko Fujiwara, Hidetake Tachinami, Shuichi Imaue, Makoto Noguchi

    ORAL SCIENCE INTERNATIONAL   15 ( 1 )   36 - 39   2018年1月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    Scimitar syndrome is a rare congenital cardiac condition with a poor prognosis. It is frequently accompanied by concordant pulmonary hypoplasia and aortopulmonary collateral arteries connected to the hypoplastic lung. Here we report a case involving a 58-year-old woman with scimitar syndrome who developed stage II oral cancer. Surgical treatment was deemed high risk because of difficulty in respiratory management through mechanical ventilation during general anesthesia, and hence, she was treated with chemoradiotherapy, which was successfully completed. The findings from this case suggest that chemoradiotherapy is a useful strategy that can contribute to improved clinical outcomes for oral cancer in patients with scimitar syndrome. (C) 2017 Published by Elsevier Ltd on behalf of Japanese Stomatological Society.

    DOI: 10.1016/S1348-8643(17)30043-5

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  • Primary peri-implant oral intra-epithelial neoplasia/carcinoma in situ: a case report considering risk factors for carcinogenesis. 査読 国際誌

    Makoto Noguchi, Hiroaki Tsuno, Risa Ishizaka, Kumiko Fujiwara, Shuichi Imaue, Kei Tomihara, Takashi Minamisaka

    International journal of implant dentistry   3 ( 1 )   47 - 47   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Major risk factors for oral squamous cell carcinoma (SCC) are tobacco smoking, a betel quid chewing habit, and heavy alcohol consumption. However, around 15% of oral SCCs cannot be explained by these risk factors. Although oral SCC associated with dental implants is quite rare, there has been a recent gradual accumulation of reports about it. Here, we report a case of primary peri-implant oral intra-epithelial neoplasia/carcinoma in situ (OIN/CIS) in a woman without the major risk factors for oral SCC. CASE PRESENTATION: A 65-year-old woman was referred to our clinic with a tumor in the right lower gingiva. She had no history of tobacco smoking and only drank socially. Ten years previously, mandibular right posterior teeth had been replaced with an implant-supported porcelain-fused-to-metal restoration in a dental clinic. About 7 years later, she noticed swelling on the lingual side of the gingiva around the implant-supported restoration, and was eventually referred to our clinic with the suspicion of a neoplasia around the dental implant. The upper part of the implant body was exposed on the implant corresponding to the first molar of the right side of the mandible; this was associated with painless, elastic soft, and relatively well circumscribed gingival swelling on the lingual site. A panoramic radiograph showed slight vertical bone resorption around the implants. An incisional biopsy was conducted under the suspicion of neoplasia. Pathological microscopic examination of the biopsy specimen revealed thickened squamous epithelia with slight nuclear atypism and disorders of the epithelial rete pegs. Immunohistochemical findings showed positive staining for keratin 17 and a negative staining mosaic pattern for keratin 13. High p53, p63, and Ki-67 reactivity was also observed. From these findings, OIN/CIS of the gingiva was pathologically diagnosed, and a wide local excision with rim resection of the mandible, including the implants, was performed. The pathological findings for the resected specimen were same as those for the biopsy specimen. After 1 year of follow-up, there was no evidence of recurrence. CONCLUSION: In this case, prolonged peri-implant mucositis or peri-implantitis may have been a plausible risk factor for carcinogenesis.

    DOI: 10.1186/s40729-017-0109-z

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  • Conventional osteosarcoma of the mandible successfully treated with radical surgery and adjuvant chemotherapy after responding poorly to neoadjuvant chemotherapy: a case report. 査読 国際誌

    Yutaro Kimura, Kei Tomihara, Hidetake Tachinami, Shuichi Imaue, Kenji Nakamori, Kumiko Fujiwara, Kayo Suzuki, Taketoshi Yasuda, Shigeharu Miwa, Eiji Nakayama, Makoto Noguchi

