2024/05/27 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   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

  • 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

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

  • Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with recurrent oral squamous cell carcinoma treated with nivolumab. 査読 国際誌

    Hidetake Tachinami, Kei Tomihara, Shin-Ichi Yamada, Atsushi Ikeda, Shuichi Imaue, Hideaki Hirai, Hiromi Nakai, Tomoko Sonoda, Kazuto Kurohara, Yukio Yoshioka, Takumi Hasegawa, Tomofumi Naruse, Takashi Niiyama, Tetsu Shimane, Michihiro Ueda, Souichi Yanamoto, Masaya Akashi, Masahiro Umeda, Hiroshi Kurita, Akihiro Miyazaki, Naoya Arai, Ryuji Hayashi, Makoto Noguchi

    The British journal of oral & maxillofacial surgery   61 ( 4 )   320 - 326   2023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 immune checkpoint inhibitor (ICI), nivolumab, has revolutionised the treatment of recurrent and metastatic oral cancer. However, the response rate to ICIs remains low, and identifying predictors of nivolumab response is critical. Although the neutrophil-to-lymphocyte ratio (NLR) has been suggested as a predictive marker of nivolumab response in patients with various types of cancer, its utility in oral squamous cell carcinoma (OSCC) has not been elucidated. In this retrospective multicentre cohort study, we evaluated the association between NLR and outcome of nivolumab treatment in 64 patients with OSCC treated between 2017 and 2020. The objective response and disease control rates were 25.1% and 32.9%, respectively. The rates for complete and partial responses were 15.7% (10/64) and 9.4% (6/64), respectively; stable and progressive disease rates were 7.8% (5/64) and 67.1% (43/64), respectively. Complete and partial responses were classified as responders, and stable and progressive diseases were classified as non-responders. The median (range) pre-treatment NLR among responders was 4.3 (2.8-8.0), which decreased to 4.0 (2.6-6.3) after nivolumab treatment, and the median (range) pre-treatment NLR among non-responders was 5.1 (2.7-7.9), which increased to 6.4 (4.0-14.0) with tumour growth. Moreover, overall survival was significantly worse in the group with a higher post-treatment NLR (≥5) than in the group with a lower NLR (<5). Patients with a post-treatment NLR of ≥6 had worse outcomes for salvage chemotherapy following nivolumab treatment. Thus, post-treatment NLR could be a useful marker for predicting the response to nivolumab treatment or salvage chemotherapy in patients with OSCC.

    DOI: 10.1016/j.bjoms.2023.03.012

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  • 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. 査読 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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    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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  • Successful treatment with nivolumab in a patient with unresectable oral squamous cell carcinoma following ineffective chemoradiotherapy. 査読 国際誌

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

    Clinical case reports   11 ( 12 )   e8219   2023年12月

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    記述言語:英語  

    KEY CLINICAL MESSAGE: Nivolumab has been clinically successful in prolonging the overall survival of patients with recurrent and metastatic head and neck cancer, complete remission is rare. Synergistic combinations of immunotherapy and conventional cancer treatments, such as radiotherapy or chemotherapy, are likely to be the most viable strategies for improving patient responses. ABSTRACT: Immune checkpoint inhibitors have revolutionized recurrent, metastatic oral cancer treatment; however complete remission in advanced stages is unusual. We present a case of complete remission of advanced oral squamous cell carcinoma for >4 years in a 64-year-old Japanese woman, that responded poorly to chemoradiotherapy but well to subsequent nivolumab treatment.

    DOI: 10.1002/ccr3.8219

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  • Searching for new early detection markers of oral epithelial dysplasia and oral squamous cell carcinoma using oral liquid-based cytology 査読

    Toshiyuki Akimori, Manabu Yamazaki, Tatsuya Abé, Satoshi Maruyama, Kei Tomihara, Takeyasu Maeda, Jun-ichi Tanuma

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   2023年11月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.ajoms.2023.11.007

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  • Complete Response to Cetuximab Plus Paclitaxel Therapy in Nivolumab-Refractory Patients in Distant Metastasis of Squamous Cell Carcinoma of the Tongue: A Report of Two Cases. 査読 国際誌

    Hidetake Tachinami, Kei Tomihara, Danki Takatsuka, Atsushi Ikeda, Shin-Ichi Yamada, Makoto Noguchi

    Cureus   15 ( 11 )   e49198   2023年11月

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    記述言語:英語  

    Herein, we report two cases of patients diagnosed with nivolumab-refractory distant metastatic squamous cell carcinoma of the tongue who were successfully treated with a combination of paclitaxel and cetuximab. Case 1 had controllable local recurrence and distant metastasis. Case 2 had controllable distant metastatic disease. Thus, demonstrating that some nivolumab-refractory patients with recurrent or distant metastatic oral squamous cell carcinoma may benefit from subsequent salvage chemotherapy.

    DOI: 10.7759/cureus.49198

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  • The EGF/EGFR axis and its downstream signaling pathways regulate the motility and proliferation of cultured oral keratinocytes. 査読 国際誌

    Ryota Kobayashi, Emi Hoshikawa, Taisuke Saito, Orakarn Suebsamarn, Eriko Naito, Ayako Suzuki, Seiichiro Ishihara, Hisashi Haga, Kei Tomihara, Kenji Izumi

    FEBS open bio   13 ( 8 )   1469 - 1484   2023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)  

    We previously reported that the cell and colony motion of oral keratinocytes are correlated with proliferative capacity, and speculated that this may be a specific index for monitoring cell quality. However, how cell motility and proliferation are regulated by signaling pathways remains unelucidated. Here, we found that the regulation of cell motility and proliferative capacity of oral keratinocytes can be attributed to the epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) axis. The EGFR downstream cascade involving the Src/PI3K/Akt/mTOR signaling pathway showed a major effect on cell motility and proliferative capacity in oral keratinocytes. Furthermore, both EGFR and Src attenuated E-cadherin expression. Taken together, these findings provide a potential basis for future quality control of cells for therapeutic use.

    DOI: 10.1002/2211-5463.13653

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  • Management of odontogenic foci of infection (dental caries, periodontal disease and odontogenic infections) in the oral functional management of patients receiving cancer treatments: Guidelines based on a systematic review 査読

    Hiroshi Kurita, Masahiro Umeda, Takaaki Ueno, Narikazu Uzawa, Yasuyuki Shibuya, Norifumi Nakamura, Hitoshi Nagatsuka, Takafumi Hayashi, Itaru Mizoguch, Kei Tomihara, Yumiko Ikegami, Kazuma Noguchi, Yuichi Takiguchi, Nobuyuki Yamamoto, Hironori Sakai

    Oral Science International   2023年7月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:Wiley  

    Abstract

    In cancer treatment, perioperative oral functional management is used as a part of supportive care. Its main objectives are as follows: (1) preventing and reducing adverse events, (2) maintaining or improving nutritional status, (3) improving cancer treatment outcomes, (4) maintaining or improving quality of life, (5) providing high quality medical care through comprehensive oral care, (6) controlling odontogenic foci of infection, and (7) maintaining or improving oral function. A literature search was conducted using the electronic databases of Medical Journal and PubMed. Electronic database searches were performed using various combinations of the following key words: cancer, surgery, treatment, chemotherapy, radiotherapy and dental disease, oral care, oral management, dental intervention, oral health, dental care, and dental management. The selection of literature for inclusion in the review was restricted to dental management of patients receiving cancer treatment. In the course of the literature review, hand searches were also added as needed. The guideline was developed by summarizing the results of the review. Based on a review of the literature on the management of dental foci of infection in the oral functional management of patients undergoing cancer treatment, a guideline was developed by summarizing the results of the review. This report is a secondary publication of our previous review report “J. Stomatol. Soc. 70(4): 279–289. Dec 2021.”