    Journal of medical case reports   11 ( 1 )   210 - 210   2017年8月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Osteosarcoma, the most common primary bone malignancy, has an extremely poor prognosis and a high rate of local recurrence and distal metastases. Because osteosarcomas of the head and neck region are rare, accounting for less than 10% of all osteosarcoma cases, limited information is available about their treatment and prognosis. Because of the high rate of distal metastases associated with extragnathic osteosarcoma, surgery combined with chemotherapy is currently considered essential in its treatment. However, the role of chemotherapy has not been well elucidated in the treatment of head and neck osteosarcoma because of the rarity of this condition. CASE PRESENTATION: In this report, we present the case of a 58-year-old Japanese woman with osteosarcoma of the mandible that was treated with radical surgery combined with neoadjuvant and adjuvant chemotherapy. Because the tumor showed rapid growth during neoadjuvant chemotherapy, neoadjuvant chemotherapy was suspended and surgical resection was performed, followed by adjuvant chemotherapy. No evidence of local recurrence and distal metastasis was found 14 months after initial treatment. Local control is considered a principal prognostic factor for head and neck osteosarcoma. CONCLUSIONS: Wide surgical excision should be considered a primary goal even during neoadjuvant chemotherapy, especially in cases that respond poorly to neoadjuvant chemotherapy.

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  • Different effect of resveratrol to induction of apoptosis depending on the type of human cancer cells. 査読 国際誌

    Michinori Takashina, Sayaka Inoue, Kei Tomihara, Kengo Tomita, Kohshi Hattori, Qing-Li Zhao, Tokiko Suzuki, Makoto Noguchi, Wakana Ohashi, Yuichi Hattori

    International journal of oncology   50 ( 3 )   787 - 797   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The effect of resveratrol on various human cancer cells was investigated with special focus on apoptotic cell death, in an attempt to further characterize its mechanism of action. There were great differences in the anti-viability effect of resveratrol between different types of human cancer cells. While the inhibition of cell viability by resveratrol was marked in U937 and MOLT-4 leukemia cells, resveratrol moderately inhibited cell viability in MCF-7 breast, HepG2 liver, and A549 lung cancer cells, and the effect was slight on cell viability in Caco-2, HCT116, and SW480 colon cancer cells. Following resveratrol treatment, U937 and MOLT-4 markedly increased the population of late apoptotic cells but MCF-7 and HepG2 underwent apoptosis with an increased population of early apoptosis, and resveratrol-induced DNA fragmentation was observed only in leukemic cells. Activation of sirtuin 1 and adenosine-monophosphate-activated protein kinase was not responsible for resveratrol-induced cancer cell death. Instead, resveratrol significantly reduced Akt activation with the downregulation of H-Ras, resulting in facilitation of Bax translocation to mitochondria in leukemic cells. This study suggests that resveratrol can induce apoptotic cell death in human leukemic cells to a greater extent than in human solid tumor cells via reducing Akt activation due to Ras downregulation.

    DOI: 10.3892/ijo.2017.3859

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  • Successful multimodal treatment of intraoral salivary duct carcinoma in a patient with multiple lymph node metastases: a case report. 査読 国際誌

    Shuichi Imaue, Kei Tomihara, Takeru Hamashima, Gakuto Tomizawa, Kuninori Nomura, Masakiyo Sasahara, Makoto Noguchi

    World journal of surgical oncology   15 ( 1 )   18 - 18   2017年1月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary gland malignancy that is associated with an aggressive clinical behavior and poor prognosis. Herein, we report on a long surviving case of SDC of the minor salivary gland with multiple lymph node metastases (LNMs). CASE PRESENTATION: An 83-year-old woman presented with a history of lymphadenopathy in the right side of the neck and recent onset and rapid growth of a mass in the right buccal region. Clinical examinations and biopsy findings were suggestive of a salivary gland malignant tumor with regional LNMs. The patient was treated with neoadjuvant chemotherapy. Tumor excision and ipsilateral radical neck dissection were performed, followed by adjuvant chemoradiotherapy. Postoperative histological examination revealed a tumor with irregular nests of atypical ductal epithelial cells, a cribriform growth pattern, and comedo-like central necrosis that lead to a final diagnosis of SDC. LNMs were observed in six lymph nodes of the right side of the neck. The patient underwent postoperative chemotherapy using single-agent cisplatin that was administered concurrently with radiotherapy (total, 65 Gy). There was no evidence of local recurrence or distant metastasis for >6 years. CONCLUSIONS: Although available data on treatment modalities for SDC remain limited, multimodal therapy may contribute to improved clinical outcomes in patients with advanced intraoral SDC.

    DOI: 10.1186/s12957-016-1090-3

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  • Invasive micropapillary salivary duct carcinoma mixed with mucin-rich salivary duct carcinoma in minor salivary gland: a rare case report. 査読 国際誌

    Kei Tomihara, Shigeharu Miwa, Takeshi Takazakura, Yuichi Kamisaki, Makoto Noguchi

    Oral surgery, oral medicine, oral pathology and oral radiology   121 ( 6 )   e162-7   2016年6月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Invasive micropapillary salivary duct carcinoma (SDC) is a rare variant of SDC. Although several cases involving major salivary glands have been reported, no cases arising de novo in minor salivary glands have been reported to date. Here we report the first case of invasive micropapillary SDC that arose in a minor salivary gland of the parapharyngeal space. METHODS: A 72-year-old male patient presented with an enlarging mass in the left parapharyngeal region along with trismus and swollen lymph nodes. Clinical examinations and biopsy findings were suggestive of a salivary gland malignant tumor with regional lymph node metastases. The tumor, therefore, was excised with partial mandibulectomy with unilateral radical neck dissection. RESULTS: Histologically, the tumor consisted of an invasive micropapillary growth pattern of SDC and mixed with mucinous component of SDC. Local recurrence and lung metastasis developed, and the patient died of disease 13 months after the initial treatment. CONCLUSIONS: We describe the clinical and histologic features of this extremely rare case of minor salivary gland SDC that was histologically characterized by the presence of both invasive micropapillary growth pattern and mucinous component.

    DOI: 10.1016/j.oooo.2015.10.012

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  • Extracellular Ca(2+)-dependent enhancement of cytocidal potency of zoledronic acid in human oral cancer cells. 査読 国際誌

    Sayaka Inoue, Naoya Arai, Kei Tomihara, Michinori Takashina, Yuichi Hattori, Makoto Noguchi

    European journal of pharmacology   761   44 - 54   2015年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Direct antitumor effects of bisphosphonates (BPs) have been demonstrated in various cancer cells in vitro. However, the effective concentrations of BPs are typically much higher than their clinically relevant concentrations. Oral cancers frequently invade jawbone and may lead to the release of Ca(2+) in primary lesions. We investigated the effects of the combined application of zoledronic acid (ZA) and Ca(2+) on proliferation and apoptosis of oral cancer cells. Human oral cancer cells, breast cancer cells, and colon cancer cells were treated with ZA at a wide range of concentrations in different Ca(2+) concentration environments. Under a standard Ca(2+) concentration (0.6mM), micromolar concentrations of ZA were required to inhibit oral cancer cell proliferation. Increasing extracellular Ca(2+) concentrations greatly enhanced the potency of the ZA cytocidal effect. The ability of Ca(2+) to enhance the cytocidal effects of ZA was negated by the Ca(2+)-selective chelator EGTA. In contrast, the cytocidal effect of ZA was less pronounced in breast and colon cancer cells regardless of whether extracellular Ca(2+) was elevated. In oral cancer cells incubated with 1.6mM Ca(2+), ZA up-regulated mitochondrial Bax expression and increased mitochondrial Ca(2+) uptake. This was associated with decreased mitochondrial membrane potential and increased release of cytochrome c. We suggest that ZA can specifically produce potent cytocidal activity in oral cancer cells in an extracellular Ca(2+)-dependent manner, implying that BPs may be useful for treatment of oral squamous cell carcinoma with jawbone invasion leading to the hypercalcemic state.

    DOI: 10.1016/j.ejphar.2015.04.032

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  • Use of hyperdry amniotic membrane in operations for cleft palate: a study in rats. 査読 国際誌

    Hiroaki Tsuno, Makoto Noguchi, Motonori Okabe, Kei Tomihara, Toshiko Yoshida, Toshio Nikaido

    The British journal of oral & maxillofacial surgery   53 ( 4 )   358 - 63   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The growth of maxillary bone and the development of dentition are often impaired in patients who have had pushback operations for repair of a cleft palate. There has been considerable discussion about the most suitable technique or material used in such repairs to resolve the problem. Hyperdry amniotic membrane, a new preservable material derived from human amnion, has recently been introduced in several procedures. We have evaluated its use during pushback surgery in animal studies to try to correct the inhibition of growth and development of the maxilla. Mucosal defects were created in 3-week-old rats, and then covered with hyperdry amniotic membrane or not. Healing was assessed by histological and morphological examination at 1 week and 7 weeks postoperatively. In the group treated with hyperdry amniotic membrane, submucosal tissue was reconstructed successfully during the early postoperative period. Lateral palatal growth was not inhibited as much, and medial inclination of the teeth was less, after a period of growth using this material. The results suggest that hyperdry amniotic membrane is a suitable new dressing material for use in the treatment of cleft palate.