    DOI: 10.1002/osi2.1209

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  • Effect of Yokukansan on preoperative anxiety and postoperative pain in mandibular third molar extraction: A pilot study 査読

    Kensuke Yoshida, Yasumitsu Kodama, Anna Kiyomi, Kyongsun Pak, Takahiro Nagai, Chie Saito, Kyosuke Yamazaki, Munetoshi Sugiura, Akira Toyama, Kei Tomihara

    ORAL SCIENCE INTERNATIONAL   2023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)   出版者・発行元:WILEY  

    ObjectivesManaging perioperative anxiety improves postoperative recovery significantly by reducing postoperative pain. However, little is known about association between preoperative anxiety and postoperative pain in oral surgical procedures. In the present study, we examined the effect between preoperative anxiety and postoperative pain in mandibular third molar extraction and the anxiolytic effect of Yokukansan (YKS) during the perioperative period. Materials and methodsWe conducted a prospective cohort study from September 2021 to May 2022. For patients with a complaint of insomnia on the day before surgery, 2.5 g per package of YKS was administered before sleep on the day before surgery. Twelve patients were administered YKS, and 23 patients were not (non-YKS). ResultsPerioperative anxiety was assessed by the Hospital Anxiety and Depression Scale (HADS) and amylase in saliva, and perioperative pain was assessed by the Numerical Rating Scale (NRS) and the total number of times pain medication. There were no significant differences in HADS and amylase in saliva between the YKS and non-YKS. The median postoperative NRS was 5 for YKS and 7 for non-YKS. The maximum use of pain medication was 16 in YKS and 24 in non-YKS. Although no significant difference was observed in the anxiolytic effects and the improvement of postoperative pain during the perioperative period of mandibular third molar extraction between patients who took YKS and those who did not, NRS and the maximum use of pain medication were less in the YKS patients. ConclusionsTherefore, YKS may be useful for managing postoperative pain through the preoperative anxiolytic effect in oral surgical procedures.

    DOI: 10.1002/osi2.1202

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  • Presurgical imaging of the subscapular artery with three-dimensional-computed tomography angiography: Application to harvesting subscapular system free-flaps. 査読 国際誌

    Shuichi Imaue, Ryusuke Osada, Wataru Heshiki, Katsuhisa Sekido, Mineyuki Zukawa, Kumiko Fujiwara, Kei Tomihara, Makoto Noguchi

    Clinical anatomy (New York, N.Y.)   2023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)  

    A subscapular system free-flap is extremely useful for maxillofacial reconstruction since it facilitates the simultaneous harvesting of multiple flaps using one subscapular artery (SSA) alone. However, cases of aberrations in the SSAs have been reported. Therefore, the morphology of SSA needs to be confirmed preoperatively before harvesting the flaps. Recent developments in imaging, such as three-dimensional (3D) computed tomography angiography (3D CTA), facilitate obtain high-quality images of blood vessel images. Therefore, we examined the utility of 3D CTA in navigating the course of the SSA before harvesting subscapular system free-flaps. We examined the morphology and aberrations of the SSA using 39 sides of the 3D CTA data and 22 sides of Japanese cadavers. SSAs can be classified into types S, I, P, and A. Type S SSAs are significantly long (mean length = 44.8 mm). Types I and P SSAs have short mean lengths, measuring ≤2 cm in approximately 50% of cases. In type A, the SSA is absent. The frequency of types S, I, P, and A SSAs were 28.2%, 7.7%, 51.3%, and 12.8%, respectively. Type S can be advantageous for harvesting the SSA in subscapular system free-flaps, because it is significantly longer. In contrast, types I and P might be dangerous because their mean lengths are shorter. In type A, caution is needed not to injure the axillary artery because the SSA is absent. When surgeons need to harvest the SSA, presurgical 3D CTA is recommended.

    DOI: 10.1002/ca.24053

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  • Hospital pharmacist interventions for the management of oral mucositis in patients with head and neck cancer receiving chemoradiotherapy: a multicenter, prospective cohort study. 査読 国際誌

    Kensuke Yoshida, Shinichi Watanabe, Naoto Hoshino, Kyongsun Pak, Noriaki Hidaka, Noboru Konno, Masaki Nakai, Chinami Ando, Tsuyoshi Yabuki, Naoto Suzuki, Kouji Katsura, Kei Tomihara, Akira Toyama

    Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer   31 ( 5 )   316 - 316   2023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)  

    PURPOSE: Oral mucositis is a severe adverse event in patients with head and neck cancer (HNC) receiving chemotherapy and radiotherapy that may cause the termination of cancer treatment. In this study, we aimed to reveal the benefits of pharmacist interventions in oral health care for patients with HNC receiving concurrent chemoradiotherapy (CCRT). METHODS: We conducted a multicenter, prospective cohort study on 173 patients from September 2019 to August 2022. We evaluated the association between the occurrence of oral mucositis during CCRT and various factors in the absence or presence of direct medication instructions from hospital pharmacists. RESULTS: Sixty-eight patients received medication instructions from pharmacists (the pharmacist intervention group), whereas 105 patients did not receive instructions (the control group). Logistic regression analysis showed that grade 2 (Gr 2) oral mucositis was significantly lower in patients receiving pharmacist interventions than in patients in the control group (adjusted odds ratio [aOR], 0.42; 95% confidence interval [CI], 0.18-0.96; P = 0.04). The time to onset of Gr 2 oral mucositis was significantly longer in the pharmacist intervention group than in the control group (hazard ratio, 0.53; 95% CI, 0.29-0.97; P = 0.04). CONCLUSION: Direct intervention, especially when provided by hospital pharmacists, can have a real effect in supporting patients with HNC experiencing severe side effects of treatments. Moreover, the integration of pharmacists into the oral healthcare team is becoming even more essential to reduce the severity of side effects.

    DOI: 10.1007/s00520-023-07784-6

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  • Liquid-based cytology for differentiating two cases of pemphigus vulgaris from oral squamous cell carcinoma. 査読 国際誌

    Satoshi Maruyama, Manabu Yamazaki, Tatsuya Abé, Yusuke Kato, Hiroyuki Kano, Yoshimasa Sumita, Kei Tomihara, Jun-Ichi Tanuma

    Diagnostic cytopathology   51 ( 5 )   E170-E175   2023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)  

    Pemphigus vulgaris (PV) is a rare autoimmune disease characterized by blisters on the skin and mucous membrane. Since it often appears in the oral mucosa first, it may be diagnosed by oral mucosal cytology. Although the cytologic finding is characterized by acantholytic cells, that is, Tzanck cells, it is important to distinguish PV from neoplastic lesions of the oral mucosal epithelium, including differentiation from atypical parabasal/basal cells, which appear in squamous cell carcinoma (SCC). In this study, we examined the cellular findings in two cases of PV and a case of well-differentiated SCC with loss of epithelial cell cohesion. The samples were prepared using liquid-based cytology, which showed small round-shaped and deeply stained atypical, orangeophilic keratinocytes not only in SCC but also in PV, which made differentiation between the two difficult. However, Tzanck cells found in PV differ from the deep atypical parabasal/basal cells of SCC, suggesting that the cell outline is indistinct and small protrusions and brush-like structures are observed. This feature of Tzanck cells may be useful in cytological judgment.

    DOI: 10.1002/dc.25117

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  • A Transient Sinus Arrest Caused by Intraoral Disinfection Maneuver in Maxillofacial and Oral Surgery Under General Anesthesia: A Case Report 査読

    Yuhei Koyama, Toru Yamamoto, Junrong Qi, Kei Tomihara, Kenji Seo

    Journal of Maxillofacial and Oral Surgery   2023年

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    掲載種別:研究論文(学術雑誌)  

    DOI: 10.1007/s12663-023-01955-y

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  • 多数の過剰歯と集合型歯牙腫を同時に認めた1例 査読

    相澤有香, 池田順行, 永井孝宏, 齋藤夕子, 隅田賢正, 西山秀昌, 阿部達也, 冨原圭

    新潟歯学会雑誌   53 ( 1 )   2023年

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    J-GLOBAL

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  • 二段階口蓋形成手術法における軟口蓋形成術前の後方裂幅と乳歯列期咬合関係の関連 査読

    大湊麗, 大湊麗, 大湊麗, 小野和宏, 小野和宏, 児玉泰光, 結城龍太郎, 永井孝宏, 小林亮太, 市川佳弥, 丹原惇, 佐藤真由美, 濃野要, 飯田明彦, 若槻華子, 宮田昌幸, 小林正治, 齋藤功, 高木律男, 冨原圭

    日本口蓋裂学会雑誌   48 ( 2 )   2023年

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    担当区分:最終著者  

    J-GLOBAL

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  • 症例から学ぶ小児や障害者の口腔疾患

    冨原圭

    月刊小児歯科臨床   28 ( 4 )   2023年

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  • Multicenter retrospective study of nivolumab for recurrent/metastatic oral squamous cell carcinoma. 査読 国際誌