    DOI: 10.1016/j.bjoms.2015.01.018

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  • Sarcomatoid salivary duct carcinoma of the palate: a rare case report. 査読 国際誌

    Kei Tomihara, Takeru Hamashima, Toshitaka Nagao, Kenji Nakamori, Masakiyo Sasahara, Makoto Noguchi

    Oral surgery, oral medicine, oral pathology and oral radiology   119 ( 1 )   e27-32   2015年1月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Salivary duct carcinoma (SDC) is an uncommon neoplasm that most commonly occurs in major salivary glands, mainly the parotid gland. SDC is rarely found in the minor salivary glands of the oral cavity. This report presents an extremely rare case of sarcomatoid SDC originating in a minor salivary gland of the palate. The tumor was histologically characterized by the presence of both carcinomatous and sarcomatoid components. The patient presented with a painless mass in the right palate, which slowly increased in size over 20 years. The clinical course of the present case suggests that the tumor most probably developed as a result of malignant transformation of a preexisting benign tumor of the palatal salivary gland. This report describes the clinical and histologic features of this extremely rare case of sarcomatoid SDC with reference to the relevant literature.

    DOI: 10.1016/j.oooo.2014.08.007

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  • Clinical significance of computed tomography assessment for third molar surgery. 査読 国際誌

    Kenji Nakamori, Kei Tomihara, Makoto Noguchi

    World journal of radiology   6 ( 7 )   417 - 23   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Surgical extraction of the third molar is the most commonly performed surgical procedure in the clinical practice of oral surgery. Third molar surgery is warranted when there is inadequate space for eruption, malpositioning, or risk for cyst or odontogenic tumor formation. Preoperative assessment should include a detailed morphologic analysis of the third molar and its relationship to adjacent structures and surrounding tissues. Due to developments in medical engineering technology, computed tomography (CT) now plays a critical role in providing the clear images required for adequate assessment prior to third molar surgery. Removal of the maxillary third molar is associated with a risk for maxillary sinus perforation, whereas removal of the mandibular third molar can put patients at risk for a neurosensory deficit from damage to the lingual nerve or inferior alveolar nerve. Multiple factors, including demographic, anatomic, and treatment-related factors, influence the incidence of nerve injury during or following removal of the third molar. CT assessment of the third molar prior to surgery can identify some of these risk factors, such as the absence of cortication between the mandibular third molar and the inferior alveolar canal, prior to surgery to reduce the risk for nerve damage. This topic highlight presents an overview of the clinical significance of CT assessment in third molar surgery.

    DOI: 10.4329/wjr.v6.i7.417

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  • 癌性疼痛管理に超大量の塩酸モルヒネを必要とした上顎癌の1例 査読

    阿久(武井)理恵, 今上修一, 冨原圭, 山口浩太, 仲盛健治, 野口誠

    日本口腔外科学会雑誌   60 ( 12 )   2014年

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  • [Clinical investigation of bisphosphonate-related osteonecrosis of the jaws]. 査読

    Hironari Dehari, Kei Tomihara, Megumi Ueda, Makoto Shimanishi, Masayuki Ono, Takanori Sasaki, Tomohiro Igarashi, Kaori Shiratori, Masato Abe, Kazuhiro Ogi, Kenji Nakamori, Akihiro Miyazaki, Itaru Nagai, Hiroyoshi Hiratsuka

    Gan to kagaku ryoho. Cancer & chemotherapy   36 ( 13 )   2587 - 92   2009年12月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    We examined the clinical features of bisphosphonate(BP)-related osteonecrosis of the jaws(BRONJ), a serious complication resulting from intravenous BP treatment for multiple myeloma and malignant tumors with bone metastasis. We retrospectively reviewed the medical records of 36 patients who received intravenous BP therapy for the above-mentioned conditions, at Sapporo Medical University Hospital between July 2006 and October 2008. BP therapy caused BRONJ in 7 of 24 patients, but did not affect the bones of the other 17 patients. The other 12 of the 36 patients involved in the study were prescribed BP only after they had undergone an oral examination and treatment for dental inflammation. Of these patients, 7 developed BRONJ with BP treatment, after tooth extraction or acute dental inflammation. Treating dental inflammation before prescribing BP prevented the development of BRONJ. BRONJ is highly intractable and does not resolve with the standard treatment for osteomyelitis. Therefore, preventive therapy, which can be achieved by cooperation between medical doctors and dentists, is currently the most effective strategy for BRONJ. Conservative treatment with antibiotics may also be useful for maintaining or improving the quality of life of BRONJ patients.

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  • Squamous cell carcinoma of the buccal mucosa in a young adult with history of allogeneic bone marrow transplantation for childhood acute leukemia. 査読 国際誌

    Kei Tomihara, Hironari Dehari, Akira Yamaguchi, Masato Abe, Akihiro Miyazaki, Kenji Nakamori, Masato Hareyama, Hiroyoshi Hiratsuka

    Head & neck   31 ( 4 )   565 - 8   2009年4月

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    担当区分:筆頭著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Secondary cancers are severe complications in patients who have had allogeneic bone marrow transplantation for childhood leukemia. We describe here a case of squamous cell carcinoma (SCC) of the buccal mucosa in a young adult patient who had had allogeneic bone marrow transplantation for childhood acute leukemia. METHODS AND RESULTS: The primary tumor was treated with interstitial brachytherapy, and lymph node metastasis was treated by supraomohyoid neck dissection. The patient had a history of acute lymphoblastic leukemia (ALL) at 11 years of age and had received an allogeneic bone marrow transplant from a female donor. Further investigation of the tissue specimens by fluorescent in situ hybridization (FISH) revealed that an XX chromosome pattern was dominant in the tumor region, and this suggested that donor-derived cells might affect carcinogenesis in the recipient. CONCLUSIONS: This case presents an incidence of secondary oral cancer associated with allogeneic bone marrow transplantation.

    DOI: 10.1002/hed.20931

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  • Clinical assessment of the relationship between the third molar and the inferior alveolar canal using panoramic images and computed tomography. 査読 国際誌

    Kenji Nakamori, Kumiko Fujiwara, Akihiro Miyazaki, Kei Tomihara, Manabu Tsuji, Mitsuyoshi Nakai, Yoshitaka Michifuri, Rina Suzuki, Kiyoto Komai, Makoto Shimanishi, Hiroyoshi Hiratsuka

    Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons   66 ( 11 )   2308 - 13   2008年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: To predict the relationship between lower third molars and the inferior alveolar canal (IAC) from panoramic radiographs, and to establish criteria for using computed tomography (CT). MATERIALS AND METHODS: A retrospective cohort study was performed involving 443 patients (695 teeth). Predictor variables were the distance between the third molar and the IAC, and findings according to the Rood's criteria. Outcome variables were the absence of cortication between the third molar and the IAC on the CT image, and injury of the inferior alveolar nerve (IAN). Statistical analysis was performed to assess the relationship between predictor and outcome variables. RESULTS: All patients had preoperative panoramic radiographs, and 71 patients (119 teeth) also had CT images. On CT examination, 48 teeth (40.3%) showed absence of cortication. Injury of the IAN was reported in 7 cases (1.0%), 5 of which exhibited absence of cortication; the remaining 2 did not have CT scans. Five of the 48 cases showing absence of cortication exhibited IAN injury, and none of the cases with cortication exhibited IAN injury. On the panoramic images, the following signs were strongly correlated with absence of cortication: a superimposed relationship between the third molar and the IAC; darkness of the root; and diversion and narrowing of the IAC. CONCLUSION: Presence of Rood's criteria was a predictor for a contact relationship between the third molar and the IAC, and an indication for CT examination. However, a superimposed relationship and the absence of Rood's criteria did not necessarily signify a separate relationship between third molar and the IAC.

    DOI: 10.1016/j.joms.2008.06.042

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  • [Osteomyelitis of the jaw in breast cancer patients receiving bisphosphonate therapy]. 査読

    Kei Tomihara, Itaru Nagai, Akira Yamaguchi, Akihiro Miyazaki, Hironari Dehari, Masato Abe, Kenji Nakamori, Kiyoto Komai, Mitsuyoshi Nakai, Hiroyoshi Hiratsuka

    Gan to kagaku ryoho. Cancer & chemotherapy   35 ( 1 )   113 - 6   2008年1月

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    担当区分:筆頭著者, 責任著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Osteonecrosis of the jaw is a severe new complication in cancer patients with bone metastases receiving bisphosphonate. Currently, there is no effective treatment for bisphosphonate-related osteonecrosis of the jaw, and the pathogenesis of this complication has not been completely elucidated. It has been shown that a potential risk factor for the complication is dentoalveolar trauma including extraction of teeth during bisphosphonate therapy. Attention should be paid to dental care in patients prior to the initiation of bisphosphonate therapy, and extraction of teeth during bisphosphonate therapy should be avoided to prevent this complication. Therefore, the communication between general physicians prescribing bisphosphonate and dentists is important.