    Nobuhiro Yamakawa, Masahiro Umeda, Yumi Yoshii, Kenji Mitsudo, Makoto Noguchi, Jingo Kusukawa, Akira Katakura, Hideki Nakayama, Masashi Sasaki, Tadahide Noguchi, Michihiro Ueda, Hiroki Bukawa, Kazuhiro Yagihara, Akihisa Horie, Akihiro Miyazaki, Daichi Chikazu, Kei Tomihara, Katsuaki Mishima, Mitsunobu Otsuru, Seiji Asoda, Shigeyoshi Fujiwara, Yoshio Ohyama, Hiroshi Kurita, Hitoshi Kawamata, Masayuki Fukuda, Yukari Shintani, Takanori Kobayashi, Takahiro Kanno, Ichiro Oh-Iwa, Kenji Kawano, Yoshio Yamashita, Wataru Kobayashi, Yoichi Ohiro, Katsuhiro Uzawa, Yoshihide Ota, Tadaaki Kirita

    Oral diseases   2022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)  

    OBJECTIVES: Immunotherapy with nivolumab for patients with recurrent/metastatic oral squamous cell carcinoma has not been evaluated. Here, we aimed to examine the efficacy, safety, and prognostic factors of nivolumab in these patients. MATERIALS AND METHODS: This multicenter retrospective observational study involved patients who received nivolumab between April 2017 and June 2019. The patient characteristics were evaluated for association with progression-free and overall survival. Progression-free and overall survival rates were calculated; parameters that were significant in the univariate analysis were used as explanatory variables. Independent factors for progression-free and overall survival were identified using multivariate analysis. RESULTS: Totally, 143 patients were included. The overall response and disease control rates were 27.3% and 46.2%, respectively. The median, 1- and 2-year progression-free survival rates were 2.7 months, 25.4%, and 19.2%, respectively; those for overall survival were 11.2 months, 47.3%, and 33.6%, respectively. The independent factors affecting progression-free survival were performance status and immune-related adverse event occurrence, whereas those affecting overall survival were performance status, target disease, and number of previous lines of systemic cancer therapy. Eight patients reported grade ≥3 immune-related adverse events. CONCLUSION: Nivolumab was effective for recurrent/metastatic oral squamous cell carcinoma treatment and was well tolerated by patients.

    DOI: 10.1111/odi.14471

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  • Perioperative bridging anticoagulation in patients with oral cancer surgery: a multicenter retrospective study 査読

    Ryo Kajihara, Shin ichi Yamada, Takumi Hasegawa, Hitoshi Yoshimura, Hidetake Tachinami, Kei Tomihara, On Hasegawa, Sumiyo Hishida, Nobuhiro Ueda, Kenjiro Okamoto, Sakiko Soutome, Yuya Denda, Masaaki Miyakoshi, Kiriko Matsuzawa, Eiji Kondo, Yoshimasa Kitagawa, Daichi Chikazu, Yoshihide Ota, Yasuyuki Shibuya, Masaya Akashi, Tatsushi Matsumura, Masahiro Umeda, Tadaaki Kirita, Makoto Noguchi, Hiroshi Kurita

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   34 ( 6 )   734 - 739   2022年11月

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    掲載種別:研究論文(学術雑誌)  

    The number of patients administered oral antithrombotic drugs who require elective surgery has increased. Perioperative heparin bridging needs to be considered for patients at a high risk of thromboembolism. The present study investigated the effects of perioperative heparin bridging therapy on perioperative complications (postoperative bleeding and thrombotic events) in oral cancer surgery. The medical records of 98 patients who underwent oral cancer surgery with perioperative bridging therapy were retrospectively analyzed. Postoperative hemorrhage occurred in 16 patients (16.3%) and thrombotic events (deep venous thrombosis) in 5 (5.1%), which were higher than in other surgeries. A multivariate analysis identified the administration of prostaglandins as the only significant independent risk factor for postoperative hemorrhage, and a longer duration of postoperative heparin bridging therapy was associated with the incidence of deep venous thrombosis. The present results suggest a higher incidence of thrombotic and bleeding events in patients who underwent oral cancer surgery with heparin bridging, and the nature of surgery (such as revascularization and prolonged bed rest) may be a contributing factor. Future studies are needed to establish whether heparin bridging is effective in oral cancer surgery.

    DOI: 10.1016/j.ajoms.2022.06.008

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  • Adenosquamous Carcinoma with the Acantholytic Feature in the Oral Cavity: A Case Report and Comprehensive Literature Review 査読

    Tatsuya Abé, Manabu Yamazaki, Satoshi Maruyama, Nobuyuki Ikeda, Yoshimasa Sumita, Kei Tomihara, Jun-ichi Tanuma

    Diagnostics   12 ( 10 )   2398 - 2398   2022年10月

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    掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Adenosquamous carcinoma (ASC) is an aggressive subtype of squamous cell carcinoma (SCC). Due to its poor prognosis, a precise pathological diagnosis of ASC is essential but challenging because its pathological criteria are still unclear. Here, we present a rare case of oral ASC accompanied by acantholytic features. The tumor was raised in the mandibular gingiva and recurred locally approximately 13 months after the initial surgery with cervical lymph node metastasis. Pathological specimens of the primary lesion showed acantholysis in a large area of the SCC. Mucous cells, the characteristic finding indicating glandular differentiation, were imperceptible in the initial surgical specimen but increased in the locally recurrent and metastatic lymph node specimens. In a comprehensive literature review of oral ASC cases, the present case was the only case of ASC with acantholytic features. We reconfirmed that ASC has poor prognoses, such as low 5-year overall survival and disease-free survival, high locoregional recurrence, and high distant metastasis rates. A precise diagnosis of ASC is required for estimating prognosis and undergoing close follow-up, even if the adenocarcinomatous component is limited to a small area in the lesion.

    DOI: 10.3390/diagnostics12102398

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  • Clinicopathologic factors influencing the screening accuracy of oral cytology: A retrospective cohort study 査読 国際誌

    MASAMI KAWAHARADA, SATOSHI MARUYAMA, MANABU YAMAZAKI, TATSUYA ABÉ, NYEIN NYEIN CHAN, AKINORI FUNAYAMA, ATSUSHI UENOYAMA, TOSHIYUKI AKIMORI, KEI TOMIHARA, JUN-ICHI TANUMA

    Oncology letters   24 ( 385 )   385 - 385   2022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)  

    Cytology is a simple and non-invasive screening method for oral cancer. However, this method is not yet routinely used by clinicians because of its high false negative rate (FNR) and due to lack of sufficient studies examining the factors for high FNRs. The present retrospective study aimed to compare the screening performance of conventional cytology (CC) and liquid-based cytology (LBC) through histological validation, and to elucidate factors inducing false negative screening in oral cytology. Cytological specimens with histological examination and intraoral digital images of the lesion were retrospectively collected between January 2017 and December 2018 for CC and between October 2019 and September 2021 for LBC. Oral cytological screening was conducted based on the oral Bethesda system for oral cytology. Clinical subtypes were re-evaluated using intraoral digital images. The screening accuracy of oral cytology was calculated considering the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detecting the malignant transformation of oral lesions. No statistically significant difference was noted in the inadequate rate between CC and LBC groups. For CC and LBC, the sensitivities were 60.9 and 59.2%, the specificities were 87.3 and 79.1%, the PPVs were 85.8 and 76.2%, and the NPVs were 63.9 and 63.2%, respectively. Thus, the screening accuracy was similar between methodologies. Among the clinicopathological factors investigated, histological diagnosis and cellularity contributed to false negative results. Homogeneous findings of oral epithelial dysplasia and the superficial growth of carcinoma in situ/squamous cell carcinoma resulted in false negative findings for CC and LBC. Furthermore, LBC samples with a lower cell number (<2,000 squamous cells) exhibited statistically significantly increased FNRs. The present study found that the cytological methods did not affect the inadequate rate and screening accuracy, whereas clinical subtype and cellularity decreased screening accuracy. Therefore, cytological screening and subsequent follow-up should be performed while considering clinical findings and the cellularity of cytology smears.