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  • 口腔癌由来ミエロイド系抑制性細胞の機能解析

    布施浩樹, 冨原圭, 平識亘, 野口誠

    日本口腔科学会雑誌   64 ( 2 )   2015年

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  • PDGF受容体の二量体は,遊走線維芽細胞に異なった形態を誘導する

    山田浩太, 冨原圭, 布施浩樹, 仲盛健治, 野口誠

    日本口腔科学会雑誌   64 ( 2 )   2015年

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  • 小唾液腺から発生した浸潤性微小乳頭唾液腺導管癌の一例

    冨原圭, 野口誠

    日本臨床口腔病理学会総会・学術大会プログラム・抄録集(Web)   26th   2015年

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  • 上唇に発生した多形腺腫の1例

    藤多睦, 武井理恵, 冨原圭, 野口誠一

    日本口腔科学会雑誌   63 ( 3 )   2014年

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  • 嚢胞からの癌化が疑われた口腔癌の3例

    川端厚司, 今上修一, 冨原圭, 武井理恵, 新井直也, 野口誠

    日本口腔科学会雑誌   63 ( 3 )   2014年

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  • カルシウムによるゾレドロネートの抗腫瘍効果の増強:口腔扁平上皮癌細胞株を用いた研究

    井上さやか, 新井直也, 冨原圭, 野口誠

    日本口腔科学会雑誌   63 ( 1 )   2014年

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  • Bone targeting therapyに関連する顎骨壊死に顎骨周囲膿瘍を併発した2例

    加藤智規, 保田賢司, 飯田裕朗, 森井章裕, 野崎哲夫, 藤内靖喜, 小宮顕, 冨原圭, 仲盛健治, 野口誠, 布施秀樹

    日本癌治療学会学術集会(CD-ROM)   52nd   2014年

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  • Zoledronateの細胞毒性におけるリン酸カルシウム塩の関与

    新井直也, 井上さやか, 冨原圭, 平識亘, 古川健一朗, 野口誠

    日本口腔科学会雑誌   63 ( 1 )   2014年

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  • 口腔癌マウスモデルを用いたCD11b,Gr-1陽性細胞の機能解析

    布施浩樹, 冨原圭, 野口誠

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   32nd   2014年

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  • マウスモデルを用いた口腔癌における制御性T細胞の解析

    冨原圭, 井上さやか, 能登善弘, 津野宏彰, 立浪秀剛, 新井直也, 野口誠

    日本口腔科学会雑誌   62 ( 1 )   2013年

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  • ヒト乾燥羊膜の口蓋裂手術への効果

    津野宏彰, 野口誠, 能登善弘, 冨原圭, 井上さやか, 新井直也

    日本口蓋裂学会雑誌   38 ( 2 )   2013年

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  • 広範性表在口腔癌の臨床検討

    武井理恵, 今上修一, 大浦健宏, 冨原圭, 井上さやか, 津野宏彰, 新井直也, 野口誠

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   31st   2013年

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  • 小唾液腺原発唾液腺導管癌の2例

    平田桂子, 大浦健宏, 冨原圭, 今上修一, 武井理恵, 井上さやか, 新井直也, 野口誠

    日本口腔科学会雑誌   62 ( 3 )   2013年

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  • 上顎に発生したaggressive ossifying fibromaの1例

    立浪秀剛, 津野宏彰, 冨原圭, 大浦健宏, 新井直也, 野口誠

    日本口腔科学会雑誌   62 ( 1 )   2013年

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  • Angular branchを用いた肩甲骨付き広背筋皮弁による顎骨再建

    今上修一, 長田龍介, 頭川峰志, 冨原圭, 武井理恵, 野口誠

    日本マイクロサージャリー学会学術集会プログラム・抄録集   40th   2013年

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  • 初回治療から26年後に多発頸部転移を生じた下顎歯肉悪性黒色腫の1例

    有馬久美, 今上修一, 武井理恵, 冨原圭, 大浦健宏, 野口誠

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   31st   2013年

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  • 口腔癌に対するゲムシタビンの効果に関する基礎的研究

    武井理恵, 冨原圭, 井上さやか, 能登善行, 津野宏彰, 新井直也, 野口誠

    日本口腔科学会雑誌   62 ( 1 )   2013年

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  • 局所進展口腔癌に対する導入化学療法の臨床・病理組織学的研究

    今上修一, 冨原圭, 能登善弘, 武井理恵, 大浦健宏, 新井直也, 野口誠

    頭頸部癌   39 ( 2 )   2013年

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  • ゲムシタビンは,口腔癌に対する抗腫瘍免疫反応を増強する

    冨原圭, 武井理恵, 能登善行, 今上修一, 新井直也, 野口誠

    頭頸部癌   39 ( 2 )   2013年

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  • 口腔扁平上皮癌細胞株におけるCD44,SSEA-4陽性細胞群の特質

    能登善弘, 津野宏彰, 冨原圭, 井上さやか, 新井直也, 野口誠

    頭頸部癌   39 ( 2 )   2013年

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  • 外科的治療が有効であったビスフォスフォネート関連顎骨壊死の4例

    津野宏彰, 新井直也, 大浦健宏, 今上修一, 冨原圭, 野口誠

    日本口腔科学会雑誌   62 ( 1 )   2013年

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  • 当科における下顎骨中心性扁平上皮癌7例の検討

    武井理恵, 冨原圭, 今上修一, 井上さやか, 新井直也, 野口誠

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   30th   2012年

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  • 舌接触補助床を応用して嚥下機能回復を図った先天性ミオパチー症例

    井上さやか, 吉田敬子, 中道尚美, 冨原圭, 野口誠

    顎顔面補綴   35 ( 2 )   2012年

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  • 局所進展口腔癌に対する導入化学療法-TS-1併用CDDP超選択的動注化学療法-

    今上修一, 大浦健宏, 武井理恵, 冨原圭, 中道尚美, 新井直也, 野口誠

    頭頸部癌   38 ( 2 )   2012年

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  • マウス口腔癌モデルを用いた制御性T細胞の解析

    冨原圭, 井上さやか, 武井理恵, 今上修一, 新井直也, 野口誠

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   30th   2012年

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  • 上顎全摘後の無歯顎症例に分割顎義歯を適用した1例

    今上修一, 吉田敬子, 大浦健宏, 冨原圭, 佐渡忠治, 新井直也, 野口誠

    顎顔面補綴   34 ( 2 )   2011年

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  • 頬部に発生した孤在性線維性腫瘍の1例

    冨原圭, 仲盛健治, 関口隆, 安倍聖人, 出張裕也, 荻和弘

    日本口腔外科学会雑誌   54 ( 2 )   2008年

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  • StageI,II舌扁平上皮癌の治療成績-臨床所見との関係-

    仲盛健治, 宮崎晃亘, 出張裕也, 冨原圭, 平塚博義

    頭頸部癌   34 ( 2 )   2008年

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  • ビスフォスフォネート剤関連顎骨壊死に関する臨床的検討

    出張裕也, 冨原圭, 上田愛, 安保直樹, 島西真琴, 小林淳一, 仲盛健治, 宮崎晃亘, 永井格, 平塚博義

    日本癌治療学会誌   43 ( 2 )   2008年

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  • 癌患者に認められた下顎の痺れ(Numb chin syndrome)

    小林淳一, 冨原圭, 出張裕也, 平塚博義

    日本口腔科学会雑誌   57 ( 4 )   2008年

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  • 当科における外傷患者とその治療の推移

    小野公之, 安倍聖人, 冨原圭, 島西真琴, 佐々木敬則, 永井格, 平塚博義

    日本口腔科学会雑誌   57 ( 4 )   2008年

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  • 口腔癌細胞に対する全トランス型レチノイン酸(ATRA)を用いたbiochemical modulationに関する研究

    冨原圭, 出張裕也, 広瀬加奈子, 木戸幸恵, 仲盛健治, 平塚博義

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   25th   2007年

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  • ビスフォスフォネート製剤投与を受ける乳癌多発骨転移患者にみられた顎骨骨髄炎の症例

    冨原圭, 宮崎晃亘, 仲盛健治, 平塚博義

    日本癌治療学会誌   42 ( 2 )   2007年

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  • Stage II舌扁平上皮癌の頸部郭清の適応基準-標準的治療の確立を目指して-