    DOI: 10.3892/ol.2022.13505

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  • Unusual generalized tetanus evolving from odontogenic infection: A case report and review of recent literature. 査読 国際誌

    Muhammad Akbar, Muhammad Ruslin, Andi Sitti Hajrah Yusuf, Paolo Boffano, Kei Tomihara, Tymour Forouzanfar

    Heliyon   8 ( 9 )   e10810   2022年9月

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    記述言語:英語  

    Tetanus is an acute and vaccine-preventable disease caused by anaerobic bacteria, Clostridium tetani. This bacterium can enter the human body via a deep wound, burn injury or medical procedure; however, certain cases also originate from odontogenic infection. In the present study, a tetanus infection associated with dental origin in a 44-year-old man is reported. The case was complicated by lockjaw and difficulty swallowing that worsened over a few days, followed by a generalized spasm. Furthermore, a literature review was performed, in which six reported cases of tetanus, presumed to be of dental or oral origin, were identified between 2011and 2021. General practitioners, especially dentists, should be aware of tetanus associated with odontogenic origin even without a history of an external penetrating wound or other medical procedures:.

    DOI: 10.1016/j.heliyon.2022.e10810

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  • Rosai-Dorfman disease of the maxilla: A rare case report and literature review 査読

    Takahiro Nagai, Manabu Yamazaki, Atsushi Nishikawa, Yasumitsu Kodama, Hideyoshi Nishiyama, Takafumi Hayashi, Jun-ichi Tanuma, Ritsuo Takagi, Kei Tomihara

    Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology   34 ( 5 )   665 - 671   2022年9月

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    担当区分:最終著者   掲載種別:研究論文(学術雑誌)   出版者・発行元:Elsevier BV  

    DOI: 10.1016/j.ajoms.2022.02.007

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  • Complete response to cetuximab plus paclitaxel therapy in nivolumab-refractory patients in distant metastasis of squamous cell carcinoma of the tongue: a report of two cases 査読

    Hidetake Tachinami, Kei Tomihara, Danki Takatsuka, Atsushi Ikeda, Shinichi Yamada, Makoto Noguchi

    2022年7月

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    出版者・発行元:Authorea, Inc.  

    <p id="p1">Herein, we report two cases of patients diagnosed withnivolumab-refractory distant metastatic squamous cell carcinoma of thetongue who were successfully treated with a combination of paclitaxeland cetuximab, thus demonstrating that some nivolumab-refractorypatients with recurrent or distant metastatic oral squamous cellcarcinoma may benefit from subsequent salvage chemotherapy.</p>

    DOI: 10.22541/au.165881754.43971495/v1

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  • Novel strategy to predict high risk of inferior alveolar nerve injury during extraction of lower third molars based on assessment of computed tomographic images of multiple anatomical features. 査読 国際誌

    Danki Takatsuka, Hidetake Tachinami, Kei Tomihara, Younesi Jadidi Amirreza, Atsushi Ikeda, Shuichi Imaue, Kumiko Fujiwara, Tomoko Sonoda, Kenji Nakamori, Makoto Noguchi

    The British journal of oral & maxillofacial surgery   60 ( 5 )   570 - 576   2022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)  

    Preoperative assessment is essential to prevent inferior alveolar nerve (IAN) injury during surgical extraction of the lower third molar (LM3). Here, we aimed to establish an assessment system to predict IAN injury during surgical extraction of the LM3. We conducted a retrospective cohort study on 115 patients diagnosed as 'high-risk' based on our previous risk assessment method involving three anatomical features of the inferior alveolar canal using computed tomographic (CT) images. We evaluated the occurrence of neurosensory impairment in these high-risk patients, and its association with novel anatomic features based on CT images. Neurosensory impairments were observed in 19 patients (16.5%). The inferior alveolar canal major diameter (p < 0.0001) and lingual bone thickness (p = 0.0039) were significantly associated with the occurrence of neurosensory impairment during LM3 extraction. Receiver operating characteristic curves were used to determine cut-off values of these quantitative factors to specifically predict IAN injury. Preoperative risk assessment with quantitative factors based on anatomical features observed on CT images may facilitate more appropriate surgical planning for patients at a high risk of IAN injury.

    DOI: 10.1016/j.bjoms.2021.09.014

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  • がん治療患者の口腔機能管理における歯性感染病巣(歯の齲蝕、歯周病、歯性感染症)管理:システマティックレビューに基づいた指針(完全再掲載版) 査読

    栗田 浩, 梅田 正博, 植野 高章, 鵜澤 成一, 渋谷 恭之, 中村 典史, 長塚 仁, 林 孝文, 溝口 到, 冨原 圭, 池上 由美子, 野口 一馬, 滝口 裕一, 山本 信之, 日本口腔科学会学術研究委員会, 日本口腔ケア学会学術委員会がん口腔ケアガイドライン作成委員会

    日本口腔ケア学会雑誌   16 ( 2 )   9 - 19   2022年3月

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    記述言語:日本語   出版者・発行元:(一社)日本口腔ケア学会  

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  • Clinical Application of Hyperdry Amniotic Membrane in Cleft Palate Repair. 査読 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   60 ( 6 )   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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  • RSK-Mediated Non-canonical Activation of EphA2 by Tamoxifen. 査読

    Keisuke Yonehara, Yue Zhou, Jun-Ichiro Takahashi, Satoru Yokoyama, Kei Tomihara, Makoto Noguchi, Hiroaki Sakurai

    Biological & pharmaceutical bulletin   45 ( 2 )   162 - 168   2022年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The long-term administration of tamoxifen to estrogen receptor α (ERα)-positive breast cancer patients is an established treatment that reduces mortality and recurrence. However, resistance to tamoxifen and an increased risk of endometrial cancer may occur; therefore, the mechanisms by which tamoxifen causes these adverse effects warrant further study. Tamoxifen has been shown to activate mitogen-activated protein kinase (MAPK) in an ERα-independent manner; therefore, we investigated its effects on the MAPK-mediated non-canonical activation of EphA2, a critical event regulating cell migration. Tamoxifen at slightly higher concentrations induced the rapid phosphorylation of EphA2 at Ser-897 via the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK-ribosomal S6 kinases (RSK) pathway in HeLa cells. In addition, tamoxifen significantly enhanced the migration ability of ERα-negative MDA-MB-231 breast cancer cells in RSK- and EphA2-dependent manners. Phosphorylated EphA2 was internalized and re-localized to the plasma membrane, including lamellipodia, in an RSK-dependent manner. Collectively, the present results provide novel insights into the tumor-promoting activity of tamoxifen.

    DOI: 10.1248/bpb.b21-00567

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  • [Comparison between Single and Three Times Pre-operative Administration of Amoxicillin in the Prophylactic Effects for Surgical Site Infections in Japanese Patients with Mandibular Third Molars Extraction]. 査読

    Kensuke Yoshida, Yasumitsu Kodama, Chie Saito, Kei Tomihara, Akira Toyama

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan   142 ( 12 )   1391 - 1398   2022年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    Although the dosage of oral antibiotics (OA) for the mandibular third molar extraction (MTME) varies among the administration periods according to the current guideline, our previous reports suggested that it might be possible to further shorten the administration period without increasing the incidence of surgical site infection (SSI). In the present study, we retrospectively evaluated the relationship between the incidence of SSI and the administration period of OA in patients who underwent the MTME in our hospital. This retrospective cohort study included 348 patients who underwent the MTME in our dental outpatient clinic from June 2020 to March 2022. The administrated antibiotic was amoxicillin (AMPC) in all patients. Patients were divided into two groups based on the administration period of AMPC single and three times before the surgery. The following information was collected: (1) patient factors (age, gender, body mass index, diagnosis, mandibular third molar status); (2) surgical factors (operation time, presence/absence of wound closure, presence/absence of hemostat, experience of surgeons); (3) relationship between administration period of OA and SSI occurrence; and (4) details of SSI. There were 217 cases in the single group and 131 cases in the three times group. The incidence of SSI was 1.1% (4/348), with 1.4% (3/217) in the single group and 0.8% (1/131) in the three times group; there was no significant difference between the two groups. Our result suggests that single administration of AMPC before the MTME would be sufficient for the prevention of SSI in Japanese patients without risk factors.