    仲盛健治, 平塚博義, 宮崎晃亘, 冨原圭

    日本癌治療学会誌   42 ( 2 )   2007年

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  • Excisional biopsyを行った舌扁平上皮癌の発育様式,腫瘍の厚みと頸部リンパ節転移との関連性の検討

    仲盛健治, 宮崎晃亘, 出張裕也, 冨原圭, 小林淳一, 曽我部陽平, 今井崇, 山本崇, 廣瀬加奈子, 平塚博義

    頭頸部癌   33 ( 2 )   2007年

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  • 各種IFNを用いた扁平上皮癌細胞に対する形質変化とアポトーシスの誘導

    冨原圭, 加藤和則, 中村公則, 出張裕也, 濱田洋文, 平塚博義

    日本癌学会学術総会記事   65th   2006年

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  • 舌癌の郭清範囲に関する検討

    仲盛健治, 宮崎晃亘, 出張裕也, 木戸幸恵, 冨原圭, 小林淳一, 今井崇, 曽我部陽平, 山本崇, 廣瀬加奈子, 平塚博義

    頭頸部癌   32 ( 4 )   2006年

     詳細を見る

  • 舌癌の郭清範囲に関する検討

    仲盛健治, 宮崎晃亘, 出張裕也, 竹村佳奈子, 冨原圭, 小林淳一, 木戸幸恵, 平塚博義

    頭頸部癌   32 ( 2 )   2006年

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  • 頬部に発生した孤立性線維性腫瘍の1例

    仲盛健治, 関口隆, 永井格, 針谷靖史, 宮崎晃亘, 冨原圭, 平塚博義

    日本口腔腫瘍学会誌   18 ( 4 )   2006年

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  • 頬部に発生した孤立性線維性腫瘍の1例

    仲盛健治, 永井格, 針谷靖史, 宮崎晃亘, 冨原圭, 平塚博義

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   24th   2006年

     詳細を見る

  • 口腔癌に対するCD40リガンドアデノウイルスベクターを用いた遺伝子治療の研究

    冨原圭, 加藤和則, 野口誠, 浜田洋文, 平塚博義

    日本口腔科学会雑誌   54 ( 1 )   2005年

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  • ヒト樹状細胞に対するCD40リガンド遺伝子導入による抗腫よう効果の検討

    冨原圭, 加藤和則, 増田ゆかり, 中村公則, 野口誠, 平塚博義, 浜田洋文

    日本癌学会学術総会記事   64th   2005年

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  • 抗CD38抗体とファイバー変異型アデノウイルスを用いたヒト骨髄腫細胞への標的化遺伝子導入

    増田ゆかり, 加藤和則, 冨原圭, 中村公則, 浜田洋文

    日本癌学会学術総会記事   64th   2005年

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  • 口腔癌に対するCD40リガンドアデノウイルスベクターを用いた遺伝子治療に関する研究

    冨原圭, 加藤和則, 浜田洋文, 野口誠

    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   22nd   2004年

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  • 口腔へん平上皮癌に対するCD40リガンド遺伝子導入樹状細胞の抗腫よう効果の解析

    冨原圭, 加藤和則, 増田ゆかり, 野口誠, 平塚博義, 浜田洋文

    日本癌学会総会記事   63rd   2004年

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  • 下顎骨骨肉腫7例の臨床病理学的検討

    東条秀太郎, 宮崎晃亘, 小林淳一, 冨原圭, 山口晃, 野口誠, 平塚博義

    日本口腔腫瘍学会誌   16 ( 3 )   2004年

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  • 舌初期癌の臨床型分類の意義

    宮崎晃亘, 野口誠, 東条秀太郎, 冨原圭, 小林淳一, 平塚博義

    日本口腔腫瘍学会誌   16 ( 3 )   2004年

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  • 改変型CD40リガンドによる抗腫よう免疫応答誘導と全身性副作用の軽減効果の解析

    増田ゆかり, 加藤和則, 冨原圭, 浜田洋文

    日本癌学会総会記事   63rd   2004年

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  • ファイバーRGD型アデノウイルスによるヒトCD40リガンドの白血病細胞に対する遺伝子導入と免疫応答誘導

    冨原圭, 加藤和則, 高橋聡, 増田ゆかり, 佐々木勝則, 内田宏昭, 浅野茂隆, 浜田洋文

    日本癌学会総会記事   62nd   2003年

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