    DOI: 10.1248/yakushi.22-00163

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  • 口腔癌深達度における画像と病理のdiscrepancyをどう読むか 査読

    林孝文, 高村真貴, 小林太一, 新國農, 勝良剛詞, 冨原圭, 田沼順一

    日本口腔腫瘍学会誌   34 ( 4 )   2022年

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  • 下唇へ進展した下顎歯肉癌を長掌筋腱付き前腕皮弁で再建した1例 査読

    今上修一, 仲盛健治, 冨原圭, 石戸克尚, 立浪秀剛, 櫻井航太郎, 藤原久美子, 山田慎一, 野口誠

    日本口腔腫瘍学会誌   34 ( 4 )   2022年

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  • 口腔がんの免疫療法-免疫チェックポイント阻害薬の現状と展望- 査読

    冨原圭

    新潟歯学会雑誌   52 ( 2 )   2022年

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    担当区分:筆頭著者, 責任著者  

    J-GLOBAL

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  • Sitafloxacin reduces tumor necrosis factor alpha (TNFα) converting enzyme (TACE) phosphorylation and activity to inhibit TNFα release from lipopolysaccharide-stimulated THP-1 cells. 査読 国際誌

    Ippei Sakamaki, Michika Fukushi, Wakana Ohashi, Yukie Tanaka, Kazuhiro Itoh, Kei Tomihara, Yoshihiro Yamamoto, Hiromichi Iwasaki

    Scientific reports   11 ( 1 )   24154 - 24154   2021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)  

    Sepsis is a systemic reaction to an infection and resulting in excessive production of inflammatory cytokines and chemokines. It sometimes results in septic shock. The present study aimed to identify quinolone antibiotics that can reduce tumor necrosis factor alpha (TNFα) production and to elucidate mechanisms underlying inhibition of TNFα production. We identified quinolone antibiotics reduced TNFα production in lipopolysaccharide (LPS)-stimulated THP-1 cells. Sitafloxacin (STFX) is a broad-spectrum antibiotic of the quinolone class. STFX effectively suppressed TNFα production in LPS-stimulated THP-1 cells in a dose-dependent manner and increased extracellular signal-regulated kinase (ERK) phosphorylation. The percentage of intracellular TNFα increased in LPS-stimulated cells with STFX compared with that in LPS-stimulated cells. TNFα converting enzyme (TACE) released TNFα from the cells, and STFX suppressed TACE phosphorylation and activity. To conclude, one of the mechanisms underlying inhibition of TNFα production in LPS-stimulated THP-1 cells treated with STFX is the inhibition of TNFα release from cells via the suppression of TACE phosphorylation and activity. STFX may kill bacteria and suppress inflammation. Therefore, it can be effective for sepsis treatment.

    DOI: 10.1038/s41598-021-03511-5

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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]. 査読

    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. 査読 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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    担当区分:責任著者   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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  • 下顎枝矢状分割術後に急性腹症を生じた1例 査読

    石戸克尚, 石戸克尚, 冨原圭, 平識亘, 櫻井航太郎, 野口誠

    Hospital Dentistry & Oral-Maxillofacial Surgery   31 ( 1 )   2021年

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    担当区分:責任著者  

    J-GLOBAL

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  • 高齢受刑者にみられた口底癌の治療経験 査読

    石戸克尚, 石戸克尚, 冨原圭, 石坂理紗, 平識亘, 野口誠

    Hospital Dentistry & Oral-Maxillofacial Surgery   31 ( 1 )   2021年

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  • ビスフォスフォネート製剤関連顎骨壊死から縦隔炎に進展した頸部ガス壊疽の1例 査読

    平識亘, 石戸克尚, 櫻井航太郎, 冨原圭, 野口誠

    Hospital Dentistry & Oral-Maxillofacial Surgery   31 ( 2 )   2021年

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  • がん治療患者の口腔機能管理における歯性感染病巣(歯のう蝕,歯周病,歯性感染症)管理:システマティックレビューに基づいた指針 査読

    栗田浩, 栗田浩, 栗田浩, 梅田正博, 梅田正博, 梅田正博, 植野高章, 植野高章, 鵜澤成一, 鵜澤成一, 渋谷恭之, 渋谷恭之, 渋谷恭之, 中村典史, 中村典史, 長塚仁, 長塚仁, 林孝文, 林孝文, 溝口到, 溝口到, 冨原圭, 冨原圭, 池上由美子, 池上由美子, 野口一馬, 野口一馬, 滝口裕一, 滝口裕一, 山本信之, 山本信之

    日本口腔科学会雑誌(Web)   70 ( 4 )   2021年

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  • 外傷歯に起因した小児脳膿瘍の1例 査読

    村本 知歌子, 冨原 圭, 堀 さやか[(若尾], 石戸 克尚, 藤原 久美子, 野口 誠

    小児口腔外科   30 ( 1 )   32 - 36   2020年6月

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    担当区分:責任著者   記述言語:日本語   出版者・発行元:(一社)日本小児口腔外科学会  

    1歳8ヵ月男児。3ヵ月前に転倒により両側上顎乳中切歯を受傷し、前医で外傷性歯冠破折と診断された。破折歯の処置は行われず、抗菌薬と鎮静剤の内服で経過観察となった。3ヵ月後、発熱と頭痛が出現し、当科紹介受診となった。両側上顎乳中切歯が水平方向に歯冠破折し、破折部から歯髄息肉を認め、両側上顎乳中切歯の歯冠破折による慢性増殖歯髄炎と診断した。MRIで左前頭葉に脳の正中偏位を伴う膿瘍を認め、救命目的に脳膿瘍に対し穿頭ドレナージ手術を施行した。術直後に膿瘍腔は縮小し、脳の正中偏位が改善した。術後の心エコーで2~3mmの卵円孔開存を認めたが、心機能は正常であった。穿頭ドレナージの膿液からStreptococcus intermedius、Parvimonas micraが検出され、歯科疾患が原因と判断した。両側上顎乳中切歯を抜歯したところ、発熱や頭痛、左前頭葉の膿瘍が完全消失し、抜歯後30日に退院となった。

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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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  • パラグライダーのプロペラを研磨中に受傷した顔面裂傷の1例 査読

    石戸 克尚, 冨原 圭, 藤原 久美子, 今上 修一, 野口 誠

    口腔顎顔面外傷   16 ( 2 )   67 - 70   2017年10月

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    記述言語:日本語   出版者・発行元:日本口腔顎顔面外傷学会  

    症例は61歳男性で、直径約90cmのパラグライダーのプロペラを研磨していた際に、プロペラが弾かれて顔面を直撃した。顔面の裂創を認めたため救急要請した。左鼻根部から頬部と、右頬部からオトガイ部の2ヶ所に裂傷を認め、一部は上顎洞前壁と右下顎前歯部の歯槽骨に達していた。下顎前歯部では歯槽骨の骨折と歯根破折を認め、さらに歯冠の破折により残根状態となっていた。左頬部の裂傷は耳下腺の導管に達し、導管の断裂を認めた。顔面裂傷、左耳下腺管断裂、右下2、3、4、5部歯槽骨骨折・歯根破折と診断した。全身麻酔下に創縫合術、右下2、3、4、5抜歯術、耳下腺導管再建術を施行した。術後10日目に退院し、外来にて経過観察を行っていた。左頬部の瘢痕拘縮が著明となったため、術後4ヵ月に全身麻酔下に瘢痕修正術を施行した。創部は瘢痕の形成も少なく良好に治癒した。審美性の改善が得られ、耳下腺乳頭からの唾液の流出も良好に認めた。

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    その他リンク: https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J05290&link_issn=&doc_id=20171030220004&doc_link_id=10.24787%2Fjsomft.16.2_67&url=https%3A%2F%2Fdoi.org%2F10.24787%2Fjsomft.16.2_67&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • 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.

    DOI: 10.1186/s13256-017-1386-0

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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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  • 下唇に発生した脂腺癌の1例 査読

    新井 直也, 冨原 圭, 武井 理恵, 能登 善弘, 和田 重人, 野口 誠

    日本口腔外科学会雑誌   61 ( 4 )   217 - 221   2015年4月

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    記述言語:日本語   出版者・発行元:(公社)日本口腔外科学会  

    61歳男。10年前より右下唇の腫瘤を自覚するも放置し、最近になり増大傾向を認めた。初診時、右下唇に小指頭大の腫脹を認め、内部に長径15mmの類円形、弾性硬で可動性のある腫瘤を触知した。生検の結果、脂腺癌と診断され、全身麻酔下に腫瘍切除術を施行した。病理診断も脂腺癌であった。術後2年の現在、再発や転移はなく経過良好である。

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    その他リンク: https://search.jamas.or.jp/default/link?pub_year=2015&ichushi_jid=J01073&link_issn=&doc_id=20150507250003&doc_link_id=10.5794%2Fjjoms.61.217&url=https%3A%2F%2Fdoi.org%2F10.5794%2Fjjoms.61.217&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • 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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  • ビスフォスフォネート関連顎骨壊死に関する臨床的検討 査読

    出張 裕也, 冨原 圭, 上田 愛, 島西 真琴, 小野 公之, 佐々木 敬則, 五十嵐 友彦, 白鳥 香理, 安倍 聖人, 荻 和弘, 仲盛 健治, 宮崎 晃亘, 永井 格, 平塚 博義

    癌と化学療法   36 ( 13 )   2587 - 2592   2009年12月

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    記述言語:日本語   出版者・発行元:(株)癌と化学療法社  

    目的:近年、悪性腫瘍の骨転移や多発性骨髄腫の治療に用いられるビスフォスフォネート(以下BP)注射剤の重篤な有害事象として、顎骨壊死(bisphosphonate related osteonecrosis of the jaw:BRONJ)が注目されている。本研究ではBRONJの現状を把握する目的で臨床的検討を行った。対象:2006年7月~2008年10月までの2年3ヵ月間にBP注射剤投与に関連して当科を受診した36例を対象とした。結果:BP剤投与前顎骨精査依頼は12例で、BP剤投与患者24例であった。BP投与患者7例にBRONJが認められ、17例は発症しなかった。7例はBP剤投与中に抜歯や急性歯性感染症を契機にBRONJを発症していた。BP投与前およびBRONJを発症していない患者に対する歯性感染症の原因除去治療は新たなBRONJの発生を予防した。結論:BRONJは通常の骨髄炎の治療に反応せず、極めて難治性であることが最大の問題点である。したがって、現状ではBRONJ発症予防に重点を置いた対応が最も効果的であり、医科と歯科の良好な連携が必要であると考えられた。また、BRONJの治療は抗生剤を主とした保存的アプローチが患者のQOLの維持や向上につながると考えられた。(著者抄録)

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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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  • Prediction of subclinical regional lymph node metastasis in stage I/II squamous cell carcinoma of the oral tongue based on clinical findings 査読

    K. Nakamori, A. Miyazaki, K. Tomihara, Y. Sogabe, T. Imai, T. Yamamoto, H. Hiratsuka

    Oral Surgery   1 ( 4 )   190 - 197   2008年11月

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    掲載種別:研究論文(学術雑誌)  

    Background: Although tumour depth appears to be a powerful predictor of regional lymph node metastasis in squamous cell carcinoma of the oral tongue, measurement is usually based on histological findings following surgical resection. The predictive value of clinical findings on lymph node metastasis in the absence of surgical intervention is unclear. Methods: We retrospectively evaluated 90 previously untreated cases of stage I/II squamous cell carcinoma of the oral tongue to analyse the relationship between greatest dimension, growth pattern, depth of tumour and regional lymph node metastasis. Results: Lymph node metastasis was recognised in 15 of 90 cases. A positive correlation between greatest dimension and tumour depth was seen for endophytic-type tumours only. Logistic regression analysis revealed that growth pattern was an independent predictor of lymph node metastasis (P = 0.0014). Conclusion: Combination analysis of tumour growth pattern and greatest dimension may predict lymph node metastasis of squamous cell carcinoma of the oral tongue. © 2008 John Wiley & Sons A/S.

    DOI: 10.1111/j.1752-248X.2008.00042.x

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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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  • 頬部に発生した孤在性線維性腫瘍の1例 査読

    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 )   54 - 58   2008年2月

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    担当区分:筆頭著者   記述言語:日本語   出版者・発行元:(公社)日本口腔外科学会  

    52歳女。8ヵ月前頃より左頬部の無痛性腫瘤を自覚し、縮小傾向がないため歯科口腔外科を受診したが、生検で確定診断は得られず、精査目的で当科紹介された。左頬粘膜部、耳下腺乳頭下部に25mm大の境界明瞭、可動性で弾性硬の腫瘤を触知した。CTでは左咀嚼筋隙に、下顎枝前縁から咬筋の内側、内側翼突筋の外側に接する境界明瞭で均一な造影性を示す腫瘤を認め、MRIのT1強調像で低信号、T2強調像では高信号を呈した。前医での病理所見は異型性に乏しい紡錘形細胞が主体であったことより、生検瘢痕組織を含め腫瘍摘出術を施行した。術後1年6ヵ月で再発・転移の徴候はない。病理組織学的所見で、病変は線維性被膜内に限局していた。腫瘍細胞は短紡錘形細胞が不規則かつびまん性に増殖し、細胞異型は乏しく、ごく少数の核分裂像を認めた。腫瘍間質はstaghorn vesselsや扁平な内皮細胞と壁の薄い血管周囲に膠原線維の形成を伴っていた。免疫染色ではCD34およびvimentinが陽性、Ki-67陽性細胞数は少なく標識率2.1%で、孤在性線維性腫瘍と病理診断した。

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    その他リンク: https://search.jamas.or.jp/default/link?pub_year=2008&ichushi_jid=J01073&link_issn=&doc_id=20080229420003&doc_link_id=10.5794%2Fjjoms.54.54&url=https%3A%2F%2Fdoi.org%2F10.5794%2Fjjoms.54.54&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

  • [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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    癌の臨床   64 ( 2 )   133 - 137   2018年8月

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    記述言語:日本語   出版者・発行元:(株)篠原出版新社  

    広範囲切除・再建術を伴う進行口腔癌の治療では長期の経腸栄養が必要であり、消化管合併症の対策が重要である。糖尿病を有する舌再建後の患者に粘度可変型流動食を使用し、術後の回復に有効であった症例を報告する。患者は67歳の男性で、合併症に糖尿病を認めた。右側舌癌T4aN0M0の診断の下、可動部舌亜全摘、頸部郭清術、広背筋皮弁再建術、胃瘻造設術を施行した。術後から糖尿病用濃厚流動食を開始したが、術後1ヵ月から難治性の下痢が出現した。粘度可変型流動食への変更を行ったところ、投与後から下痢症状の改善を認め、術後4ヵ月で退院となった。粘度可変型流動食は糖尿病を有する口腔癌患者の術後回復期に有効であると考えられた。(著者抄録)

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    日本口腔科学会学術集会プログラム・抄録集   71st   2017年

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    日本口腔腫瘍学会総会・学術大会プログラム・抄録集   35th   2017年

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    日本口腔科学会学術集会プログラム・抄録集   71st   2017年

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    冨原圭, 今上修一, 藤原久美子, 野口誠

    日本口腔科学会学術集会プログラム・抄録集   70th   2016年

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    布施浩樹, 冨原圭, 平識亘, 野口誠

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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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    日本口腔科学会雑誌   63 ( 3 )   2014年

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    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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    日本口腔科学会雑誌   63 ( 1 )   2014年

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

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    日本口腔科学会雑誌   63 ( 1 )   2014年

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    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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    日本口腔科学会雑誌   62 ( 1 )   2013年

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    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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    日本口腔科学会雑誌   62 ( 3 )   2013年

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    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

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    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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    日本口腔科学会雑誌   62 ( 1 )   2013年

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    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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    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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  • 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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  • 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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  • 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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  • CD10 TARGETED SELECTIVE GENE THERAPY FOR B CELL LYMPHOMA THROUGH FZ33 FIBER MODIFIED ADENOVIRAL VECTORS

    Shu Takahashi, Kazunori Kato, Kiminori Nakamura, Yukari Masuta, Kei Tomihara, Rika Nakano, Kazuishi Kubota, Hirofumi Hamada

    JOURNAL OF GENE MEDICINE   11 ( 12 )   1168 - 1168   2009年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS LTD  

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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

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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, 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

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  • CD40-リガンドの非切断細胞表面変異体は抗白血病免疫反応を誘導し,全身性炎症性反応を予防する(Non-cleavable cell surface mutant of CD40-ligand induce anti-leukemic immune response and prevent systemic inflammatory reaction)

    冨原 圭, 加藤 和則, 増田 ゆかり, 佐々木 勝則, 濱田 洋文

    基盤的癌免疫研究会総会抄録   9回   53 - 53   2005年6月

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    記述言語:英語   出版者・発行元:日本がん免疫学会  

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  • ヒト多発性骨髄腫に対する抗体を介した標的化遺伝子導入と免疫応答誘導

    増田 ゆかり, 加藤 和則, 冨原 圭, 中村 公則, 濱田 洋文

    基盤的癌免疫研究会総会抄録   9回   54 - 54   2005年6月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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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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  • ファイバー改変型アデノウイルスベクターによるCD40リガンド遺伝子導入と抗腫瘍免疫応答誘導

    加藤 和則, 高橋 聡, 冨原 圭, 増田 ゆかり, 浅野 茂隆, 濱田 洋文

    基盤的癌免疫研究会総会抄録   7回   59 - 59   2003年7月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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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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▶ 全件表示

共同研究・競争的資金等の研究

  • 腫瘍関連免疫抑制性細胞を標的とした口腔癌に対する新たな免疫療法の開発研究

    研究課題/領域番号:22K10214

    2022年4月 - 2025年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    冨原 圭, 山崎 学, 立浪 秀剛, 野口 誠

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

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  • 死細胞貪食による口腔がん細胞活性化:脂質クオリティが果たす役割を探る

    研究課題/領域番号:21K09856

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    山崎 学, 阿部 達也, 丸山 智, 冨原 圭, 泉 健次, 田沼 順一

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    配分額:4160000円 ( 直接経費:3200000円 、 間接経費:960000円 )

    がん細胞は正常細胞とは異なる脂質代謝を有し、近年、がんにおける脂質クオリティ(脂質組成)の重要性が明らかになりつつある。本研究課題では、「死細胞貪食を起点としたがん細胞活性化の機序に、死細胞由来脂質によってもたらされる脂質クオリティ変化が関与する」という仮説のもと、(1)がん細胞のおける死細胞由来脂質の局在変化を追跡し、(2)貪食後に生じるがん細胞の脂質クオリティを解析することで、(3)細胞増殖・遊走・浸潤能に関わる分子機構との接点を明らかにすることを目的としている。今年度は、以下の疑問を解決すべく検討をおこなった。
    1) ネクローシス細胞は生活がん細胞に貪食されるのか?: 口腔扁平上皮癌由来培養細胞株を脂質親和性色素PKH26にて標識後、凍結融解によって誘導したネクローシス細胞を、同種の生活がん細胞と共培養した。共焦点レーザー顕微鏡解析の結果、PKH26陽性を示す死細胞断片は生活がん細胞の細胞質内に認められた。これより、ネクローシス細胞は生活がん細胞によって貪食されることが示された。
    2) 細胞内コレステロール変化は細胞機能を変化させるのか?: これまでの検討により、ネクローシス細胞と共培養した際、生活がん細胞内にコレステロールが蓄積される可能性が推測された。そこでまず、細胞内コレステロールレベル変化による細胞の機能変化を検索した。コレステロール-MCD複合体の添加により、細胞内コレステロールを上昇させると、細胞形態は多辺形から扇状へと変化し、細胞遊走能が亢進することが示された。

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  • 免疫学的アプローチによるびまん性浸潤口腔扁平上皮癌の制御に関する基礎的研究

    研究課題/領域番号:21K10065

    2021年4月 - 2024年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    野口 誠, 山崎 学, 藤原 久美子, 冨原 圭

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    骨髄由来免疫抑制性細胞(MDSC)は腫瘍局所で破骨細胞分化を促進機序、腫瘍局所におけるMDSCの特異的標的化について、C3H/HeNマウス由来の口腔扁平上皮癌NR-S1K細胞およびSCCVII細胞と同マウスを用いシンジェニック口腔癌モデルを作製し、以下の内容について3年計画で検証を予定している。
    1.口腔扁平上皮癌担癌宿主におけるMDSCの形質や機能の特性とその標的化を検証する。
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    2.MDSCの標的化戦略に基づいて抗腫瘍効果を、マウスモデルを用いた治療実験で検証する。研究代表者の先行研究で、低用量ゲムシタビン投与が、口腔癌担癌マウスの腫瘍組織から、MDSCを選択的に除去することを明らかとした。また、口腔癌マウス由来のMDSCでは、PD-L1の発現が増強し、免疫抑制機能に重要な役割を果たしていることを明らかとした。そこで、以下のような治療実験を行う。
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    コロナ禍のため動物実験が思うように進ま図にいるが、ここ数年間の感染状況を例に今後は年間に計画的なスケジュールをたて遂行する予定である。しかしながら、ヒト口腔癌患者のMDSCサブセットを同定したことでPD-1免疫チェックポイント阻害剤投与後の2に対するヒトでの検証が可能となり今後も継続予定である。

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  • 口腔癌の免疫逃避機構の解除による新たな治療戦略に関する研究

    研究課題/領域番号:20K10157

    2020年4月 - 2023年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    今上 修一, 野口 誠, 冨原 圭

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    本研究は、免疫チェックポイント阻害薬の抗腫瘍効果を最大限に発揮するための新規治療法の開発を目的とし、免疫チェックポイント阻害薬に対する抵抗性の機序の一端を、口腔癌宿主免疫応答における免疫逃避機構の解析により明らかとしようとした基礎的な研究である。免疫チェックポイント阻害薬の一つであるニボルマブは、2017年より切除不能・再発口腔癌に対しての使用が可能となった。口腔癌を含む頭頸部癌に対する免疫チェックポイント阻害薬の効果は、これまでの報告では20~30%程度と未だ限定的であり、これらの薬剤に対する効果予測を可能とする予知因子の同定が重要とされている。
    本研究において検討を予定した指標は好中球/リンパ球数比(NLR)である。これは、様々な癌腫において、その予後や化学療法、放射線療法などに対する治療効果、また最近では免疫チェックポント阻害薬に対する反応性との関連性が報告されている指標であり、担癌宿主で増加する好中球の中にある免疫抑制性の細胞が、癌の治療に対する抵抗性に極めて重要な役割を果たしていることが示唆しているものである。本研究では、すでに進行口腔癌に対して免疫チェックポイント阻害薬による治療が行われ、奏効例と非奏効例において、このNLRが効果を予測する因子である可能性を証明してきた。

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  • 骨髄由来免疫抑制性細胞の特性解析による口腔癌の新規免疫療法の開発

    研究課題/領域番号:19K10262

    2019年4月 - 2022年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    冨原 圭, 山崎 学, 野口 誠

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    口腔癌に対する有効な免疫療法の開発を目的とし、免疫チェックポイント阻害薬による抗腫瘍効果を最大限に引き出す新規免疫療法の可能性について究明した。ヒトにおけるがんの発生に近い動物モデルの作製として老齢C3H/HeNマウスと、同マウス由来口腔扁平上皮癌細胞株NR-S1K細胞を用いた老齢マウス口腔癌モデルを作製し、老齢担癌宿主における免疫抑制機序について解析を行った。老齢口腔癌マウスでは若齢のものに比べて、免疫抑制性細胞の割合が増加し、さらにメモリーT細胞の割合も増加していた。以上の結果、口腔癌担癌宿主の加齢変化に伴う免疫抑制においては、免疫抑制性細胞の増加がその一端を担っている可能性が示唆された。

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  • ミエロイド系細胞を介した口腔癌の浸潤促進機序の解明と新規標的化治療の開発

    研究課題/領域番号:18K09741

    2018年4月 - 2021年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    野口 誠, 山崎 学, 笹原 正清, 藤原 久美子, 冨原 圭

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    配分額:4290000円 ( 直接経費:3300000円 、 間接経費:990000円 )

    口腔癌担癌マウスを用いた解析によって、腫瘍局所におけるPDGFRα発現陽性の細胞が著しく増加していることが明らかとなり、それらの細胞はCD11bおよびGr-1の発現が陽性であり、MDSCとの関連が強く示唆される結果であった。さらに口腔癌担癌マウスの腫瘍組織から分離したMDSCは、他の臓器から分離したMDSCと比べて有意に破骨細胞への分化能が増強していることも明らかとなった。以上の結果より、口腔癌の局所進展、特に骨浸潤過程においては、腫瘍局所で増加するMDSCからの癌関連線維芽細胞を介した浸潤過程、さらにMDSCからの破骨細胞分化による顎骨浸潤促進の機序の可能性を示唆する結果であった。

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  • 老齢マウス口腔癌モデルを用いたミエロイド系抑制性細胞の治療標的化に関する研究

    研究課題/領域番号:16K11720

    2016年4月 - 2019年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    冨原 圭, 山崎 学, 野口 誠

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    配分額:4680000円 ( 直接経費:3600000円 、 間接経費:1080000円 )

    本研究は、免疫老化現象を背景とした癌免疫逃避機構の解明とその制御機構について、ミエロイド系抑制性細胞(MDSC)に着目した解析を行った。その結果、末梢血、脾臓、腫瘍組織などの各部位においてMDSCが著しく集簇し、形質的にも機能的にも異なっていることを明らかとした。特に、腫瘍由来のMDSCは、PD-L1の発現が増強し、PD-L1がT細胞に対する免疫抑制能にとって重要であることが明らかとした。また、老齢マウスでは、このMDSCの割合が若年マウスに比べて有意に高いことも明らかとなった。これらの結果は、特に老齢の担癌宿主におけるMDSCの標的化が、より効果的な抗腫瘍免疫応答の誘導する可能性を示唆した。

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  • ミエロイド系抑制性細胞の形質変化を利用した口腔癌に対する免疫ワクチン療法の開発

    研究課題/領域番号:25861922

    2013年4月 - 2016年3月

    制度名:科学研究費助成事業

    研究種目:若手研究(B)

    提供機関:日本学術振興会

    冨原 圭

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    配分額:4030000円 ( 直接経費:3100000円 、 間接経費:930000円 )

    口腔癌担癌マウスを用いたミエロイド系抑制性細胞MDSCとその他の免疫抑制性細胞との相互作用についての解析では、腫瘍移植後の腫瘍組織内でMDSCが制御性T細胞(Treg)や腫瘍浸潤マクロファージ(TAM)などと同様に著しく増加していることが確認された。また、低用量の抗がん剤を投与した担癌マウスでは、腫瘍組織内では、樹状細胞上のCD80、CD86、CD40、CD54、CD83などのT細胞共刺激分子群の発現が増強し、また、腫瘍細胞表面上においても、T細胞共刺激分子やVCAM-1やP-selectinなど、免疫細胞の接着に関わる分子群の発現が増強していることも確認された。

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  • ビスホスホネート性顎骨壊死におけるカルシウム作用の解明とその制御に基づく予防戦略

    研究課題/領域番号:24592983

    2012年4月 - 2015年3月

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    新井 直也, 冨原 圭

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    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    骨吸収抑制薬であるビスフォスフォネート(BP)は粘膜毒性を有することが知られている。本研究では、注射用BPであるゾレドロネート(ZA)を用いて、BPの上皮細胞毒性がカルシウムにより増強されることをin vitroで示してきた。単独では作用を有さない低濃度のZAが、培地中のカルシウム濃度の上昇に伴い増殖抑制やアポトーシス誘導を発揮するようになることは、BPの粘膜毒性を解明する上で重要な知見であると考えられた。

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  • 口腔癌顎骨浸潤の免疫学的機序の解明と新規治療戦略の開発

    研究課題/領域番号:23592957

    2011年 - 2013年

    制度名:科学研究費助成事業

    研究種目:基盤研究(C)

    提供機関:日本学術振興会

    野口 誠, 新井 直也, 冨原 圭

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    配分額:5070000円 ( 直接経費:3900000円 、 間接経費:1170000円 )

    本研究は、口腔癌の顎骨浸潤の免疫学的機序の解明と新たな治療戦略の開発を目的とし、口腔癌の顎骨浸潤過程における破骨細胞(OC)の分化に着目した。リウマチなどの炎症性疾患においては、破骨細胞の分化過程においては、CD4陽性ヘルパーT細胞(Th)が関与していることが示唆されているが、腫瘍局所におけるTh反応系とOCとの相互作用は未だ不明である。われわれは、マウス口腔癌モデルを用いた解析で、腫瘍内に浸潤しているCD4陽性T細胞のうちで、50%以上がFoxP3陽性のTregであり、さらに、腫瘍内のTregはCTLA-4を強発現し、このCTLA-4を介してOC分化を有意に抑制していることを確認した。

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  • 未成熟ミエロイド系細胞を標的とした口腔癌に対する新たな免疫療法の開発

    研究課題/領域番号:23890069

    2011年 - 2012年

    制度名:科学研究費助成事業

    研究種目:研究活動スタート支援

    提供機関:日本学術振興会

    冨原 圭

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    配分額:3250000円 ( 直接経費:2500000円 、 間接経費:750000円 )

    口腔癌マウスモデルを用いた解析により、腫瘍局所においてミエロイド系抑制性細胞が増加していることが確認された。それらは、化学療法剤である低用量のゲムシタビンを使用することにより抑制することが確認された。

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  • 口腔癌に対するCD154遺伝子治療に関する研究

    研究課題/領域番号:20791538

    2008年

    制度名:科学研究費助成事業

    研究種目:若手研究(B)

    提供機関:日本学術振興会

    冨原 圭

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    配分額:1560000円 ( 直接経費:1200000円 、 間接経費:360000円 )

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  • CD40リガンド遺伝子導入樹状細胞による口腔癌に対する抗腫瘍効果の解析

    研究課題/領域番号:18791511

    2006年 - 2007年

    制度名:科学研究費助成事業

    研究種目:若手研究(B)

    提供機関:日本学術振興会

    冨原 圭

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    配分額:2200000円 ( 直接経費:2200000円 )

    これまでに,ヒトCD40リガンド(CD40L)遺伝子を組込んだファイバー改変型アデノウイルスベクターをヒト末梢血単核球より分離した樹状細胞に遺伝子導入を行ったところ,遺伝子導入された樹状細胞が成塾化に伴う形質変化をするばかりではなく,大量のインターフェロンγ(IFN-γ)を産生し,扁平上皮癌細胞に対して増殖卸制効果を示すこと,TRAIL受容体の発現増強およびリコンビナントTRAILを介したアポトーシスを増強することなどの様々な抗腫瘍効果について報告してきた。平成19年度は,このCD40L遺伝子導入により成熟化した樹状細胞が,IFN-γを介してNK細胞を活性化できるかどうか,そしそ樹状細胞と共培養することによりTRAIL受容体およびTRAIL感受性を増強した扁平上皮癌細胞に対して,NK細胞を介した抗腫瘍効果を誘導することができるかどうかを解析した。CD40L遺伝子導入により活性化した樹状細胞とトランスウェルプレートで接着を介さずに共培養したNK細胞は,細胞表面上のCD69やTRAILの発現を増強,IFN-γの産生増強などを示した。このCD40L遺伝子導入をした樹状細胞により活性化したNK細胞は,同様に樹状細胞と共培養することによりTRAIL感受性を増強した扁平上皮癌に対して,優位に細胞傷害性を示すことがわかった。これらの結果は,CD40Lが樹状細胞を活性化することによりTRAIL-TRAIL受容体を介した抗腫瘍効果を誘導する極めて重要な分子であり,その手法としてファイバー改変型アデノワイルスベクターを介した遺伝子導入が効果的であり,扁平上皮癌に対する新たな免疫遺伝子治療の可能性を示唆する結果となった。

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担当経験のある授業科目

  • 口腔外科学I

    2023年
    -
    現在
    機関名:新潟大学

  • 歯科口腔外科学演習IIB

    2022年
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    現在
    機関名:新潟大学

  • 歯科口腔外科学演習IA

    2022年
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    現在
    機関名:新潟大学

  • 歯科口腔外科学演習IB

    2022年
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    現在
    機関名:新潟大学

  • 歯科口腔外科学演習IIA

    2022年
    -
    現在
    機関名:新潟大学

  • 口腔外科学II

    2021年
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    現在
    機関名:新潟大学

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